bluuebunny/crossref_metadata_2025 huggingface dataset:
A quantitative determination of multi-protein interactions by the analysis of confocal images using a pixel-by-pixel assessment algorithm
Authors: Goucher D. R. , Wincovitch S. M. , Garfield S. H. , Carbone K. M. , Malik T. H.
Published: June 2005

Motivation: Recent advances in confocal microscopy have allowed scientists to assess the expression, and to some extent, the interaction/colocalization of multiple molecules within cells and tissues. In some instances, accurately quantifying the colocalization of two or more proteins may be critical. This can require the acquisition of multiple Z plane images (Z stacks) throughout a specimen and, as such, we report here the successful development of a freeware, open-source image analysis tool, IMAJIN_COLOC, developed in PERL (v. 5.8, build 806), using the PERLMagick libraries (ImageMagick). Using a pixel-by-pixel analysis algorithm, IMAJIN_COLOC can analyze images for antigen expression (any number of colors) and can measure all possible combinations of colocalization for up to three colors by analyzing a Z stack gallery acquired for each sample. The simultaneous (i.e. in a single pass) analysis of three-color colocalization, and batch analysis capabilities are distinctive features of this program.

Results: A control image, containing known individual and colocalized pixel counts, was used to validate the accuracy of IMAJIN_COLOC. As further validation, pixel counts and colocalization values from the control image were compared to those obtained with the software packaged with the Zeiss laser-scanning microscope (LSM AIM, version 3.2). The values from both programs were found to be identical. To demonstrate the applicability of this program in addressing novel biological questions, we examined the role of neurons in eliciting an immune reaction in response to viral infection. Specifically, we successfully examined expression of the chemokine RANTES in measles virus (MV) infected hippocampal neurons and quantified changes in RANTES production throughout the disease period. The resultant quantitative data were also evaluated visually, using a gif image created during the analysis.

Availability: PERL (ActivePerl, version 5.8) is available at activestate.com; the PERLMagick libraries are available at imagemagick.org, and IMAJIN_COLOC, the source code and user documentation can be downloaded from http://www.fda.gov/cber/research/imaging/imageanalysis.htm

Contact:  Malik@cber.fda.gov
Q
-ball imaging of macaque white matter architecture
Authors: Tuch David S , Wisco Jonathan J , Khachaturian Mark H , Ekstrom Leeland B , Kötter Rolf , Vanduffel Wim
Published: June 2005

Diffusion-weighted magnetic resonance imaging holds substantial promise as a technique for non-invasive imaging of white matter (WM) axonal projections. For diffusion imaging to be capable of providing new insight into the connectional neuroanatomy of the human brain, it will be necessary to histologically validate the technique against established tracer methods such as horseradish peroxidase and biocytin histochemistry. The macaque monkey provides an ideal model for histological validation of the diffusion imaging method due to the phylogenetic proximity between humans and macaques, the gyrencephalic structure of the macaque cortex, the large body of knowledge on the neuroanatomic connectivity of the macaque brain and the ability to use comparable magnetic resonance acquisition protocols in both species. Recently, it has been shown that high angular resolution diffusion imaging (HARDI) can resolve multiple axon orientations within an individual imaging voxel in human WM. This capability promises to boost the accuracy of tract reconstructions from diffusion imaging. If the macaque is to serve as a model for histological validation of the diffusion tractography method, it will be necessary to show that HARDI can also resolve intravoxel architecture in macaque WM. The present study therefore sought to test whether the technique can resolve intravoxel structure in macaque WM. Using a HARDI method called
q
-ball imaging (QBI) it was possible to resolve composite intravoxel architecture in a number of anatomic regions. QBI resolved intravoxel structure in, for example, the dorsolateral convexity, the pontine decussation, the pulvinar and temporal subcortical WM. The paper concludes by reviewing remaining challenges for the diffusion tractography project.
Estimating brain functional connectivity with sparse multivariate autoregression
Authors: Valdés-Sosa Pedro A , Sánchez-Bornot Jose M , Lage-Castellanos Agustín , Vega-Hernández Mayrim , Bosch-Bayard Jorge , Melie-García Lester , Canales-Rodríguez Erick
Published: June 2005

There is much current interest in identifying the anatomical and functional circuits that are the basis of the brain's computations, with hope that functional neuroimaging techniques will allow thein vivostudy of these neural processes through the statistical analysis of the time-series they produce. Ideally, the use of techniques such as multivariate autoregressive (MAR) modelling should allow the identification of effective connectivity by combining graphical modelling methods with the concept of Granger causality. Unfortunately, current time-series methods perform well only for the case that the length of the time-series Nt is much larger thanp, the number of brain sites studied, which is exactly the reverse of the situation in neuroimaging for which relatively short time-series are measured over thousands of voxels. Methods are introduced for dealing with this situation by using sparse MAR models. These can be estimated in a two-stage process involving (i) penalized regression and (ii) pruning of unlikely connections by means of the local false discovery rate developed by Efron. Extensive simulations were performed with idealized cortical networks having small world topologies and stable dynamics. These show that the detection efficiency of connections of the proposed procedure is quite high. Application of the method to real data was illustrated by the identification of neural circuitry related to emotional processing as measured by BOLD.
Race, Compensation and Contract Length in the NBA: 2001–2002*
Authors: KAHN LAWRENCE M. , SHAH MALAV
Published: June 2005

We study race and pay in the NBA for 2001–2002. For players who were neither free agents nor on rookie scale contracts, there were large, statistically significant ceteris paribus nonwhite shortfalls in salary, total compensation, and contract duration. But for players under the rookie salary scale (first‐round draft picks) and free agents, race effects were small and insignificant. These results suggest discrimination against marginal nonwhite players.
What Makes Mediation Work? Mediators’ Perspectives on Resolving Disputes*
Authors: MARESCHAL PATRICE M.
Published: June 2005

This research explores federal mediators’ perspectives on successful conflict resolution in contract disputes. The results indicate that mediator skill base and a collaborative orientation on the part of the disputants are positively related to the likelihood of reaching agreement, while relationship hostility is negatively related to the likelihood of reaching agreement. Other independent variables, such as management outlook and mediator acceptability, were in‐directly related to the likelihood of reaching agreement. Consistent with most previous research, mediator tactics were unrelated to the likelihood of reaching agreement. Limitations and suggestions for future research are discussed.
Predicting Counterproductive Performance Among Temporary Workers: A Note*
Authors: POSTHUMA RICHARD A. , CAMPION MICHAEL A. , VARGAS AMBER L.
Published: June 2005

Using prehire biographic and work history data, temporary help agency workers (N= 201) were classified as marginal or satisfactory. Marginal temps had characteristics suggesting poor work histories and willingness to accept any kind of employment. In prior jobs, they were paid less and more likely to have been laid off. They had also been temps for longer periods of time, and were more willing to work weekends and nights. The classification of temps as marginal versus satisfactory was validated using posthire data, showing that marginal temps had lower performance evaluations, and exhibited more counterproductive behaviors (e.g., late, absent, unsafe, or careless).
Evolutions and Limits of New Public Management—Inspired Budgeting Practices in Italian Local Governments
Authors: Anessi‐Pessina Eugenio , Steccolini Ileana
Published: June 2005

In Italy, New Public Management (NPM)‐inspired reforms have been mostly legislation‐driven. For Italian Local Governments (LGs), one of the most significant reforms was the introduction, in 1995, of an “Executive Management Plan” (EMP). The EMP has been interpreted and applied by Italian LGs differently across space and over time. Some LGs have introduced it only formally. Others have interpreted it as a tool to define individual managers's spending authorizations. Only some have viewed it as a building block of a wider management control system. Over time, LGs have since been making continuous changes to their budgeting systems, without yet reaching a new steady state.
Toward a Theory of Performance Reporting to Achieve Public Sector Accountability: A Field Study
Authors: Cunningham Gary M. , Harris Jean E.
Published: June 2005

Governments in many countries are implementing performance reporting systems. Many advocates claim that performance reporting results in accountability and effectiveness. There is no theory to justify these claims and guide implementation. This paper presents five field studies of five performance‐reporting systems to begin building theory.

Four locations are optimistic; one is not. Mere adoption of performance reporting is not effective. Broad involvement across all government levels is important. Communication and integration with strategic planning and agency management are essential. Two theoretical streams, accounting in organized anarchies and the constitutive role of accounting, are useful theoretical bases.
Have Cities Shifted to Outcome‐Oriented Performance Reporting?—A Content Analysis of City Budgets
Authors: Ho Alfred Tat‐Kei , Ni Anna Ya
Published: June 2005

“Outcome” orientation has been emphasized in performance measurement and reporting in recent years. Using budgetary documents of the largest cities in the United States, this paper analyzes more than 4,800 performance measures reported by 21 cities to show that clear progress toward outcome‐oriented performance measurement has been made. It also shows that the selection of performance measures differs among types of municipal services and is driven partly by professionalism in city management and the influence of professional organizations. The paper concludes by discussing the implications of the findings and potential future improvements of performance reporting.
“Robin Hood” and Texas School District Borrowing Costs
Authors: Benson Earl D. , Marks Barry R.
Published: June 2005

The “Robin Hood” system of school financing in Texas takes property tax funds from wealthy school districts and gives them to poorer districts. This paper examines Permanent School Fund‐insured, school district debt and discovers that under the “Robin Hood” system, Texas school districts with either Aa or A1 underlying credit ratings have higher borrowing costs than districts with lower ratings. Also, the borrowing costs of Texas school districts with underlying credit ratings of Aa and A1 are higher than those for non‐Texas, privately insured school districts with the same ratings, while the borrowing costs of A and Baa‐rated Texas school districts are lower.
Lupus erythematosus panniculitis (lupus profundus): Clinical, histopathological, and molecular analysis of nine cases
Authors: Massone Cesare , Kodama Kazuo , Salmhofer Wolfgang , Abe Riichiro , Shimizu Hiroshi , Parodi Aurora , Kerl Helmut , Cerroni Lorenzo
Published: June 2005

Background:  The diagnosis of lupus erythematosus panniculitis (LEP) may be very difficult in cases in which involvement of the subcutaneous fat is the only manifestation of the disease. The main differential diagnosis is subcutaneous panniculitis‐like T‐cell lymphoma (SPTCL).

Methods:  We performed a retrospective study reviewing the histopathologic features of 11 biopsy specimens from nine patients with LEP (M : F = 2 : 7; median age: 48 years; range: 20–71 years).

Results:  Histopathologically, all biopsies revealed a lobular panniculitis, with concomitant septal involvement in 82% of them. Dermal changes included the presence of superficial and deep infiltrates (82%) and mucin deposition (73%). The majority of cases (73%) presented also some form of epidermal involvement. The subcutaneous infiltrate was composed of lymphocytes in all cases, admixed with plasma cells in 91% of cases. Lymphoid follicles with reactive germinal centers were detected in 45% of cases. Immunohistochemistry showed a predominance of α/β‐T‐helper and cytotoxic lymphocytes in 80% of cases admixed with B lymphocytes. The polymerase chain reaction analysis of the T‐cell receptor (TCR)‐γ gene showed a polyclonal smear in all cases.

Conclusions:  Our study shows that the most useful histopathologic criteria for distinguishing LEP from SPTCL are the presence of involvement of the epidermis, lymphoid follicles with reactive germinal centers, mixed cell infiltrate with prominent plasma cells, clusters of B lymphocytes, and polyclonal TCR‐γ gene rearrangement.
Histologic similarities between lentigo maligna and dysplastic nevus: importance of clinicopathologic distinction
Authors: Farrahi Farinaz , Egbert Barbara M. , Swetter Susan M.
Published: June 2005

Background: Lentigo maligna (LM) can histologically simulate dysplastic nevus (DN). Partial biopsy of LM may lead to misdiagnosis.

Methods: One hundred and fourteen cases of LM and LM melanoma (LMM) were diagnosed at the Veterans Affairs Palo Alto Health Care System (1993–2002). Biopsy and excision specimens for 68in situand 28 invasive melanomas were classified as having predominant classical LM features, predominant DN‐like morphology, or a mixed pattern.

Results: Biopsy specimens demonstrated a predominant classical pattern in 38% (25/65) LM and 36% (10/28) LMM, predominant DN‐like features in 43% (28/65) LM and 25% (7/28) LMM, and mixed pattern in 15% (10/65) LM and 29% (8/28) LMM. Most LM and LMM biopsies were partial. Significant DN‐like features were present in 51% LM and 57% LMM excision specimens. Median age was 72 years for LM and 73 years for LMM, mean lesion diameters were 1.3 and 1.7 cm for LM and LMM, respectively, and 85% of LM and 75% of LMM cases were located on heavily sun‐exposed sites.

Conclusions: Misdiagnosis of LM or LMM as DN could have devastating results. Large pigmented lesions on sun‐damaged skin in elderly individuals should warrant consideration of LM/LMM diagnosis, even in the setting of DN‐like features histologically. Excisional biopsy may help to avoid misdiagnosis.
Lymphoepithelioma‐like carcinoma of the skin with spindle cell differentiation
Authors: Clarke Loren E. , Ioffreda Michael D.
Published: June 2005

Background:  Primary cutaneous LELC is a cutaneous neoplasm with histopathologic features identical to those seen in the undifferentiated subtype of nasopharyngeal carcinoma. It is extremely rare, with only approximately 30 cases reported in the literature.

Methods:  We report a case of primary cutaneous LELC arising on the forehead of a 72 year‐old male in which a proportion of the neoplastic cells demonstrated distinctive spindle cell morphology.

Results:  Microscopic examination showed a dense lymphoplasmacytic infiltrate admixed with large spindle‐shaped cells with vesicular nuclei, prominent nucleoli, and frequent mitotic figures. These cells were negative for an extensive panel of immunohistochemical markers and positive only for broad‐spectrum cytokeratins and epithelial membrane antigen. There was no connection between the tumor and the epidermis and no epidermal dysplasia. In situ hybridization for Epstein‐Barr virus was negative.

Conclusions:  The spindle cell differentiation in this case is unusual and suggests that in some cases the differential diagnosis of cutaneous spindle cell neoplasms might include primary cutaneous LELC.
Histologic variants of fibrous papule
Authors: Bansal Cheryl , Stewart David , Li Ailing , Cockerell Clay J.
Published: June 2005

Fibrous papules (FPs) are common benign lesions usually of the face. Most are readily recognizable histologically, although several variants exist that may not be as easily diagnosed. These include hypercellular, clear cell, pigmented, pleomorphic, and inflammatory variants. A granular cell variant has also been described. We microscopically evaluated 212 FPs, and of those, 184 demonstrated features of one of the variants. We conclude that variants of FP may be encountered not uncommonly. Dermatopathologists should be aware of these to avoid misdiagnosis.
Acroangiodermatitis (pseudo‐Kaposi sarcoma) associated with verrucous hyperplasia induced by suction‐socket lower limb prosthesis
Authors: Sbano Paolo , Miracco Clelia , Risulo Massimiliano , Fimiani Michele
Published: June 2005

Abstract:  Increasing use of suction‐socket lower limb prostheses has been associated with an increased frequency of dermatological manifestations, linked to the fact that the skin of the amputation stump must adapt to an entirely new environment. In particular, verrucous hyperplasia and rare cases of acroangiodermatitis (pseudo‐Kaposi sarcoma) have been described. We report a case of amputation stump dermatitis, clinically resembling verrucous hyperplasia, but with predominant histological aspects of acroangiodermatitis in a patient with a suction‐socket lower limb prosthesis.
The Long Run Abnormal Performance of UK Acquirers and the Free Cash Flow Hypothesis
Authors: Gregory Alan
Published: June 2005

Abstract:  Evidence from recent US and UK studies reveals a pattern of poor long run post acquisition performance by acquiring firms. One explanation, due to Jensen (1986) is that acquirers with an excess of free cash flow (FCF) will have a propensity to squander this on wasteful investments, including take‐overs. In this paper, using a dataset of UK take‐overs and proxies for free cash flow similar to those used by Lang, Stulz and Walking (1991), we find no support for the FCF hypothesis and show that this conclusion is robust to the model of long run returns employed. Contrary to the free cash flow hypothesis there is evidence that acquirers with high free cash flow perform better than acquirers with low free cash flow. Although not consistent with the Jensen hypothesis, this evidence is compatible with the emerging UK evidence that shows cash flow‐to‐price measures are associated with market returns.
Investment Opportunity Set and Voluntary Disclosure of Prospective Information: A Simultaneous Equations Approach
Authors: Hossain Mahmud , Ahmed Kamran , Godfrey Jayne M.
Published: June 2005

Abstract:  This paper examines empirically the relationship between the level of disclosure of prospective information and the investment opportunity set for firms in New Zealand. Using a systems (two‐stage least squares) approach that explicitly controls for potential endogeneity between disclosure and IOS, we find that the level of prospective information disclosure is significantly and positively related to IOS in both specifications in our simultaneous analysis. Further, we document that prospective information disclosure is positively related to firm size and new security offerings, and is not related to inside ownership and firm profitability. IOS is positively impacted by a firm's investments in fixed assets and its profitability. Finally, we find that forward looking disclosure levels are positively related to the proportion of outside directors on the board and negatively related to barriers to entry, but these findings are not robust across alternative model specifications.
Incentive Effects, Monitoring Mechanisms and the Market for Corporate Control: An Analysis of the Factors Affecting Public to Private Transactions in the UK
Authors: Weir Charlie , Laing David , Wright Mike
Published: June 2005

Abstract:  This paper investigates the factors that influence the decision to change the status of a publicly quoted company to that of a private company. We find that firms that go private are more likely to have higher CEO ownership and higher institutional ownership. In relation to their board structures, firms going private tend to have more duality but there is no statistical difference in the proportion of non‐executive directors. They do not show signs of having excess free cash flows but there is some evidence of lower growth opportunities. We do not find that firms going private experience a greater threat of hostile acquisition. The results are therefore consistent with incentive and monitoring explanations of going private. Calculation of the probability of going private shows that incentive effects are stronger than the monitoring effects.
The International Transmission of Arbitrage Information Across Futures Markets
Authors: Bilson Chris , Brailsford Tim , Evans Twm
Published: June 2005

Abstract:  This paper examines whether deviations from a domestic spot‐futures relation, as identified through mispricing series in stock index futures, spillover international boundaries. Such spillovers suggest that information from a mispricing series in one market conveys a signal of similar mispricing in another market. In the presence of arbitrage traders and in the absence of market frictions, mispricing series should be independent across international boundaries. The study employs a VAR analysis of stock index futures mispricing across three large futures markets – Australia, the UK and the USA. Using time zone differences, tests are conducted for the daily transmission of arbitrage information. The results reveal the relationship between mispricing series is bi‐directional. Based on this finding, a trading strategy is employed to examine the economic significance of apparent profits. The results show that some profits are possible after transaction costs but that a long horizon, probably beyond the scope of most traders, is required to exploit the spillover information.
Employee Relations and the Likelihood of Occurrence of Corporate Financial Distress
Authors: Kane Gregory D. , Velury Uma , Ruf Bernadette M.
Published: June 2005

Abstract:  In this paper, we investigate the association of employee relations with the occurrence of onset of financial distress. We argue that if adverse economic conditions arise, firms that have maintained good employee relations will be more effective in obtaining temporary labor concessions. As a result, firms with good employee relations, to the extent they are dependent on labor in the conduct of business operations, should be more likely to avoid the onset of future financial distress. The empirical findings we document support this prior.
International Publishing Patterns: An Investigation of Leading UK and US Accounting and Finance Journals
Authors: Jones Michael John , Roberts Roydon
Published: June 2005

Abstract:  Research quality is often measured by the quality of the journals in which articles are published. This article looks at 1,867 articles published in six highly‐rated UK and six highly‐rated US academic journals from 1996 to 2000. The authors publishing in the UK journals come mainly from UK and US institutions, but just over a third come from other countries. However, almost ninety per cent of authors publishing in top US journals come from US institutions. Contributions from authors from institutions in non‐English speaking countries in these top journals are rare. The implications of this research are that although accounting is growing increasingly international, academic research, especially in the top US journals remains stubbornly nationally‐orientated.
FRS17 and the Sterling Double A Corporate Yield Curve
Authors: Skinner Frank S. , Ioannides Michalis
Published: June 2005

Abstract:  We argue that the appropriate discount rate used to report defined benefit pension plan liabilities in the financial statements is a yield derived from an estimate of a double A corporate yield curve. We show that parsimonious yield curve techniques are easily applicable to the sterling double A corporate bond market. Moreover, we find that with a careful selection of the data an objective and reliable yield curve can be obtained. In all we find that using a yield from a sterling double A corporate yield curve to obtain the value of defined benefit pension plan liabilities is a feasible alternative to the current recommendations of FRS17.
Trade Credit Terms: Asymmetric Information and Price Discrimination Evidence From Three Continents
Authors: Pike Richard , Cheng Nam Sang , Cravens Karen , Lamminmaki Dawne
Published: June 2005

Abstract:  Trade credit terms offer firms contractual solutions to informational asymmetries between buyers and sellers. The credit period permits buyers to reduce uncertainty concerning product quality prior to payment, while the seller can reduce uncertainty concerning buyer payment intentions by prescribing payment before/on delivery or through two‐part payment terms and other mechanisms. Variation in trade credit terms also offers firms price discriminating opportunities. This study, drawing on the responses of 700 large firms in the US, UK and Australia, explores trade credit terms through the twin objectives of reducing information asymmetries and discriminatory pricing. Support is found for both theories.
Preservation of phenotype in an organotypic cell culture model of a recessive keratinization defect of Norfolk terrier dogs
Authors: Barnhart Kirstin F. , Credille Kelly M. , Ambrus Andy , Dunstan Robert W.
Published: June 2005

Abstract:  The purpose of this study is to reproduce in vitro a recessive keratinization defect of Norfolk terrier dogs characterized by a lack of keratin 10 (K10) production. Keratinocytes from skin biopsy samples of four normal dogs and two affected dogs were cultured organotypically with growth factor‐supplemented media in order to stimulate cornification. The cultured epidermis from the normal dogs closely resembled the normal epidermis in vivo and cornified. The cultured epidermis from the affected dogs displayed many phenotypic alterations identified in skin biopsies from dogs with this heritable defect. Immunohistochemistry and immunoblotting showed a marked decrease in K10 from the cultures of the affected keratinocytes, compared to that in K10 from the cultures of the normal keratinocytes. Real‐time reverse transcription polymerase chain reaction quantitation showed a 31‐fold decrease in K10, a 1.75‐fold increase in K1 and a 136‐fold increase in K2e between the affected and the normal epidermis. Organotypic keratinocytes showed a 241‐fold decrease in K10, a 31‐fold decrease in K1 and a 1467‐fold decrease in K2e between the affected and normal cultures. Although in vitro keratin expression did not precisely simulate in vivo, the morphology of the normal and the affected epidermis was largely preserved; thus, this culture system may provide an alternative to in vivo investigations for cutaneous research involving cornification.
Effective inhibition of melanosome transfer to keratinocytes by lectins and niacinamide is reversible
Authors: Greatens Amanda , Hakozaki Tomohiro , Koshoffer Amy , Epstein Howard , Schwemberger Sandy , Babcock George , Bissett Donald , Takiwaki Hirotsugu , Arase Seiji , Wickett R. Randall , Boissy Raymond E.
Published: June 2005

Abstract:  Skin pigmentation results in part from the transfer of melanized melanosomes synthesized by melanocytes to neighboring keratinocytes. Plasma membrane lectins and their glycoconjugates expressed by these epidermal cells are critical molecules involved in this transfer process. In addition, the derivative of vitamin B3, niacinamide, can inhibit melanosome transfer and induce skin lightening. We investigated the effects of these molecules on the viability of melanocytes and keratinocytes and on the reversibility of melanosome‐transfer inhibition induced by these agents using an in vitro melanocyte–keratinocyte coculture model system. While lectins and neoglycoproteins could induce apoptosis in a dose‐dependent manner to melanocytes or keratinocytes in monoculture, similar dosages of the lectins, as opposed to neoglycoproteins, did not induce apoptosis to either cell type when treated in coculture. The dosages of lectins and niacinamide not affecting cell viability produced an inhibitory effect on melanosome transfer, when used either alone or together in cocultures of melanocytes–keratinocytes. Cocultures treated with lectins or niacinamide resumed normal melanosome transfer in 3 days after removal of the inhibitor, while cocultures treated with a combination of lectins and niacinamide demonstrated a lag in this recovery. Subsequently, we assessed the effect of niacinamide on facial hyperpigmented spots using a vehicle‐controlled, split‐faced design human clinical trial. Topical application of niacinamide resulted in a dose‐dependent and reversible reduction in hyperpigmented lesions. These results suggest that lectins and niacinamide at concentrations that do not affect cell viability are reversible inhibitors of melanosome transfer.
Assessment of platelet activity as expressed by plasma levels of platelet factor 4 and β‐thromboglobulin in patients with chronic idiopathic urticaria
Authors: Kasperska‐Zajac Alicja , Rogala Barbara , Nowakowski Marek
Published: June 2005

Abstract:  Blood platelet significance in inflammation is recognized but poorly characterized in urticaria. It is known that platelets are activated during inflammatory processes and are involved in modulating inflammatory and immune response via various mediator release. The aim of our study was to investigate the functional state of platelets, expressed by release reaction of C‐X‐C chemokines such as platelet factor 4 (PF‐4) and β‐thromboglobulin (β‐TG) in chronic idiopathic urticaria (CIU). Plasma levels of PF‐4 and β‐TG, which are established markers of in vivo platelet activation and which play important role in inflammatory processes, were measured by enzyme‐linked immunosorbent assay in 19 patients with CIU and in 25 healthy subjects. Mean plasma PF‐4 level in CIU patients and control subjects was 5.01 ± 1.67 and 4.13 ± 2.05 IU/ml, respectively, whereas that for β‐TG was 29.3 ± 14.0 and 25.2 ± 12.6 IU/ml, respectively. In our small study, there have been no significant differences found between the members of the control and CIU group regarding plasma levels of PF‐4 and β‐TG. Further studies should be performed to elucidate whether any systemic platelet activation occurs in CIU.
Epidermal growth factor (EGF)‐mediated DNA‐binding activity of AP‐1 is attenuated in senescent human epidermal keratinocytes
Authors: Shi Biao , Isseroff R. Rivakh
Published: June 2005

Abstract:  The proliferative responses of cells to mitogens decrease during aging, and this may result from age‐related defects in signal transduction in response to mitogens. In this study, we have investigated the age‐related alteration of responses to epidermal growth factor (EGF) in cultured human keratinocytes that were senesced in vitro by repeated passage. The stimulation with EGF increased the DNA‐binding activity of activator protein 1 (AP‐1), an important transcription factor for cell proliferation, in young keratinocytes, whereas the binding activity showed little or slight change in the senescent cells. The induced DNA‐binding activity of AP‐1 in young cells was inhibited by PD 98059, an inhibitor of MEK, and partially inhibited by GF 109203X, an inhibitor of protein kinase C. Western blot analysis demonstrated that EGF induced dramatic increase in the phosphorylation of EGF receptor (EGFR) and extracellular signal‐regulated kinases (ERK) in young cells, while this phosphorylation was much less profound in senescent cells. Finally, the application of EGF to young cells resulted in increased phosphorylation of Fra‐2, a Fos protein component of the Jun/Fos heterodimer AP‐1 complex. This EGF‐induced Fra‐2 phosphorylation was attenuated in senescent cells. Taken together, our study suggests that the signal transduction mediated by EGF/ERK pathway is altered in senescent human keratinocytes, and this change may be attributed, in part, to the decreased AP‐1 transcription activity observed in senescent keratinocytes.
Definition of anti‐tyrosinase MAb T311 linear determinant by proteome‐based similarity analysis
Authors: Willers Jörg , Lucchese Alberta , Mittelman Abraham , Dummer Reinhard , Kanduc Darja
Published: June 2005

Abstract:  Using non‐self discrimination as a driving force in generating peptide immunogenicity, we have developed a computer‐assisted proteomic analysis in order to identify the protein antigenic regions that have evoked humoral response. The purpose of this study was to further validate the computational analysis for melanoma‐associated antigens and, at the same time, to assess the efficacy of the methodology in defining antigenic regions of autoantigens associated to autoimmune diseases. To achieve this two‐fold objective, we have examined the enzyme tyrosinase, a protein that represents an important autoantigen in patients with vitiligo or melanoma. Here, we report that the antigenic linear determinant of the monoclonal antibody (Mab) T311 raised against the melanoma/vitiligo tyrosinase autoantigen is located in the low similarity 15‐mer amino acid sequence tyrosinase 233–247 IPYWDWRDAEKCDIC, within the fragment 237–247. These data confirm non‐similarity to the host proteome as a factor that participates in shaping peptide immune reactivity and may be a first step towards designing tyrosinase antigenic peptides to be used for (i) direct neutralization of harmful melanocytes‐attacking autoantibodies in vitiligo, or (ii) production of antibodies against tyrosinase‐positive melanomas. Moreover tyrosinase peptide antigens might be used as key tools in studying the boundaries between self‐tolerance and autoimmunity phenomena.
Tectonic modification of the Australian North‐West Shelf: episodic rejuvenation of long‐lived basin divisions
Authors: Harrowfield Mat , Keep Myra
Published: June 2005

Neogene collision between Australia and the Banda Arc modified two adjacent depocentres within Australia's North‐West Shelf, the Browse and Bonaparte Basins. We identify two components of this modification: (1) continuous long‐wavelength amplification of Permo‐Carboniferous basement topography, and (2) flexure and normal faulting of Triassic–Recent sedimentary cover. Although this deformation was continuous across the Browse and Bonaparte Basins, the degree of basement architectural control, mechanisms of fault linkage and distribution of syntectonic accommodation space varied significantly between the two basins. These variations reflect fundamental differences in the structural relief, amplitude and depth of rifted basement on either side of a rupture‐barrier‐style accommodation zone, the Browse/Bonaparte Transition. This long‐lived architectural divide, of which there is no discrete structural expression, was amplified by Neogene collision. We examine tectonic rejuvenation of the Browse/Bonaparte Transition and describe a mechanism for actively sustaining long‐lived segmentation of the continental shelf.
Aqueous and petroleum fluid flow associated with sand injectites
Authors: Jonk Rene , Parnell John , Hurst Andrew
Published: June 2005

Field, petrographic and fluid inclusion characteristics of sand injectites from five outcrop localities and from the subsurface of the Tertiary of the south Viking Graben are described. Although the case studies are from a wide variety of sedimentological, stratigraphic and tectonic settings, and hence their diagenetic evolutions differ significantly, it is possible and useful to assign diagenetic events to three distinct phases of fluid flow associated with sand injectites in sedimentary basins. Firstly, there is fluid flow associated with the injection of the fluid–sediment mix during shallow burial. Early diagenetic imprints in sand injectites reveal that basinal fluids, which may be released during movement along deeper‐seated faults, can be associated with this process and thus the injection process may reveal information on the timing of basin‐scale movement of fluids. Secondly, following the injection process, basinal fluids continue to migrate through uncemented injectites and mix with the ambient meteoric and/or marine pore fluids that invade injectites from the overlying and surrounding host sediments. Early, often pervasive, carbonate cementation is common within sand injectites and rapidly turns sand injectites into flow barriers during shallow (<1 km) burial. If early carbonate cementation is not pervasive, fluid inclusions in late quartz cement (∼>2 km of burial) reveal additional information on fluid flow associated with sand injectites during deeper burial. The latest phase of fluid flow occurs when sand injectites are reactivated as preferential fluid conduits during phases of deformation, when well‐cemented subvertical sand injectites become sites of focussed brittle deformation (fracturing). This study shows that sand injectites are a common and volumetrically important type of structural heterogeneity in sedimentary basins and that long‐lived fluid flow associated with sand injectites in very different settings can be assessed and compared systematically using a combination of petrography and fluid inclusion studies.
Burial and exhumation history of Pennsylvanian strata, central Appalachian basin: an integrated study
Authors: Reed Jason S. , Spotila James A. , Eriksson Kenneth A. , Bodnar Robert J.
Published: June 2005

An inferred burial and exhumation history of Pennsylvanian strata in the central Appalachian foreland basin is constrained by integrating palaeothermometers, geochronometers and estimated palaeogeothermal gradients. Vitrinite reflectance data and fluid inclusion homogenization temperatures indicate that burial of Lower and Upper Pennsylvanian strata of the Appalachian Plateau in West Virginia exceeded ∼4.4 km during the late Permian and occurred at a rate of ∼100 m Myr−1. Exhumation rates of ∼10 m Myr−1 from the late Permian to the early Cretaceous are constrained using maximum burial conditions and published apatite fission track (AFT) ages. AFT and radiogenic helium ages indicate exhumation rates of ∼30–50 m Myr−1 from the early to late Cretaceous. Radiogenic helium dates and present day sampling depths indicate that exhumation rates from the late Cretaceous to present were ∼25 m Myr−1. Exhumation rates for Upper and Lower Pennsylvanian strata within the Appalachian Plateau are remarkably similar. Early slow exhumation was possibly driven primarily by isostatic rebound associated with Triassic rifting. The later, more rapid exhumation can be attributed to thermal expansion followed by lithospheric flexure related to sediment loading along the passive margin.
Susceptibility to infection in patients with neutropenia: the role of the innate immune system
Authors: Neth O. W. , Bajaj‐Elliott M. , Turner M. W. , Klein N. J.
Published: June 2005

Chemotherapy‐induced neutropenia increases the risk of infection. There appears to be a wide variability in the severity and length of infective episodes. Susceptibility to infections is determined by the underlying malignant disease and its treatment, environmental factors (e.g. nutritional state of the patient and hygiene) and genetically determined variations of the immune system. The majority of primary immunodeficiencies are rare (c. frequency one in 10 000), whereas some genetic polymorphisms in the innate immune system, such as profound mannose‐binding lectin deficiency, are much more common (c. frequency one in 10). Here, we review the potential role of the innate immune system in determining susceptibility to infections in patients with neutropenia.
Psychological complications in sickle cell disease
Authors: Anie Kofi A
Published: June 2005

This review examines the evidence for some of the common psychological complications found across the life span of patients with sickle cell disease (SCD), which are likely to be encountered by haematologists responsible for their medical management. Electronic searches of medical and psychological databases were conducted with a focus on three main areas: psychological coping, quality of life and neuropsychology. Psychological complications were identified in both children and adults with SCD, and included inappropriate pain coping strategies; reduced quality of life owing to restrictions in daily functioning, anxiety and depression; and neurocognitive impairment. There were wide variations in design and consistency of the studies, therefore, some caution needs to be observed in the findings. Moreover, interventional studies were lacking in some areas such as neuropsychology. Utilization of psychological interventions including patient education, cognitive behavioural therapy, and special educational support to help improve the quality of life of patients are recommended.
Benefit of dexamethasone compared with prednisolone for childhood acute lymphoblastic leukaemia: results of the UK Medical Research Council ALL97 randomized trial
Authors: Mitchell C. D. , Richards S. M. , Kinsey S. E. , Lilleyman J. , Vora A. , Eden T. O. B. ,   the Medical Research Council Childhood Leukaemia Working Party
Published: June 2005

Corticosteroids are an essential component of treatment for acute lymphoblastic leukaemia (ALL). Prednisolone is the most commonly used steroid, particularly in the maintenance phase of therapy. There is increasing evidence that, even in equipotent dosage for glucocorticoid effect, dexamethasone has enhanced lymphoblast cytotoxicity and penetration of the central nervous system (CNS) compared with prednisolone. Substitution of dexamethasone for prednisolone in the treatment of ALL might, therefore, result in improved event‐free and overall survival. Children with newly diagnosed ALL were randomly assigned to receive either dexamethasone or prednisolone in the induction, consolidation (all received dexamethasone in intensification) and continuation phases of treatment. Among 1603 eligible randomized patients, those receiving dexamethasone had half the risk of isolated CNS relapse (P = 0·0007). Event‐free survival was significantly improved with dexamethasone (84·2% vs. 75·6% at 5 years; P = 0·01), with no evidence of differing effects in any subgroup of patients. The use of 6·5 mg/m2 dexamethasone throughout treatment for ALL led to a significant decrease in the risk of relapse for all risk‐groups of patients and, despite the increased toxicity, should now be regarded as part of standard therapy for childhood ALL.
SHP1 expression in bone marrow biopsies of myelodysplastic syndrome patients: a new prognostic factor
Authors: Mena‐Duran Armando V. , Togo Summanuna H. , Bazhenova Lyudmila , Cervera Jose , Bethel Kelly , Senent Maria L. , Nieva Jorge , Sanz Guillermo F. , Sanz Miguel A. , Saven Alan , Mustelin Tomas
Published: June 2005

Myelodysplastic syndrome (MDS) progresses into acute leukaemia with a variable time course. We analysed 45 newly diagnosed patients and found that the expression of the Src homology 2 domain‐containing tyrosine phosphatase 1 (SHP1) had a significant impact on disease severity, progression and overall prognosis. Global or lineage‐specific loss of SHP1 was observed by immunohistochemistry in bone marrow biopsies of MDS patients who progressed rapidly (P = 0·0021) and had shorter survival (P < 0·001). Cox regression analysis demonstrated that SHP1 expression in megakaryocytes had prognostic relevance for time to progression (P = 0·009) and overall survival (P = 0·001).
PAD combination therapy (PS‐341/bortezomib, doxorubicin and dexamethasone) for previously untreated patients with multiple myeloma
Authors: Oakervee Heather E. , Popat Rakesh , Curry Nicola , Smith Pat , Morris Curly , Drake Mary , Agrawal Samir , Stec Jim , Schenkein David , Esseltine Dixie‐Lee , Cavenagh Jamie D.
Published: June 2005

Bortezomib (formerly PS‐341) has significant activity in patients with relapsed multiple myeloma (MM), its efficacy is increased with the addition of dexamethasone and it demonstrates synergy with doxorubicin, thus providing the rationale for combination therapy with bortezomib, doxorubicin and dexamethasone (PAD). Patients with untreated MM received four 21‐d cycles of PAD, comprising bortezomib 1·3 mg/m2 on days 1, 4, 8 and 11, along with dexamethasone 40 mg on days 1–4, 8–11 and 15–18 during cycle 1 and days 1–4 during cycles 2–4. During days 1–4, patients also received 0, 4·5 or 9 mg/m2 of doxorubicin at dose levels 1, 2, and 3 respectively. Following peripheral blood stem cell (PBSC) collection, patients received high‐dose melphalan (MEL200) with PBSC transplantation (PBSCT). After PAD induction alone, 20 of 21 patients (95%) achieved at least a partial response (PR), including complete response (CR) in five patients (24%). Twenty of 21 had PBSC mobilized, and 18 of 20 received MEL200/PBSCT. In an intention‐to‐treat analysis, response rates were: CR 43%, near CR 14%, very good PR 24%, PR 14% and stable disease 5%. PAD was effective, did not prejudice subsequent PBSC collection, and should be further evaluated in prospective randomized trials.
Red cell pyruvate kinase deficiency: 17 new mutations of the PK‐LR gene
Authors: Fermo Elisa , Bianchi Paola , Chiarelli Laurent R. , Cotton Frederic , Vercellati Cristina , Writzl Karin , Baker Kerry , Hann Ian , Rodwell Robin , Valentini Giovanna , Zanella Alberto
Published: June 2005

The PK‐LR gene was studied in 23 patients with congenital haemolytic anaemia associated with erythrocyte pyruvate kinase (PK) deficiency. Twenty‐seven different mutations were detected among the 42 mutated alleles identified: 19 missense mutations, four splice site mutations and one nonsense, one single base deletion and two large deletions. Seventeen of them (107G, 278T, 403T, 409A, 661A, 859C, 958A, 1094T, 1190T, 1209A, 1232C, 1369G, 507A, IVS9 −1c, IVS9 +43t, del C224, del 5006bp IVS3→ nt 1431) were new. Although all the exons, the flanking regions and the promoter were sequenced in all cases, we failed to detect the second expected mutation in four subjects. To correlate genotype to phenotype, the molecular results were related to the biochemical properties of the mutant enzymes by an analysis of the three‐dimensional structure of erythrocyte PK. The new mutant 409A, found in association with the large deletion of 5006 bp in a newborn baby who died soon after birth, was functionally characterized by mutagenesis and in vitro expression of the protein to investigate its contribution in the severity of the clinical pattern. However, the biochemical data obtained for the mutant enzyme cannot explain the severe anaemia found in the PK‐deficient patient hemizygous for this mutation.