bluuebunny/crossref_metadata_2025 huggingface dataset:
Splicing enhances translation in mammalian cells: an additional function of the exon junction complex
Authors: Nott Ajit , Le Hir Hervé , Moore Melissa J.
Published: January 2004

In mammalian cells, spliced mRNAs yield greater quantities of protein per mRNA molecule than do otherwise identical mRNAs not made by splicing. This increased translational yield correlates with enhanced cytoplasmic polysome association of spliced mRNAs, and is attributable to deposition of exon junction complexes (EJCs). Translational stimulation can be replicated by tethering the EJC proteins Y14, Magoh, and RNPS1 or the nonsense-mediated decay (NMD) factors Upf1, Upf2, and Upf3b to an intronless reporter mRNA. Thus, in addition to its previously characterized role in NMD, the EJC also promotes mRNA polysome association. Furthermore, the ability to stimulate translation when bound inside an open reading frame appears to be a general feature of factors required for NMD.
Decentralisation and EC antitrust policy: a critical commentary on the EU Commission's radical antitrust proposals
Authors: Davison Leigh M.
Published: January 2004

The EU Commission's radical proposals to change the rule set controlling the implementation of Article 81 and 82 in antitrust matters are critically explored in this paper. This includes the Commission's reasoning behind the proposed changes, particularly the assertion that it will lead to a more effective application of community antitrust instruments, thus helping to safeguard the Single Market. The aim of the proposals is to establish a network of cooperating enforcers applying Articles 81 and 82 in an effective and uniform way, with the Commission guaranteeing this. The proposed decentralisation of antitrust applications stands in marked contrast to merger control at the EU level, with the Commission retaining exclusive jurisdiction over mergers having a community dimension. However, the Commission, in the longer term, particularly in the light of enlargement, is much more likely to rethink the architecture of EU merger control.
Reforming the Russian aviation industry
Authors: de Kort Joop , Kluiters Steven
Published: January 2004

This paper discusses the question of whether the Russian aviation industry has restructured sufficiently to create a position for itself as a supplier of aircraft. It describes the collapse of the market for aeroplanes in Russia which wiped away domestic demand for airplanes and discusses the policies of privatisation and restructuring of the industry. The results are of a mixed nature. On the one hand, a deep restructuring has been avoided only to become more pressing. On the other hand, firms have shown great creativity in surviving and the Putin government pursues a process of further concentration and consolidation.
Consumer driven and bi‐directional value chain diffusion models
Authors: Svensson Göran
Published: January 2004

This article provides a non‐mainstream discussion on the value chain concept, which challenges generally believed positions in the area of supply chain management. The author argues that the ultimate consumer is the trigger in the supply chain. The article discusses the concept of value and the value chain, and proposes a modified meaning and interpretation of the value chain model from the point of view of a holistic supply chain context. The author proposes a modified consumer driven value chain diffusion model and an extended bi‐directional value chain diffusion model.
E‐business process networks – successful value chains through standards
Authors: Kirchmer Mathias
Published: January 2004

In the 1990s, companies focused on the design and implementation of their internal business processes to overcome functional barriers. The 2000s are about the integration between enterprises and inter‐enterprise processes, particularly the improvement of supply chain management and customer relationship processes, The major enabler is the Internet, which has resulted in entire networks of e‐business processes across various organizations. To design and implement those processes efficiently and effectively, more and more organizations use available industry standards in the form of reference models, e.g. the supply chain reference model (SCOR), the RosettaNet Standards, or software reference models. Unclear for many enterprises is how to use those standards. This article describes a comprehensive methodology for the use of reference models, to design and implement inter‐enterprise collaborations within value chain networks. The methodology leads to fast and reliable results in value chain improvement. It increases the performance of the implementation procedure and the resulting business processes.
Effectiveness of using an enterprise system to teach process‐centered concepts in business education
Authors: Noguera Jose H. , Watson Edward F.
Published: January 2004

This study investigates whether or not student’s performance, self‐efficacy, and satisfaction are enhanced by the use of an enterprise system as a support tool for learning business process and enterprise systems concepts. The study compares three instructional delivery methods. A traditional instruction method (lecture format plus reading/exercises) serves as the control. The second and third instructional methods are computer‐based methods. In the second method, students receive traditional lecture format with full access to hands‐on an enterprise system transaction exercise. In the third method, students receive traditional lecture format, but also have full access to simulated hands‐on an enterprise system via Web transaction exercises (i.e. ScreenCam movies). A statistically significant difference between‐instructional methods effect is found.Post hocanalysis showed that the simulated hands‐on instruction group’s performance score was significantly higher than that of the control group. There were no other statistically significant differences found, but practical considerations at this learning environment are discussed.
Market responsive manufacturing for the automotive supply chain
Authors: Waller Ben
Published: January 2004

Building to order enables manufacturing to better respond to market conditions. The time lost between changes in customer preferences and product mix disappears and customer demand can both be anticipated and shaped by the sales system. An automotive build to order supply chain must be able to meet seasonality within markets, and understand the detailed demand volatility for certain elements of the complex product mix, from which much of the profitability is derived. Market responsive manufacturing entails adaptive and flexible production and supply capability in conjunction with real‐time market interaction through revenue management. The combination of late capacity setting and revenue management can enable the whole extended enterprise to operate as a single entity. This article outlines the demand volatility examined for automotive products, integrated revenue and demand management as a solution, and the subsequent order system investment requirements.
An investigation on the readiness of Turkish companies for enterprise resource management
Authors: Baki Birdogˇan , Dereli Türkay , Baykasogˇlu Adil
Published: January 2004

Enterprise resource planning (ERP) is a game plan for planning and monitoring all of the resources of a manufacturing company. It has been recognized as an effective management system leading to excellent planning and scheduling capability and significant improvements in productivity. It also provides dramatic increases in customer service, much higher inventory turns, and greater reduction in materials costs. The enterprise resource management (ERM) organizational assessment checklist provides a simple and practical reference to determine whether companies are ready for today’s competitive business environment. In this study, the checklist has been surveyed within the companies using ERP systems through a questionnaire. The survey data were analyzed to determine whether the companies (using ERP software) in Turkey are ready to implement ERM..
An organizational information network for corporate responsiveness and enhanced performance
Authors: Büyüközkan Gülçin
Published: January 2004

Today, companies are confronting a changing environment, which has never been faced before. It has been well accepted that with recent technological advances, barriers are eliminated and a new global market has been established. In order to obtain better results and customer satisfaction, the companies have to listen the voice of the customer and to produce value added products and services by reducing the cycle time. This requires an active and an effective management of operational functions and customer/supplier relationship. Information systems and technologies are the most important strategic tools supporting information and knowledge management in order to increase corporate responsiveness and enhanced performance. The objective of this study is to suggest an information‐based responsive organizational network framework supporting efficient management of company‐wide functions and customer/supplier relationships.
An integrated model for order release and due‐date demand management
Authors: Saad Sameh M. , Pickett N. , Kittiaram K.
Published: January 2004

In this paper, an integrated model for order release and due‐date management is developed to enhance manufacturers’ confidence in the due‐dates offered to customers. The proposed model utilised the backward finite scheduling order release control method and five different due‐date assignment rules. The proposed model is implemented using C++ computer programming language. Due‐date of each order is calculated by a due‐date assignment rule selected. Then the program tries to schedule the whole order with as lowest value as possible of tightness parameter (k). The output of the C++ program is production schedule of the whole order using backward finite scheduling order release method. Experiment results indicate that the modified number of operations due‐date rule_MNOP is superior with respect to the other due‐dates rules of the whole order.
Efficacy‐information for implementing learning in construction
Authors: Jawahar Nesan L.
Published: January 2004

This paper, while emphasizing the linkage between the concepts of “empowerment” and “learning”, argues that empowerment provides the most appropriate base to effectively implement learning in construction organizations. It is argued that “efficacy‐information”, being a derivative of empowerment, helps influence employees’ behavior in seeking, managing and utilizing knowledge at job sites. Within this context, this paper proposes the efficacy‐information model being developed out of a series of detailed case studies conducted at large civil and building construction organizations in UK. The model presented in this paper depicts several types of efficacy‐information, of which, most put employees as being responsible for seeking and deploying them at job site. It must be noted that the efficacy‐information model should not be considered as complete but it should continually evolve based on future investigations.
The knowledge entrepreneurship challenge
Authors: Coulson‐Thomas Colin
Published: January 2004

While many organisations have embraced a succession of management fads, general training and knowledge management initiatives, there is evidence these have failed to equip key work groups with specific knowledge, pragmatic skills and practical tools they need to become more effective. In particular, changes are not making it easier for people dealing with customers, clients or citizens to do a better job or deliver more bespoke responses to individual requirements.
Novel mutations in the CHST6 gene causing macular corneal dystrophy
Authors: Abbruzzese C , Kuhn U , Molina F , Rama P , De Luca M
Published: January 2004

Macular corneal dystrophy (MCD) is an autosomal recessive disease characterized by corneal opacities and caused by mutations in a carbohydrate sulfotransferase gene, known as CHST6. MCD type I patients show missense mutations in the CHST6‐coding region, and MCD type II patients show a large deletion and replacement in the upstream region of CHST6. The objective of this study was to identify the genetic defect in CHST6 gene causing MCD in Italian families. We investigated MCD genotype by using polymerase chain reaction followed by direct sequencing, and results were confirmed by restriction analysis. An enzyme‐linked immunosorbent assay was performed to assess the presence of sulfated keratan sulfate in the serum of MCD patients. Biochemical analysis revealed a MCD type I phenotype in two families and a type II phenotype in another family. Two novel missense mutations and a polymorphism in the coding region of CHST6 gene were identified in patients with MCD type I. In one MCD II family, a homozygous deletion in the upstream region of CHST6 gene was found.
Genetic variation at the hormone sensitive lipase: gender‐specific association with plasma lipid and glucose concentrations
Authors: Qi L , Shen H , Larson I , Barnard JR , Schaefer EJ , Ordovas JM
Published: January 2004

Hormone‐sensitive lipase (HSL) catalyzes the intracellular hydrolysis of triacylglycerols and cholesteryl esters, and it is involved in regulating body fat, steroidogenesis, and insulin secretion. Thus, genetic variability at the HSL locus (LIPE) may play a significant role on lipid metabolism and the risk of obesity and type 2 diabetes. Therefore, we have examined two LIPE single nucleotide polymorphism (SNP) [14672C>G in the promoter region and 17948C>T (rs1206034) on intron 2] in relation to plasma lipids, anthropometrical and glucose‐related phenotypes in a population of mostly overweight and obese men (373) and women (361). In women, the 17948T allele was associated with decreased total cholesterol (TC, p = 0.001), LDL‐cholesterol (LDLc, p < 0.001) and apoE concentrations (p = 0.041). Conversely, female carriers of the LIPE 14672G allele had significantly higher TC (p = 0.047), LDLc (p = 0.041), and apoE (p = 0.041) levels. Although we did not find significant associations in men, we observed that male carriers of the LIPE 14672G who did not drink alcohol showed higher glucose levels than non‐carriers (p = 0.008), whereas there were no allele‐related differences among drinkers (p = 0.019 for the interaction). These SNPs were not significantly associated with anthropometrical variables. In summary, variation at this locus showed gender‐specific associations with lipids and glucose measures, and the latter was influenced by alcohol drinking.
Concordance of phenotypic expression and gender identity in a large kindred with a mutation in the androgen receptor
Authors: Hooper HT , Figueiredo BC , Pavan‐Senn CC , De Lacerda L , Sandrini R , Mengarelli JK , Japp K , Karaviti LP
Published: January 2004

A 14‐year‐old female presented to the Pediatric Endocrine Clinic, Universidade Federal o Parana Curitiba, Brazil, for obesity. A few years later, despite normal breast development, the patient had failed to menstruate and lacked pubic and axillary hair. Laboratory analyses revealed high levels of testosterone. Karyotype analysis was XY. Direct sequencing of her genomic DNA showed a G to T transition at nucleotide 2089 at exon 2 in the androgen receptor gene, resulting in a substitution of Phe for Cys at position 576. This mutation disrupts the first Zn finger critical to DNA binding and transcriptional activity and results in complete androgen‐insensitivity syndrome (CAIS). This individual was part of 700‐member multigenerational kindred of German origin living in small villages in Southern Brazil. Family members who gave informed consent were screened using a polymerase chain reaction‐based method. Nineteen CAIS‐affected individuals and carriers were identified. All presented with infertility and lack of or sparse pubic hair. The prevalence of common AIS within the kindred greatly exceeds that of the general population and is due in part to their isolated familial and community structures. All individuals are genuinely feminine in their appearance, sex behavior, gender identity, and integration within their communities. We conclude that CAIS leads to complete feminization of XY individuals and results in individuals who are psychologically and socially established and integrated as women within the familial and cultural contexts of their communities.
The influence of APOAV polymorphisms (T‐1131>C and S19>W) on plasma triglyceride levels and risk of myocardial infarction
Authors: Hubacek JA , Škodová Z , Adámková V , Lánská V , Poledne R
Published: January 2004

The importance of an APOAV gene for plasma triglyceride level determination has been shown on transgenic and knockout mice. We examined whether APOAV variants are associated with plasma triglyceride levels and risk of myocardial infarction (MI). We have evaluated the influence of APOAV polymorphisms (T‐1131>C and S19>W) on plasma triglycerides in 1191 males and 1368 females representatively selected from the Czech population. Triglycerides have been analysed in 1997 and 2001. Subsequently, we have analysed the genotype frequencies of the APOAV polymorphism in 435 patients with MI. T‐1131>C variation in the APOAV gene affects the plasma triglyceride showing a higher level in C‐1131 carriers than in T/T‐1131 homozygotes. This association has been observed both in males and females (p < 0.001). Similarly, plasma triglycerides were also significantly influenced by the S19>W APOAV genotypes. In both males and females, the W19 carriers have triglycerides significantly (p < 0.001) higher compared to the S19 homozygotes. In a group of MI patients, the frequency of the rare homozygotes for at least one APOAV polymorphism (C/C‐1131 and/or W/W19) was significantly higher than that in the population sample (7.4 vs 2.0%, p < 0.00001). We conclude that variations in the APOAV gene not only play a role in genetic determination of triglyceride levels but also could influence risk of MI.
Real‐time PCR‐based gene dosage assay for detecting BRCA1 rearrangements in breast–ovarian cancer families
Authors: Barrois M , Bièche I , Mazoyer S , Champème M‐H , Bressac‐de Paillerets B , Lidereau R
Published: January 2004

BRCA1 and BRCA2 germline mutations, mainly point mutations and other small alterations, are responsible for most hereditary cases of breast–ovarian cancer. However, the observed frequency of BRCA1 alterations is lower than that predicted by linkage analysis. Several large BRCA1 rearrangements have been identified with a variety of technical approaches in some families. We have developed a gene dosage assay based on real‐time quantitative PCR and used it to extensively analyze 91 French families of breast–ovarian cancer in which no BRCA1 or BRCA2 point mutations was identified. This gene dosage method calculates the copy number of each BRCA1 exon to readily detect one, two, and three or more copies of BRCA1 target exons. In the series of 91 families at high risk of carrying BRCA1 mutations, we detected seven large rearrangements of the BRCA1 gene by using this real‐time PCR approach. This simple, rapid, and semiautomated real‐time quantitative polymerase chain reaction (PCR) assay is a promising alternative technique to Southern blot, bar code analysis on combed DNA, quantitative multiplex PCR of short fluorescent fragments, and cDNA length analysis for the detection of large rearrangements. Therefore, this technique should be considered as a powerful diagnostic method for breast/ovarian cancer susceptibility in clinical and research genetic surveys.
Gaucher's disease: a paradigm for interventional genetics
Authors: Germain DP
Published: January 2004

Gaucher's disease (GD) is one of the most prevalent lysosomal storage disorders (LSDs) and a rare genetic disease for which specific therapy is now available. GD is an autosomal, recessive, inborn error of glycosphingolipid metabolism, due to a deficiency in the enzyme acid β‐glucosidase. Partial deficiency of acid β‐glucosidase is associated with parenchymal disease of the liver, spleen, and bone marrow with concomittant anemia and thrombocytopenia in non‐neuronopathic, type 1 GD. Severe deficiency of glucocerebrosidase caused by severe mutations is additionally associated with neurological manifestations in the less common type 2 and type 3 GD subtypes. Outside of the Ashkenazi Jewish community, a high molecular diversity is observed. Clarification of genotype/phenotype relationship and the identification of modifier loci that impact on GD phenotypes remains a critical area for research. Enzyme replacement therapy (ERT) is proven to be safe and effective in the treatment of type 1 GD, establishing imiglucerase as the current standard of care. Amelioration of hepatosplenomegaly and of hematological manifestations is usually apparent within 6–12 months, whereas the bone disease responds more slowly. ERT cannot reverse the neurological deficits in type 2 or type 3 GD. Small molecule inhibitors of glucosylceramide synthase are being developed for substrate reduction therapy. Other potential therapeutic options such as chaperon‐mediated enzyme enhancement therapy and gene therapy are being explored.
Effective long‐term control of cardiac events with β‐blockers in a family with a common LQT1 mutation
Authors: Wedekind H , Schwarz M , Hauenschild S , Djonlagic H , Haverkamp W , Breithardt G , Wülfing T , Pongs O , Isbrandt D , Schulze‐Bahr E
Published: January 2004

The congenital long QT syndrome (LQTS) is characterized by a prolonged QT interval on the surface electrocardiogram and an increased risk of recurrent syncope and sudden cardiac death. Mutations in seven genes have been identified as the molecular basis of LQTS. β‐blockers are the treatment of choice to reduce cardiac symptoms. However, long‐term follow‐up of genotyped families with LQTS has been rarely reported. We have clinically followed a four‐generation family with LQTS being treated with β‐blocker therapy over a period of 23 years. Seven family members were carriers of two amino acid alterations in cis (V254M‐V417M) in the cardiac potassium channel gene KCNQ1. Voltage‐clamp recordings of mutant KCNQ1 protein in Xenopus oocytes showed that only the V254M mutation reduced the IKs current and that the effect of the V417M variant was negligible. The family exhibited the complete clinical spectrum of the disease, from asymptomatic patients to victims of sudden death before β‐blocker therapy. There was no significant reduction in QTc (556 ± 40 ms½ before therapy, 494 ± 20 ms½ during 17 years of treatment; n = 5 individuals). Of nine family members, one female died suddenly before treatment, three females of the second generation were asymptomatic, and four individuals of the third and fourth generation were symptomatic. All mutation carriers were treated with β‐blockers and remained asymptomatic for a follow‐up up to 23 years. Long‐term follow‐up of a LQT1 family with a common mutation (V254M) being on β‐blocker therapy was effective and safe. This study underscores the importance of long‐term follow‐up in families with specific LQT mutations to provide valuable information for clinicians for an appropriate antiarrhythmic treatment.
Amlodipine‐induced immune thrombocytopenia
Authors: Garbe E. , Meyer O. , Andersohn F. , Aslan T. , Kiesewetter H. , Salama A.
Published: January 2004

Background and Objectives  Drug‐induced thrombocytopenia is a serious, but rare, side‐effect of treatment with a number of drugs. In this report, we investigate the suspicion that amlodipine, a calcium‐channel blocker, was responsible for immune thrombocytopenia in a 79‐year‐old patient.

Patient and Methods  Our patient experienced two attacks of thrombocytopenic purpura after 10 years of treatment with amlodipine. Antibodies to platelets were tested by standard methods.

Results  Initially, the platelet count increased owing to treatment with prednisolone and intravenous immunoglobulin G, but decreased shortly after discontinuation of this treatment. The patient's serum was found to contain amlodipine‐dependent antibodies to platelets, and he recovered after stopping the drug.

Conclusions  Amlodipine can induce immune thrombocytopenia, which may strongly resemble autoimmune thrombocytopenia.
Platelet function abnormalities in qualified whole‐blood donors: effects of medication and recent food intake
Authors: Paglieroni T. G. , Janatpour K. , Gosselin R. , Crocker V. , Dwyre D. M. , MacKenzie M. R. , Holland P. V. , Larkin E. C.
Published: January 2004

Background and Objectives  Platelet function abnormalities have been reported in blood donors who have not consumed aspirin. Our objective was to identify factors other than aspirin that may contribute to impaired platelet function in qualified volunteer blood donors.

Materials and Methods  Blood samples were obtained from 24 donors following routine blood donation. Donors completed a study questionnaire that included questions about recent food consumption, medication and medical history. Platelet activation was measured using monoclonal antibodies and flow cytometry. CD62P expression and PAC‐1 binding on platelets were used as indicators of platelet activation. Platelet function was measured on a platelet function analyser (PFA‐100®) using both collagen/epinephrine (cEPI) and collagen/ADP (cADP) cartridges.

Results  Fifty‐four per cent of donors (13 of 24) had normal platelet function. Thirty‐eight per cent (nine of 24) had prolonged cEPI closure times, of whom four (17%) had no cEPI closure (> 300 seconds). No closure was associated with aspirin use (two donors) or chocolate consumption (two donors) before donation. Two donors (8%) had either a shortened cEPI or cADP closure time.

Conclusions  Platelet dysfunction in qualified blood donors is underestimated. Platelet function screening can identify donors with diet‐related platelet dysfunction or with poor recollection of aspirin use.
Continuous cytomegalovirus seroconversion in a large group of healthy blood donors
Authors: Hecker M. , Qiu D. , Marquardt K. , Bein G. , Hackstein H.
Published: January 2004

Background and Objectives  Transmission of cytomegalovirus (CMV) to seronegative, immunocompromised recipients can cause serious and fatal complications. Although the seroprevalence of CMV is high, the risk of primary CMV infection among healthy blood donors has not yet been analysed in a large population.

Materials and Methods  We developed an algorithm to determine the rate of CMV seroconversion in an overall cohort of 24 260 subjects who donated 176 474 blood units during an 11‐year observation period.

Results  We detected CMV seroconversion in all relevant age groups (18–60 years) with an overall seroconversion rate of 0·55% per year. Both CMV seroconversion and seroprevalence occurred more frequently in female donors (P = 0·02 and P < 0·001, respectively). We identified 30–35‐year‐old blood donors as the group with the highest rate of CMV seroconversion per year (1·33% vs. 0·46%; P < 0·0001).

Conclusions  We conclude that the risk of primary CMV infection is a continuous lifelong event and correlates with age and female gender.
Diffuse melanosis after chemotherapy‐induced tumor lysis syndrome in a patient with metastatic melanoma
Authors: Busam Klaus J. , Wolchok Jedd , Jungbluth Achim A. , Chapman Paul
Published: January 2004

Abstract:  Diffuse melanosis is a rare event associated with advanced metastatic malignant melanoma. A 35‐year‐old woman with stage IV melanoma is presented, who developed slate bluish‐gray to brown discoloration of her skin after chemotherapy‐induced tumor lysis syndrome. A number of studies were performed to re‐evaluate possible mechanisms of melanosis. Skin tissue was examined on routine hematoxylin‐and‐eosin‐stained sections, Fontana stains, immunohistochemical studies with antibodies for Melan‐A, gp100, tyrosinase, FXIIIa, and CD68, and by electron microscopy. The main cell types found to contain melanin pigment were histiocytes and dendritic cells. In the dermis, they were distributed mainly around venules. In the subcutaneous fat, they were scattered throughout the fat lobule. Melanin pigment was not only seen within cells but also extracellularly. No melanoma cells were seen in the skin. No increase in melanin pigment or number of melanocytes was seen in the epidermis. A bone marrow biopsy contained melanophages but no melanoma cells. Ultrastructural examination of the patient's serum revealed the presence of melanosomes. Sequence analysis of the tumor's cDNA failed to identify any mutations in the tyrosinase gene, and no tyrosinase protein was detected in non‐melanocytic cells, indicating that it was unlikely that a mutation had resulted in a secretory form of the protein. These findings document that diffuse melanosis may result from tumor lysis, with release of melanosomes into the bloodstream.
Borrelia burgdorferi‐associated lymphocytoma cutis: clinicopathologic, immunophenotypic, and molecular study of 106 cases
Authors: Colli Claudia , Leinweber Bernd , Müllegger Robert , Chott Andreas , Kerl Helmut , Cerroni Lorenzo
Published: January 2004

Lymphocytoma cutis (LC) is considered as the stereotypical example of the cutaneous B‐cell pseudolymphomas. It can be induced by various antigenic stimuli including arthropod bites, vaccination, and drugs among others. In endemic regions, Borrelia burgdorferi is the principal causative agent for LC. We studied retrospectively 108 biopsies from 106 patients (male : female, 48 : 58; mean age, 44.6; median, 51.5; range, 3–81) with B. burgdorferi‐associated LC retrieved from the files of the Department of Dermatology of the University of Graz (Austria). Only cases with a B. burgdorferi etiology (typical locations, positivity of serologic and/or polymerase chain reaction (PCR) tests, clinical history) were included in the study. Lesions were located on the nipple (63 cases), earlobe (18 cases), genital region (9 cases), and trunk or extremities (16 cases). PCR analysis of B. burgdorferi DNA was positive in 54 of 80 cases tested (67.5%). In 47 cases, we could retrieve data on serologic examination for B. burgdorferi antibodies performed at the time of diagnosis of LC. Positivity was found in 45 patients (IgG+/IgM+, 5 cases; IgG+/IgM–, 37 cases; IgG–/IgM+, 3 cases; IgG–/IgM–, 2 cases). Histology revealed dense lymphoid infiltrates with prominent germinal centers (GCs) in all cases. Atypical morphologic and/or immunophenotypic features of the GCs were commonly observed. In 5 cases, due to confluence of large follicles, the histopathologic pattern simulated that of a large B‐cell lymphoma. PCR analysis of the IgH gene rearrangement performed in 33 cases showed a polyclonal pattern in 31 cases and a monoclonal band in 2. In summary, B. burgdorferi‐associated LC can present with misleading histopathologic, immunophenotypic, and molecular features, and integration of all data is necessary for a correct diagnosis.
CD117, CK20, TTF‐1, and DNA topoisomerase II‐α antigen expression in small cell tumors
Authors: Yang David T. , Holden Joseph A. , Florell Scott R.
Published: January 2004

Background:  Distinguishing merkel cell carcinoma (MCC), small cell lung carcinoma (SCLC) metastatic to the skin, and atypical basal cell carcinoma (BCC) can be problematic in some cases. Significant differences in the biology of these tumors necessitate that they need to be distinguished from one another.

Methods:  We evaluated the immunophenotypic characteristics of 22 MCCs, nine SCLCs, and 19 BCCs using antibodies to cytokeratin 20 (CK20), thyroid transcription factor‐1 (TTF‐1), CD117, and DNA topoisomerase II‐α (topo II).

Results:  Nineteen of 22 MCCs stained with the antibody to CK20, none stained with anti‐TTF‐1, and 13 stained with anti‐CD117. No SCLC stained with anti‐CK20, all stained with anti‐TTF‐1, and eight stained with anti‐CD117. No BCC stained with any of the three markers. The proliferative index (PI), determined by the expression of topo II, was similar for SLCLs (mean 58.5 ± 9.0%) and MCCs (mean 45.2 ± 12.4%) and was lowest in BCCs (mean 25.0 ± 8.7%).

Conclusions:  CK20 and TTF‐1 appear to be reliable in distinguishing MCC from SCLC. CD117 is expressed in both MCC and SCLC, limiting its diagnostic utility. CK20, TTF‐1, and CD117 are not expressed in BCC. The high PI seen in MCCs suggests a role for topoisomerase II inhibitors in their treatment.
The T1796A mutation of the BRAF gene is absent in Spitz nevi
Authors: Palmedo Gabriele , Hantschke Markus , Rütten Arno , Mentzel Thomas , Hügel Heino , Flaig Michael J. , Yazdi Amir S. , Sander Christian A. , Kutzner Heinz
Published: January 2004

Background:  BRAF, a serine/threonine kinase, is a component of the retrovirus‐associated sequence (RAS)–RAF–extracellular‐regulated protein kinase (ERK)–MAP kinase signal transduction pathway mediating signals from RAS to ERK.

The T1796A single point mutation in exon 15 of the BRAF gene has recently been reported in a high percentage of malignant melanomas and benign melanocytic lesions such as congenital nevi, compound nevi, intradermal nevi and dysplastic nevi. The T1796A mutation has been shown to promote cell proliferation.

Methods:  We screened 21 Spitz nevi and six spitzoid malignant melanomas for the presence of the T1796A BRAF mutation.

Results:  The T1796A BRAF mutation could not be detected in any of the 21 Spitz nevi but was present in two of the six spitzoid malignant melanomas.

Conclusions:  Our results, in conjunction with data from a previous investigation, suggest that the melanocytic proliferation of Spitz nevi might be induced by components of the RAS–RAF–ERK–MAP kinase pathway different from BRAF, possibly combined with other genetic aberrations. The lack of the T1796A BRAF mutation might be of practical importance in distinguishing Spitz nevi from other melanocytic lesions simulating Spitz nevi as a part of a future complex diagnostic assay.
Calciphylaxis and metastatic calcification associated with nephrogenic fibrosing dermopathy
Authors: Edsall Lisa C. , English Joseph C. , Patterson James W.
Published: January 2004

Background:  Calciphylaxis and metastatic calcification are known complications of chronic renal failure. Recently, a sclerosing condition of the skin termed nephrogenic fibrosing dermopathy (NFD) has been described in patients with renal disease, many of whom have undergone hemodialysis and/or renal transplantation. To our knowledge, the simultaneous occurrence of both conditions in the same patient, in the same lesion, has not been previously reported.

Case report:  We report the clinical, microscopic, and immunohistochemical features of two patients with chronic renal failure whose lesional skin biopsies showed both subcutaneous calcification and NFD. We consider the possible mechanisms that might explain the coexistence of these two disorders.

Results:  Both patients presented with erythematous, indurated skin over the lower extremities. Purpuric, reticulated patches, necrosis, or ulceration were not observed. Microscopic examination showed the characteristic changes of NFD involving dermis and subcutaneous septa. In addition, biopsies of both individuals showed subcutaneous calcification, one in a diffuse distribution and the other involving the walls of subcutaneous vessels, as seen in calciphylaxis. Calcification was not suspected clinically in either case.

Conclusions:  Metastatic calcification or calciphylaxis and NFD can occur simultaneously in patients with chronic renal failure and may be found together in the same lesion. Because subcutaneous calcification may not be suspected clinically in these cases, and in view of the adverse outcomes frequently associated with calciphylaxis, we recommend deep incisional biopsy of patients presenting with the clinical features of NFD. Both the fibrosis and the calcification of chronic renal failure may be related to the activity of transforming growth factor‐β/Smad signaling cascades.
HMB‐45 (gp103) and MART‐1 expression within giant cells in an atypical fibroxanthoma: a case report
Authors: Smith‐Zagone Megan J. , Prieto Victor G. , Hayes Ruth A. , Timperman Walter W. , Diwan A. Hafeez
Published: January 2004

Background:  Atypical fibroxanthoma (AFX) is a cutaneous tumor that primarily occurs in the sun‐damaged skin of the head and neck of adults. It is often a rapidly growing, solitary lesion that may clinically resemble squamous cell carcinoma, malignant melanoma, or lobular hemangioma. The histologic differential diagnosis primarily includes spindle cell squamous carcinoma and spindle cell melanoma, and immunohistochemical studies are often needed to establish the diagnosis.

Case report:  We report an unusual case of an AFX with aberrant HMB‐45 and MART‐1 (melanoma antigen recognized by T cells‐1) immunohistochemical expression. Clinical information was obtained. Histologic examination and immunohistochemical studies were performed.

Results:  A 54‐year‐old woman presented with a 1.5 cm posterior scalp lesion, which was excised. Microscopic examination revealed a dermal tumor composed of pleomorphic and spindled cells with numerous giant cells. The tumor cells expressed CD68 but did not express either keratin or S‐100. In addition, there was focal gp100 (with HMB‐45) and MART‐1 expression limited to the large, multinucleated cells with vacuolated cytoplasm. A diagnosis of AFX was subsequently made.

Conclusions:  This is the first reported case of an AFX with HMB‐45 and MART‐1 reactivity.
A variant of nephrogenic fibrosing dermopathy with osteoclast‐like giant cells: a syndrome of dysregulated matrix remodeling?
Authors: Hershko Klilah , Hull Cheryl , Ettefagh Leila , Nedorost Susan , Dyson Senait , Horn Thomas , Gilliam Anita C.
Published: January 2004

Nephrogenic fibrosing dermopathy (NFD) is a disorder characterized by dramatic thickening and hardening of skin in the extremities and trunk, which occurs in individuals on dialysis for renal disease. The pathophysiology is unknown. Increased transforming growth factor‐β (TGF‐β) and collagen deposition have been reported in a small group of patients studied by Jimenez et al.1 We report two patients with NFD and osteoclast‐like giant cells in the fibrotic dermis; one patient also had dystrophic cutaneous calcification. These findings have been seen in a small percentage of NFD patients (estimated 2–5%) and may represent a variant of the disease. The hypothesis of altered matrix dysregulation due to altered TGF‐β, metalloproteinases, and activation of osteoclasts as an explanation for this variant is proposed.
Single‐neuron evidence for a contribution of the dorsal pontine nuclei to both types of target‐directed eye movements, saccades and smooth‐pursuit
Authors: Dicke Peter W. , Barash Shabtai , Ilg Uwe J. , Thier Peter
Published: January 2004

The primate dorsolateral pontine nucleus (DLPN) is a key link in a cerebro‐cerebellar pathway for smooth pursuit eye movements, a pathway assumed to be anatomically segregated from tegmental circuits subserving saccades. However, the existence of afferents from several cerebrocortical and subcortical centres for saccades suggests that the DLPN and neighbouring parts of the dorsal pontine nuclei (DPN) might contribute to saccades as well. In order to test this hypothesis, we recorded from the DPN of two monkeys trained to perform smooth pursuit eye movements as well as visually and memory‐guided saccades. Out of 281 neurons isolated from the DPN, 138 were responsive in oculomotor tasks. Forty‐five were exclusively activated in saccade paradigms, 68 exclusively by smooth pursuit and 25 neurons showed responses in both. Pursuit‐related responses reflected sensitivity to eye position, velocity or combinations of velocity and position with minor contributions of acceleration in many cases. When tested in the memory‐guided saccades paradigm, 65 out of 70 neurons activated in saccade paradigms showed significant saccade‐related bursts and 20 significant activity in the memory period. Our finding of saccade‐related activity in the DPN in conjunction with the existence of strong anatomical input from saccade‐related cerebrocortical areas suggests that the DPN serves as a precerebellar relay for both pursuit and saccade‐related information originating from cerebral cortex, in addition to the classical tecto‐tegmental circuitry for saccades.
Cognitive generation of affect in bipolar depression: an fMRI study
Authors: Malhi Gin S. , Lagopoulos Jim , Ward Philip B. , Kumari Veena , Mitchell Philip B. , Parker Gordon B. , Ivanovski Belinda , Sachdev Perminder
Published: January 2004

Individuals with bipolar disorder manifest the full spectrum of emotions ranging from depression to mania. In attempting to understand the functional substrates of mood we attempted to identify brain regions associated with the cognitive generation of affect in bipolar depressed patients. We therefore examined ten depressed female subjects with bipolar affective disorder, and ten age‐matched and sex‐matched healthy comparison subjects using functional magnetic resonance imaging (fMRI) while viewing alternating blocks of captioned pictures designed to evoke negative, positive or no affective change. The activation paradigm involved the presentation of the same visual materials over three experiments alternating (experiment 1) negative and reference; (experiment 2) positive and reference and (experiment 3) positive and negative captioned pictures. The stimuli produced activation in both patients and comparison subjects in brain regions previously implicated in the generation and modulation of affect, in particular the prefrontal and anterior cingulate cortices. The activation in patients, when compared with healthy subjects, involved additional subcortical regions, in particular the amygdala, thalamus, hypothalamus and medial globus pallidus. Patients and comparison subjects displayed differential sensitivity to affective change with negative (experiment 1) and positive (experiment 2) affect induction producing converse patterns of activation. We conclude that bipolar depressed patients perhaps recruit additional subcortical limbic systems for emotional evaluation and this may reflect state‐related or trait‐related dysfunction. The differential patterns of activation inform us about bipolar depression and have potential diagnostic and therapeutic significance.
Simple spike and complex spike activity of floccular Purkinje cells during the optokinetic reflex in mice lacking cerebellar long‐term depression
Authors: Goossens H. H. L. M. , Hoebeek F. E. , Van Alphen A. M. , Van Der Steen J. , Stahl J. S. , De Zeeuw C. I. , Frens M. A.
Published: January 2004

Cerebellar long‐term depression (LTD) at parallel fibre–Purkinje cell (P‐cell) synapses is thought to embody neuronal information storage for motor learning. Transgenic L7‐protein kinase C inhibitor (PKCI) mice in which cerebellar LTD is selectively blocked do indeed exhibit impaired adaptation in the vestibulo‐ocular reflex (VOR) while their default oculomotor performance is unaffected. Although supportive, these data do not definitively establish a causal link between memory storage required for motor learning and cerebellar LTD. As the L7‐PKCI transgene is probably activated from the early stages of P‐cell development, an alternative could be that P‐cells develop abnormal signals in L7‐PKCI mutants, disturbing mechanisms of motor learning that rely on proper P‐cell outputs. To test this alternative hypothesis, we studied simple spike (SS) and complex spike (CS) activity of vertical axis P‐cells in the flocculus of L7‐PKCI mice and their wild‐type littermates during sinusoidal optokinetic stimulation. Both SS and CS discharge dynamics appeared to be very similar in wild‐type and transgenic P‐cells at all stimulus frequencies (0.05–0.8 Hz). The CS activity of all vertical axis cells increased with contralateral stimulus rotation and lagged ipsiversive eye velocity by 165–180°. The SS modulation was roughly reciprocal to the CS modulation and lagged ipsiversive eye velocity by ∼ 15°. The baseline SS and CS discharge characteristics were indistinguishable between the two genotypes. We conclude that the impaired VOR learning in L7‐PKCI mutants does not reflect fundamental aberrations of the cerebellar circuitry. The data thus strengthen the evidence that cerebellar LTD is implicated in rapid VOR learning but not in the development of normal default response patterns.
Texture contrast attracts overt visual attention in natural scenes
Authors: Parkhurst Derrick J. , Niebur Ernst
Published: January 2004

In natural vision, the central nervous system actively selects information for detailed processing through mechanisms of visual attention. It is widely held that simple stimulus features such as color, orientation and intensity contribute to the determination of visual salience and thus can act to guide the selection process in a bottom‐up fashion. Contrary to this view, Einhäuser, W. & König, P. [(2003) Eur. J. Neurosci., 17, 1089–1097] conclude from their study of human eye movements that luminance contrast does not contribute to the calculation of stimulus salience and that top‐down, rather than bottom‐up, factors therefore determine attentional allocation in natural scenes. In this article, we dispute their conclusion and argue that the Einhäuser and König study has a number of methodological problems, the most prominent of which is the unintentional introduction of changes in texture contrast. We hypothesize that texture contrast, like luminance contrast, can contribute to the guidance of attention in a bottom‐up fashion, and that an appeal to top‐down factors is not necessary. To test this hypothesis, we implement a purely bottom‐up model of visual selective attention where salience is derived from both luminance and texture contrast. We find that the model can quantitatively account for Einhäuser and König's results and that texture contrast strongly influences attentional guidance in this particular paradigm. The significance of this result for attentional guidance in other paradigms is discussed.
Temporal and spatial patterns of Kv1.1 and Kv1.2 protein and gene expression in spinal cord white matter after acute and chronic spinal cord injury in rats: implications for axonal pathophysiology after neurotrauma
Authors: Karimi‐Abdolrezaee Soheila , Eftekharpour Eftekhar , Fehlings Michael G.
Published: January 2004

After spinal cord injury (SCI), surviving white matter axons display axonal dysfunction associated with demyelination and altered K+ channel activity. To clarify the molecular basis of posttraumatic axonal pathophysiology after SCI, we investigated the changes in expression and distribution of the axonal K+ channel subunits Kv1.1 and Kv1.2 in spinal cord white matter after in vivo SCI in the rat. Using Western blot analysis, we found an increased expression of Kv1.1 and Kv1.2 at 2 and 6 weeks after SCI. By real‐time PCR we observed an increase in Kv1.1 and Kv1.2 mRNA levels 1 day after SCI, which persisted until 6 weeks. Confocal immunohistochemistry showed a markedly dispersed labelling of Kv1.1 and Kv1.2 along the injured axons, in contrast to the tight localization of these channels to the juxtaparanodes of noninjured axons. This redistribution of Kv1.1 and Kv1.2 occurred as early as 1 h postinjury along some injured axons, and persisted at 6 weeks postinjury. In parallel with the redistribution of Kv1.1 and 1.2, contactin‐associated protein (Caspr), which is normally confined to a paranodal location, also displayed a more diffuse distribution along the injured spinal cord axons. Our results suggest that the increased expression of Kv1.1 and Kv1.2 proteins is transcriptionally regulated. In contrast, the redistribution of the axonal K+ channel subunits occurs very early postinjury and probably reflects a disruption of the juxtaparanodal axonal region due to physical trauma, as shown by altered localization of Caspr.