bluuebunny/crossref_metadata_2025 huggingface dataset:
Expression of MMP‐9, MMP‐10 and TNF‐α and lack of epithelial MMP‐1 and MMP‐26 characterize pyoderma gangrenosum
Authors: Bister Ville , Mäkitalo Laura , Jeskanen Leila , Saarialho‐Kere Ulpu
Published: October 2007

Background:  Pyoderma gangrenosum (PG) is a non‐infectious, autoimmune, chronic ulcer of the skin, often co‐existing with inflammatory bowel disease (IBD). Matrix metalloproteinases (MMPs) have been implicated as mediators of tissue destruction in chronic cutaneous and intestinal wounds.

Methods:  Twenty‐four skin biopsies with clinically and histologically confirmed PG and acute wounds were immunostained for MMP‐1, ‐7, ‐8, ‐9, ‐10 and ‐26; tissue inhibitors of matrix metalloproteinase (TIMP)‐1 and ‐3 and tumor necrosis factor‐α (TNF‐α).

Results:  MMP‐1 was generally expressed by keratinocytes distal from the wound edge, whereas MMP‐10 was detected abundantly in the epithelium. MMP‐26 was positive in 42% at the migratory front. Abundant stromal expression was evident for MMP‐1, ‐9 and ‐10, TIMP‐1 and ‐3 and TNF‐α. In acute wounds, stromal MMP‐1, ‐9 and ‐10 and TNF‐α were sparse.

Conclusions:  Unlike in normally healing cutaneous wounds, MMP‐1 and ‐26 were detected bordering the wound in only a minority of PGs and their lack may thus retard epithelial repair. Particularly, MMP‐9 and ‐10 and TNF‐α would be suitable therapeutic targets as they may contribute to the degradation of provisional matrices needed for migration in healing wounds. The presence of MMP‐1, ‐9, ‐10 and ‐26 in both PG and IBD ulcers may suggest a similar pathogenesis for cutaneous and mucosal inflammation.
Assessing competency in Dentoalveolar surgery: a 3‐year study of cumulative experience in the undergraduate curriculum
Authors: Durham J. A. , Moore U. J. , Corbett I. P. , Thomson P. J.
Published: October 2007

Aim:  To assess and observe the development of competence in oral surgical skills during a 3‐year undergraduate programme.

Method:  Over a 3‐year period 75 students were followed through from the beginning of their clinical course to their Bachelor of Dental Surgery graduation and their surgical experience monitored by the use of logbooks. Their development of competence was assessed objectively through structured assessments and subjectively by a single tutor responsible for each year. Assessments were made of their ability in exodontia, pre‐surgical assessment and the surgical extraction of teeth/roots.

Results:  Seventy‐three students completed the course (97%). Successful completion rates for the objective testing were 100% for both exodontia and pre‐surgical assessment. The surgical assessment, (surgical extraction of a tooth or root) had a successful completion rate of only 23% and the caseload for students was low with a mean of four teeth removed surgically upon graduation. Relationships were examined between total numbers of teeth extracted, total number of minor oral surgical procedures completed and the successful completion of the surgical competence assessment, but no significant relationships were found.

Conclusions:  This study demonstrates that it is possible to achieve objectively measurable levels of competence in undergraduates undertaking oral surgery procedures. It is however, a labour and time intensive process and appropriate clinical and teaching resources are required. National co‐operation towards agreed standardised competencies should be encouraged to allow data to be pooled and more powerful analyses to occur.
The flexible requirement system for grading of clinical performance of undergraduate dental students
Authors: ElBadrawy H. , Korayem M.
Published: October 2007

Abstract: A new grading system is presented for evaluating and grading dental students’ clinical competence and performance in paediatric dentistry at the undergraduate level. The Flexible Requirements System is a clinical competence evaluation system designed to address some of the common deficiencies of other requirements‐based performance evaluation systems, by utilising a unique method of collecting and manipulating certain measurements of student performance in various groups of clinical procedures. The system aimed to incorporate adequate flexibility in its requirements to afford students fair and equal opportunities, whilst maintaining adherence to departmental clinical competence criteria and standards.
General practice dentists’ knowledge of temporomandibular disorders in children and adolescents
Authors: Tegelberg Å. , Wenneberg B. , List T.
Published: October 2007

Aim:  The aim of the study was to map general practice dentists’ (GPDs) knowledge of temporomandibular disorders (TMD) in children and adolescents.

Materials and methods:  A questionnaire was mailed to 286 Swedish dentists in the Public Dental Service and 17 TMD specialists with documented research experience. The questionnaire contained 37 statements on aetiology, diagnostics, classification, chronic pain and pain behaviour, treatment, and prognosis. Each statement was judged on a 0—10 point scale with the endpoint definitions agree or disagree.

Results:  The overall response rate to the questionnaire was 87%. In 28 of all 37 statements, the TMD specialists endorsed a consensus, i.e. >75% of the specialists had the same opinion about the statement. TMD specialists differed most in opinion in the domain diagnostics and classification. In 65% of the statements, differences in knowledge between GPDs and TMD specialists were non‐significant. The greatest number of significant between‐group differences was found in the domain treatment and prognosis. Most of these statements were related to morphological factors.

Conclusion:  There is a high degree of consensus in TMD knowledge amongst the TMD specialists and a high degree of agreement in knowledge between GPDs and TMD specialists. In some areas, however, TMD specialists still need to reach a consensus which is founded on evidence‐based TMD knowledge in children and adolescents and that can be used in undergraduate teaching. It is therefore important to develope and strengthen the undergraduate dental teaching in TMD and orofacial pain.
Video‐assisted clinical instruction in dentistry. Overview and applications
Authors: Fakhry Ali , Cooper Steven , Slach Nancy , Krenz Scott
Published: October 2007

Abstract:  Dental education can benefit from adopting new technologies and modern learning practices. Video‐assisted clinical instruction in dentistry (VACID) uses video technology with the purpose of enhancing the teaching of technical skills and the acquisition of clinical knowledge, as well as fostering student‐centered learning and critical self‐appraisal. VACID is made possible through the capturing, recording, transmitting and viewing of high quality video images of live or pre‐recorded clinical procedures. As such, the implementation of VACID represents an attractive teaching tool that can complement and strengthen current clinical and didactic teaching practices used in formal dental education. The primary objective of this paper is to provide an overview of VACID and discuses its various applications in dental education. A second objective of this paper is to provide a detailed description of the video camera set‐up used at the University of Iowa for the implementation of VACID in the Department of Periodontics.
Video‐Assisted Clinical Instruction in Dentistry (VACID) enhances real‐time visualisation of clinical procedures
Authors: Fakhry Ali , Dehkordi‐Vakil Farideh H.
Published: October 2007

Aim:  The use of Video‐Assisted Clinical Instruction in Dentistry (VACID) in the training of dental students represents an innovative teaching medium. Despite the many advantages that this teaching medium promises to offer, little objective research has been published to substantiate its purported benefits. This article examines the students’ response to the application of VACID to enhance real‐time visualisation of clinical procedures while observing live clinical procedures in periodontics.

Method:  Forty third‐year dental students, observing surgical procedures during their rotation in the Department of Periodontics, were invited to participate in a survey designed to examine perceptions relating to their learning experience to using conventional and video‐assisted real‐time visualisation of clinical procedures. Students’ responses were obtained using a questionnaire administered immediately after the completion of the observational period. The survey employed attitude questions addressing both enabling and outcome criteria. Wilcoxon signed‐rank test was used to compare the student’s responses. An open‐ended question was also included in the survey to give students the opportunity to provide additional feedback regarding their experience and suggestions to improve on it.

Results:  Results suggest that the implementation of VACID in the clinical setting improves the student’s learning experience, interest and satisfaction. Ninety per cent of students strongly agreed to have VACID implemented for their next clinical observation. Responses to the open‐ended question indicated that improved visualisation was extremely helpful in understanding the progress of clinical procedures.

Conclusion:  The implementation of VACID in the clinical setting enhances real‐time visualisation of surgical procedures beyond what is offered by the conventional observational format.
ATF2 on the double – activating transcription factor and DNA damage response protein
Authors: Bhoumik Anindita , Lopez‐Bergami Pablo , Ronai Ze’ev
Published: October 2007

Signal transduction pathways play a key role in the regulation of key cellular processes, including survival and death. Growing evidence points to changes in signaling pathway that occur during skin tumor development and progression. Such changes impact the activity of downstream substrates, including transcription factors. The activating transcription factor 2 (ATF2) has been implicated in malignant and non‐malignant skin tumor developments. ATF2 mediates both transcription and DNA damage control, through its phosphorylation by JNK/p38 or ATM/ATR respectively. Here, we summarize our present understanding of ATF2 regulation, function and contribution to malignant and non‐malignant skin tumor development.
Animals lacking endothelin‐converting enzyme‐2 are deficient in learning and memory
Authors: Rodriguiz R. M. , Gadnidze K. , Ragnauth A. , Dorr N. , Yanagisawa M. , Wetsel W. C. , Devi L. A.
Published: October 2007

Endothelin‐converting enzyme (ECE)‐2 is a metalloprotease that possesses many properties consistent with it being a neuropeptide‐processing enzyme. This protease is found primarily in neural tissues, with high levels of expression in midbrain, cerebellum, hypothalamus, frontal cortex and spinal cord and moderate levels in hippocampus and striatum. To evaluate its role in neural function, mice have been generated lacking this enzyme. Physical appearance, autonomic reflexes, motor co‐ordination, balance, locomotor activity and spontaneous emotional responses appear normal in these knockout (KO) mice. However, these mutants display deficits in learning and memory as evidenced by marked impairment in the Morris water maze. Knockout mice are also deficient in object recognition memory where they show delays in discerning changes in object location and in recognizing the introduction of a novel object. In this study, perseveration appears to interfere with learning and memory. Finally, mutants are impaired in social transmission of food preference where they show poor short‐term memory and perturbations in long‐term memory; the latter can be ameliorated by reminder cues. As ECE‐2 has been implicated in Alzheimer’s disease, the deficits in learning and memory in the KO mice may provide unique insights into processes that may contribute to this disease and possible other disorders of cognition.
Breast milk composition in a cohort of pre‐term infants' mothers followed in an ambulatory programme in Colombia
Authors: Charpak N , Ruiz JG ,   M Med Sci on behalf of the KMC team
Published: October 2007

Objectives: Describing preterm breast milk evolution and composition according to gestational age (GA) and postnatal age (PNA) in a cohort of mothers cared for in an ambulatory Kangaroo Mother Care Program (KMCP) in a developing country.

Methods: A cohort involving 113 mothers who delivered ‘healthy’ preterms adequate for GA was assembled. Mothers received intensive breastfeeding support before discharge. Samples of both fore‐ and hind milk were obtained at entry into KMCP and weekly thereafter, until term. Composition was described according to PNA and postconceptional age (PCA).

Results: Protein concentration varied inversely with both PCA and PNA. Fat concentration was consistently higher in hind milk than in fore milk samples of the same feed. Lactose increased steadily with PCA. Calcium/phosphorus ratios were stable, close to 2:1 and content of both was similar in samples of different PCA and PNA.

Conclusion: Minerals concentration could be inadequate for preterms. Protein concentration decreases steadily to mature milk levels by the third week of PNA, regardless of birth GA. Therefore, from the third week of PNA onwards, protein content could be insufficient to satisfy needs of preterms born at 32 weeks or less. Feeding hind milk could increase caloric density and fat intake to better meet preterms’ nutritional needs.
Toni Morrison and Classical Tradition
Authors: Roynon Tessa
Published: October 2007

This article summarizes a significant new approach to the work of the African‐American novelist Toni Morrison: analysis of her widespread engagement with classical tradition. After discussing the prior critical perspectives on this subject, and highlighting the importance of the classics in Morrison's intellectual formation, it demonstrates that the author's ambivalent classicism is central to the rewriting of American history that her oeuvre enacts. I go on to show that her insistence on the interactions between African and Graeco‐Roman cultures contributes to her reinvention of classical tradition as a radical force, and I end by illuminating the implications for literary and American Studies that the recognition of her classicism must possess.
Recent Studies in Religion and Renaissance Drama
Authors: Coleman David
Published: October 2007

Although early works of new historicism and cultural materialism stressed the significance of early modern religion as a context for Renaissance drama, criticism in the 1990s was largely secular in focus. However, more recent years have seen the intensive development of a school of criticism which uses the methodology of historical materialism, but analyses the religious discourses and institutional structures of early modern England. This article examines in detail some of the most recent historicist accounts of the relationship between religion and Renaissance drama.
Attraction, acquisition, retention and spatiotemporal distribution of soilborne plant pathogenic fungi by shore flies
Authors: El‐Hamalawi Z.A.
Published: October 2007

Adult shore flies were experimentally shown to be aerial vectors for three soilborne plant pathogens: Verticillium dahliae, Fusarium oxysporum f.sp. basilici and Thielaviopsis basicola. Adult insects are attracted to sporulating cultures of the soilborne fungi investigated, as well as infected plant tissues. Shore flies acquired fungal propagules both by ingestion and surface contamination. The minimum acquisition time for propagules of soilborne fungi was 10–20 min and acquisition increased with time to reach 100% frass deposits infestation after 2 h of acquisition. The inoculum potential of the frass deposits was high considering that the number of viable spores deposited by one adult insect in a day was 2.38 × 107, 3.08 × 106 and 8.83 × 106 for V. dahliae, F. oxysporum f. sp. basilici and T. basicola, respectively. Electron microscopy investigation implicated body surface contamination as a means of viable propagule acquisition. Pathogen distribution by adult shore flies was rapid over time at 2.21 cm2 per hour per insect. The area over which the pathogen was distributed by adult shore flies increased with the increase in exposure time. The study showed that adult shore flies are efficient in the dispersal of the soilborne plant pathogen T. basicola.
Recent Faces of Moral Nonnaturalism
Authors: Cuneo Terence
Published: October 2007

Despite having occupied a peripheral position in contemporary metaethics, moral nonnaturalism has recently experienced a revival of sorts. But what is moral nonnaturalism? And what is there to be said in favor of it? In this article, I address these two questions. In the first place, I offer an account of what moral nonnaturalism is. According to the view I propose, nonnaturalism is better viewed not as a position, but as a theoretical stance. And, second, I critically engage with three recent arguments for moral nonnaturalism offered by Russ Shafer‐Landau, Kit Fine, and Jean Hampton, respectively.
Peroxisome proliferator‐activated receptors and inflammation: take it to heart
Authors: Smeets P. J. H. , Planavila A. , Van Der Vusse G. J. , Van Bilsen M.
Published: October 2007

Peroxisome proliferator‐activated receptors (PPARs) are ligand‐activated transcription factors acting as key regulators of lipid metabolism as well as modulators of inflammation. The role of PPARα and PPARγ in cardiac ischaemia‐reperfusion injury, infarct healing and hypertrophy is the subject of intense research. Due to the later development of PPARδ‐specific ligands, the role of this PPAR isoform in cardiac disease remains to be established. Although many studies point to salutatory effects of PPAR ligands in cardiac disease, the exact molecular mechanism is still largely unsolved. Both the metabolic (via transactivation) and the more recently discovered anti‐inflammatory (via transrepression) effects of PPARs are likely to play a role. In this review the reported, and sometimes contradictory, effects of PPAR ligands on ischaemia‐reperfusion, infarct healing and cardiac hypertrophy are critically evaluated. In particular the role of inflammation in these disease processes, the ability of PPARs to interfere with pro‐inflammatory processes, and the mechanisms of transrepression are discussed. Currently, the significance of PPARs as therapeutic targets in cardiovascular disease is receiving widespread attention. Accordingly, detailed understanding of the mechanisms controlling the activity of these nuclear hormone receptors is essential.
Effects of potassium channel openers in the isolated perfused hypokalaemic murine heart
Authors: Killeen M. J. , Thomas G. , Olesen S.‐P. , Demnitz J. , Stokoe K. S. , Grace A. A. , Huang C. L.‐H.
Published: October 2007

Aim:  We explored the anti‐arrhythmic efficacy of K+ channel activation in the hypokalaemic murine heart using NS1643 and nicorandil, compounds which augment IKr and IKATP respectively.

Methods:  Left ventricular epicardial and endocardial monophasic action potentials were compared in normokalaemic and hypokalaemic preparations in the absence and presence of NS1643 (30 μm) and nicorandil (20 μm).

Results:  Spontaneously beating hypokalaemic hearts (3 mm K+) all elicited early afterdepolarizations (EADs) and episodes of ventricular tachycardia (VT). Perfusion with NS1643 and nicorandil suppressed EADs and VT in 7 of 13 and five of six hypokalaemic hearts. Provoked arrhythmia studies using programmed electrical stimulation induced VT in all hypokalaemic hearts, but failed to do so in 7 of 13 and five of six hearts perfused with NS1643 and nicorandil respectively. These anti‐arrhythmic effects were accompanied by reductions in action potential duration at 90% repolarization (APD90) and changes in the transmural gradient of repolarization, reflected in ΔAPD90. NS1643 and nicorandil reduced epicardial APD90 from 68.3 ± 1.1 to 56.5 ± 4.1 and 51.5 ± 1.5 ms, respectively, but preserved endocardial APD90 in hypokalaemic hearts. NS1643 and nicorandil thus restored ΔAPD90 from −9.6 ± 4.3 ms under baseline hypokalaemic conditions to 3.9 ± 4.1 and 9.9 ± 2.1 ms, respectively, close to normokalaemic values.

Conclusion:  These findings demonstrate, for the first time, the anti‐arrhythmic efficacy of K+ channel activation in the setting of hypokalaemia. NS1643 and nicorandil are anti‐arrhythmic through the suppression of EADs, reductions in APD90 and restorations of ΔAPD90.
Opting out or Pushed off the Edge? The Glass Cliff and the Precariousness of Women's Leadership Positions
Authors: Ryan Michelle K. , Haslam S. Alexander , Hersby Mette D. , Kulich Clara , Atkins Cate
Published: October 2007

The glass cliff refers to the phenomenon whereby women are overrepresented in leadership roles associated with high risk and an increased chance of failure. Research into the glass cliff has focused on documenting the existence of the phenomenon and understanding the psychological processes that contribute to the appointment of women to precarious positions. This paper summarises this research and extends it by examining the implications that glass cliff positions have, both for the women who occupy them and for the organisations in which they exist. The gender‐stress‐disidentification model suggests that glass cliff positions are inherently stressful, and lead women to experience a reduced sense of organisational identification. This, in turn, has important implications for organisations in terms of reduced commitment and increased turnover. Taken together, the research presented here offers an alternative analysis of women's increasing disaffection with the workplace, which takes into account gender differences in workplace experience.
On the Emergence of Human Goal Pursuit: The Nonconscious Regulation and Motivation of Goals
Authors: Aarts Henk
Published: October 2007

Experimental research in social psychology has discovered that human goal pursuit can emerge in the absence of conscious awareness. Whereas these goal‐priming effects are commonly explained in terms of habitual automatic processes, recent studies shed new light on the matter. Building on this recent work, this paper attempts to promote a more comprehensive understanding and examination of the potential mechanisms that enable people to pursue their goals in a nonconscious fashion. Specifically, it addresses (i) the human capacity to pursue goals without awareness of the activation and operation of the goal, even when habits are inadequate; and (ii) the fundamental role of positive affect in nonconsciously modulating the motivation of goals and their pursuit.
How Can People Be Induced to Willingly Change Their Behavior? The Path from Persuasive Communication to Binding Communication
Authors: Joule Robert‐Vincent , Girandola Fabien , Bernard Françoise
Published: October 2007

How can people be induced to willingly change their behavior? The present article has three main objectives. Its first purpose is to review some of the procedures pertaining to the ‘free will’ compliance paradigm. These procedures increase the likelihood that others will freely comply to one's requests (low‐ball, teasing, foot‐in‐the door, touch, and ‘you are free to’ procedures). The second objective is to introduce a theory stemming from social psychology, namely, the theory of commitment. Finally, we wish to describe the binding communication approach that can be situated at the intersection of research conducted in both the fields of communication, more specifically in the domain of persuasive communication, and the fields of commitment and free will compliance. A project carried out to encourage school children to behave in a more environmentally friendly way will be described to illustrate the approach.
New Frontiers for the Five‐Factor Model: A Preview of the Literature
Authors: McCrae Robert R. , Sutin Angelina R.
Published: October 2007

The Five‐Factor Model (FFM) of personality traits has been widely adopted and applied to a diverse set of issues in psychology and related disciplines. In this article, we identify a number of unresolved questions and propose new directions for research using the FFM. In clinical psychology, research is needed on the optimal ways to utilize personality assessments in psychotherapy. Acculturation studies are crucial for an understanding of the origins of national differences in trait levels. The large literatures on personality and on the self should be better integrated, adding a process perspective to trait psychology. Personality psychology should begin to transcend the individual, examining the consequences of aggregate personality traits in dyads, organizations, and nations. Applications of the FFM appear to be limited only by the creativity and industry of researchers.
The case for mindfulness‐based approaches in the cultivation of empathy: Does nonjudgmental, present‐moment awareness increase capacity for perspective‐taking and empathic concern?
Authors: Block‐Lerner Jennifer , Adair Carrie , Plumb Jennifer C. , Rhatigan Deborah L. , Orsillo Susan M.
Published: October 2007

Empathic responding, most notably perspective‐taking and empathic concern, has important implications for interpersonal functioning. While empathy training approaches have received some support for a variety of populations, few extant interventions have targeted empathic responding in couples. Mindfulness‐ and acceptance‐based behavioral approaches, for couples as a unit and/or for individual family members/partners, are proposed as an adjunct to empathy training interventions. Preliminary findings suggest that the viability of these interventions for increasing empathic responding should be further investigated, and specific suggestions for this line of research are offered.
The Development of Core Competencies for the Practice of Marriage and Family Therapy
Authors: Nelson Thorana S. , Chenail Ronald J. , Alexander James F. , Crane D. Russell , Johnson Susan M. , Schwallie Linda
Published: October 2007

In response to a series of national policy reports regarding what has been termed the “quality chasm” in health and mental health care in the United States, in January 2003, the American Association for Marriage and Family Therapy convened a task force to develop core competencies (CC) for the practice of marriage and family therapy (MFT). The task force also was responding to a call for outcome‐based education and for the need to answer questions about what marriage and family therapists do. Development of the CC moves the field of MFT into a leading‐edge position in mental health. This article describes the development of the CC, outcomes of the development process for the competencies, and recommendations for their continued development and implementation.
Immune response and tolerance during chronic hepatitis B virus infection
Authors: Bertoletti Antonio , Gehring Adam
Published: October 2007

The hepatitis B virus (HBV) is a hepatotropic non‐cytopathic DNA virus that despite the presence of an effective prophylactic vaccine is estimated to infect 300 million people, with a particularly high prevalence in Asia and Africa. It causes liver diseases that vary greatly in severity from person to person. Some subjects control infection efficiently and clear the virus from the bloodstream either without clinically evident liver disease or with an acute inflammation of the liver (acute hepatitis) that can resolve without long‐term clinical sequelae. Other patients fail to clear the virus and develop chronic infection. Most chronically infected patients remain asymptomatic without life‐threatening liver disease but 10–30% develop liver cirrhosis with possible progression to liver cancer. Outcome of infection and the pathogenesis of liver disease are determined by virus and host factors, which have been difficult tofully elucidate because the host range of HBV is limited to man and chimpanzees. However, the study of animal models of related Hepadnavirus infections and transgenic mouse able to express individual HBV genes or replicate the entire viral genome have clarified several aspects connected to HBV infection. Furthermore, the ability to analyze many immunological phenomena ex vivo through direct quantification of Ag‐specific T cells in humans and chimps has considerably increased our knowledge of HBV pathogenesis. Here, we will discuss the distinctions of HBV adaptive immunity between resolved and persistently infected patients and the host/viral factors that can cause and maintain them.
Autoimmunity and HIV/simian immunodeficiency virus infection: A two edged sword
Authors: Ansari Aftab A. , Pattanapanyasat Kovit , Pereira Lara E.
Published: October 2007

The purpose of this review is to provide an overview of the spectrum of autoimmune responses that we have so far characterized in the simian immunodeficiency virus (SIV)‐infected disease susceptible rhesus macaques, the potential role of the lymphopenic state for the generation of the autoimmune response and the important new finding that such autoimmune response in fact can serve to provide both clinical benefit and clinical disease depending on the stage of the disease and the nature of the host proteins that are recognized during this process.
Novel interaction of bile acid and neural signaling in the regulation of cholangiocyte function
Authors: Fava Giammarco , Marzioni Marco , Francis Heather , Glaser Shannon , DeMorrrow Sharon , Ueno Yoshiyuki , Benedetti Antonio , Alpini Gianfranco
Published: October 2007

Cholangiocytes, the epithelial cells that line the intrahepatic biliary tree, are the target of cholangiopathies, a wide array of chronic disorders that are characterized by the progressive vanishing of bile ducts, leading to ductopenia and liver failure. The loss of bile ducts is a consequence of cholangiocyte death by apoptosis and impaired proliferative response of these cells to injury. The factors that regulate cholangiocyte proliferation and survival are poorly understood. In this regard, a major role is played by the interaction between bile acids and the autonomic nervous system. It has been shown that adrenergic and cholinergic denervation of the liver results in the induction of cell death and impaired proliferative responses of the biliary epithelium to cholestasis. In addition,bile acids have been shown to enter cholangiocytes through the apical, Na+‐dependent bile acid transporter, ASBT, which has a marked impact on cholangiocyte pathobiology. Recent evidence shows that bile acids and autonomic innervation interact in modulating cholangiocyte response to liver injury. In this review, we describe the recent advances in understanding the molecular mechanisms by which such events occur.
Characteristics of primary sclerosing cholangitis in the USA
Authors: Lindor Keith D.
Published: October 2007

Primary sclerosing cholangitis (PSC) is a chronic cholestatic liver disease of unknown etiology that is frequently associated with inflammatory bowel disease. It is characterized by diffuse inflammation and fibrosis of the biliary tree, and it usually leads to biliary cirrhosis and portal hypertension. PSC is most commonly diagnosed with endoscopic retrograde cholangiopancreatography, although magnetic resonance cholangiography (MRC) is rapidly emerging as a first choicediagnostic test. MRC has the advantage of being non‐invasive, does not require radiation, and is cost‐effective in that it does not carry the risk of pancreatitis associated with retrograde studies.2 Percutaneous cholangiography is seldom performed anymore.
Fibrate for treatment of primary biliary cirrhosis
Authors: Iwasaki Shinji , Akisawa Naoaki , Saibara Toshiji , Onishi Saburo
Published: October 2007

Recent studies of the effectiveness of ursodeoxycholic acid (UDCA) therapy in patients with primary biliary cirrhosis (PBC) reported that UDCA therapy did not necessarily stop the progression of liver fibrosis in all patients, even those with early stage PBC. Thus, there is a need for more effective treatments that could prevent asymptomatic PBC from progressing to the icteric stage. Bezafibrate is effective in approximately two‐thirds of non‐icteric patients who have not shown a complete response to UDCA. Serum bilirubin, aspartate aminotransferase and γ‐guanosine 5′‐triphosphate levelswere significantly lower in patients who responded to additional bezafibrate on univariate analysis. The putative mechanism by which bezafibrate acts in cholestasis is by increasing phospholipid output into bile, which forms micelles with the hydrophobic bile acid that reduces its toxicity.
Bioinformatic approach for cholangiocyte pathophysiology
Authors: Ueno Yoshiyuki , Fukushima Koji , Nakagome Yu , Kido Osamu , Shimosegawa Tooru
Published: October 2007

The heterogeneous functions of cholangiocytes regulate the physiology of the biliary epithelium regarding secretory, proliferative and apoptotic activities. However, due to their technical difficulties for isolation and culture, the pathophysiology of cholangiocytes was poorly understood. Recently, cutting‐edge technology, such as the microarray, has given the opportunity for investigating cholangiocytes. We have found the distinct expression profiles of two murine cholangiocytes lines, termed small and large, revealed by microarray analysis. The features of the two cholangiocyte cell lines, categorized partly according to gene ontology, indicate the specific physiological role of each cell line. Namely, large cholangiocytes are characterized as “transport” and “immune/inflammatory responses”. In contrast to large, small cholangiocytes are associated with properties of limited physiological functional ability and proliferating/migratingpotential with specific molecules like Eph receptors, comparable to mesenchymal cells. Further analysis using other modern technology, such as proteomics, will provide more information to understand the pathophysiology of cholangiocytes. These novel methods enable us to investigate the key molecules and their mutual relationship. Although the evaluation of some important biological regulatory processes like protein modification requires methodologies other than microarray, microarray technology is anticipated to grow with the development of data‐analysis theory for the comprehension of cellular cross‐talk in the liver.
Autoreactive CD8‐specific T‐cell response in primary biliary cirrhosis
Authors: Kita Hiroto
Published: October 2007

Primary biliary cirrhosis (PBC) is an autoimmune liver disease of unknown etiology. Autoimmune attack in PBC is predominantly organ‐specific, despite the presence of mitochondrial autoantigens, the major targets of autoimmunity in PBC, in all nucleated cells. Cytotoxic T lymphocytes are thought to be directly involved in the tissue injury in PBC. The major histocompatibility complex (MHC) class I‐restricted epitope for E2 components of pyruvate dehydrogenase complexes, namely amino acid 159–167, a region very close to the epitoperecognized by MHC class II‐restricted CD4 cells and by antibody, has been characterized. In addition, there was a 10‐fold increase in the frequency of autoreactive cytotoxic T lymphocytes in the liver as compared to the blood in PBC patients using tetramer technology.
Current topics relating to autoimmune hepatitis diagnosis and therapy
Authors: Takahashi Hiroki
Published: October 2007

Autoimmune hepatitis (AIH) was first reported by Professor Ian R. Mackay. Environmental factors (such as viral infection), chemical substances (including some drugs) and genetic factors (such as human leukocyte antigen‐DR) are believed to participate in the pathogenesis of AIH. Because satisfactory prognosis depends upon the patient being diagnosed with AIH correctly and receiving proper therapy immediately, it isvery important to make a correct diagnosis and perform the suitable therapy as soon as possible. In this review, current topics relating to AIH diagnosis and therapy are summarized.
Genetic background of primary biliary cirrhosis
Authors: Tanaka Atsushi
Published: October 2007

The clustering of patients in a representative family as well as relatively high concordance rate in monozygotic twins strongly indicate that genetic factors play a crucial role in modulating primary biliary cirrhosis (PBC) by conferring susceptibility to, or providing protection from, the disease. Therefore, much like other autoimmune diseases, intensive investigations have attempted to elucidate which genes are incriminated in the etiology of PBC. So far, a number of genes, including major histocompatibility complex (MHC) class I and II, cytokines and cell surface molecules, have been examined to seek the possibility of whether single nucleotide polymorphisms (SNP) of the gene might be associated with susceptibility to PBC. Nevertheless, it appears that methodologicaldifficulties, mainly the limitation of the number of individuals tested in each study, hamper the detection of a convincing and reproducible link between genetic polymorphisms and the etiology of PBC. Also, the difference in genetic background among several ethnic groups may play a role in concealing the association. In this review, I will highlight the genetic association in PBC, and review the association of genetic polymorphisms with the etiology of PBC, which have been reported in various ethnicities.
Pathology and immunopathology of immunoglobulin G4‐related sclerosing cholangitis: The latest addition to the sclerosing cholangitis family
Authors: Nakanuma Yasuni , Zen Yoh
Published: October 2007

Sclerosing cholangitis is heterogeneous in its etiopathogenesis. Recently, sclerosing cholangitis showing abundant immunoglobulin (Ig)G4+ plasma cell infiltration was added to the sclerosing cholangitis group. This form was frequently associated with sclerosing pancreatitis (autoimmune pancreatitis) and also occasionally with other diseases such as chronic sclerosing sialadenitis, all of which falls within IgG4‐related sclerosing disease. Herein, this new member, called IgG4‐related sclerosing cholangitis (IgG4‐SC), is reviewed. IgG4‐SC shows grossly medullary and fleshy lesions along the biliary tree, and histologically marked lymphoplasmacytic infiltration with extensive fibrosis, and obliterative phlebitis, sharing histopathological features with sclerosing pancreatitis. Peribiliary glands are also severely affected. Interestingly, hepatic inflammatory pseudotumor (HIP) is not infrequently associated with IgG4‐SC, and is thought as a local exaggeration of IgG4‐SC. Immunohistochemically, many IgG4+ plasma cells and CD4+/CD25+ regulatory T cells are found around the affected bile ducts and portal tracts. Incontrast, these cells are scarce in the affected bile ducts of primary sclerosing cholangitis (PSC), a prototype of sclerosing cholangitis. Biliary lining epithelia are relatively spared in IgG4‐SC in comparison with those of PSC showing degeneration and ulceration. In some cases of IgG4‐SC, IgG4+ plasma cells are also found considerably in small portal tracts, so needle liver biopsy is useful for the diagnosis of IgG4‐SC. Therapeutically, IgG4‐SC responds well to steroid therapy, while such character is not reported in PSC. Taken together, IgG4‐SC may be etiologically different from PSC, and immunopathological processes relating to IgG4 and regulatory T cells may be involved in the pathogenesis of IgG4‐SC. Further studies are needed to clarify the etiopathogenesis of IgG4‐SC and its related disorders.
Histological recurrence of autoimmune liver diseases after living‐donor liver transplantation
Authors: Haga Hironori , Miyagawa‐Hayashino Aya , Taira Kaoru , Morioka Daisuke , Egawa Hiroto , Takada Yasutsugu , Manabe Toshiaki , Uemoto Shinji
Published: October 2007

Background:  The effects of living donor liver transplantation (LDLT) on the recurrence of autoimmune liver diseases have not been well documented. Genetic similarities may be beneficial to avoid severe rejection but may facilitate the recurrence of autoimmune diseases. Because familial occurrence of autoimmune liver diseases has been documented, there is a possibility that candidates for living‐related donors may have the same disease as that of the recipients.

Method:  Between November 1994 and June 2004, 50 patients with primary biliary cirrhosis (PBC) (16‐non‐blood‐relative donors and 34 blood‐relative donors), and 28 patients with primary sclerosing cholangitis (PSC) underwent LDLT in Kyoto University Hospital.

Results:  Among 35 patients with PBC who survived more than 1 year, 10 patients (29%) showed recurrent PBC, and nine of 10 patients with recurrent PBC (90%) were associated with blood‐relative donors (mean follow‐up period, 30 months; range, 2–68). Two recipients had donors with some clinical or histological characteristics of PBC, and their grafts developedrecurrent PBC. Cirrhosis or graft failure was not observed in any patients with recurrent PBC. For PSC patients who survived more than 1 year after LDLT, 13 of 22 (59%) showed PSC‐compatible histology and radiological findings (mean follow‐up period, 31 months; range, 22–71), and five died or underwent retransplantation. Human leukocyte antigen‐DR15 was positively associated with susceptibility to PSC with ulcerative colitis. One donor was revealed to have retroperitoneal fibrosis without evidence of sclerosing cholangitis.

Conclusions:  Blood‐relative donors may be associated with susceptibility to recurrent autoimmune diseases. Recurrence of PSC, but not PBC, adversely affected the outcome of LDLT. Caution should be taken as blood‐relative donors can be at risk of autoimmune liver diseases.
Recurrence of primary biliary cirrhosis and primary sclerosing cholangitis after liver transplantation in Japan
Authors: Yamagiwa Satoshi , Ichida Takafumi
Published: October 2007

Although there was some initial controversy, there is now a consensus that primary biliary cirrhosis (PBC) does indeed recur in both cadaveric and living donated allografts. Recurrence rate after deceased donor liver transplantation (LT) was reported to be 10.9–23% at 5 years. In the present study, we reviewed 221 PBC patients who underwent living‐donor liver transplantation (LDLT) in Japan. The 5‐year overall survival rate was 79%, and the rate of recurrence based on histological findings was 10% (7/70) after a median time of 36 months. Primary immunosuppression, withdrawal of corticosteroids and human leukocyte antigen matches were not associated with the recurrence. Recurrent PBC appears to have little impact on graft function and survival, but this may become a greater problem with longer follow up.

It is noteworthy that the 10‐year survival of primary sclerosing cholangitis (PSC) patients who underwent LDLT wasfound to be only 39.1% in Japan, whereas that of PBC was 72.9%. Factors associated with the poor prognosis include biliary strictures, hepatobiliary and colorectal malignancies, and recurrence of PSC. In our study, we reviewed 66 patients with PSC who underwent LDLT in Japan. The 5‐year survival rate was 72%, and the rate of recurrence diagnosed on histological and cholangiographic findings was 25% (11/44). Well‐defined diagnostic criteria and longer studies are required to characterize the nature of recurrent PSC and its impact on graft survival in more detail.
De novo autoimmune hepatitis after liver transplantation
Authors: Lohse Ansgar W. , Weiler‐Norman Christina , Burdelski Martin
Published: October 2007

The Kings College group was the first to describe a clinical syndrome similar to autoimmune hepatitis in children and young adults transplanted for non‐immune mediated liver diseases. They coined the term “de novo autoimmune hepatitis”. Several other liver transplant centres confirmed this observation. Even though the condition is uncommon, patients with de novo AIH are now seen in most of the major transplant centres.

The disease is usually characterized by features of acute hepatitis in otherwise stable transplant recipients. The most characteristic laboratory hallmark is a marked hypergammaglobulinaemia. Autoantibodies are common, mostly ANA. We described also a case of LKM1‐positivity in a patients transplanted for Wilson's disease, however this patients did not develop clinical or histological features of AIH. Development of SLA/LP‐autoantibodies is also not described. Therefore, serologically de novo AIH appears to correspond to type 1 AIH. Like classical AIH patients respond promptly to treatment with increased doses of prednisolone and azathioprine, while the calcineurin inhibitors cyclosporine or tacrolimus areof very limited value – which is not surprising, as almost all patients develop de novo AIH while receiving these drugs. Despite the good response to treatment, most patients remain a clinical challenge as complete stable remissions are uncommon and flares, relapses and chronic disease activity can often occur.

Pathogenetically this syndrome is intriguing. It is not clear, if the immune response is directed against allo‐antigens, neo‐antigens in the liver, or self‐antigens, possibly shared by donor and host cells. It is very likely that the inflammatory milieu due to alloreactive cells in the transplanted organ contribute to the disease process. Either leading to aberrant antigen presentation, or providing co‐stimulatory signals leading to the breaking of self‐tolerance. The development of this disease in the presence of treatment with calcineurin inhibitors supports the view held by most specialists in autoimmune hepatitis that these drugs, even though effective in acute disease, are not helpful in the long‐term management of autoimmune liver diseases.
Visual Awareness of Properties
Authors: KENNEDY MATTHEW J.
Published: October 2007

I defend a view of the structure of visual property‐awareness by considering the phenomenon of perceptual constancy. I argue that visual property‐awareness is a three‐place relation between a subject, a property, and a manner of presentation. Manners of presentation mediate our visual awareness of properties without being objects of visual awareness themselves. I provide criteria of identity for manners of presentation, and I argue that our ignorance of their intrinsic nature does not compromise the viability of a theory that employs them. In closing, I argue that the proposed manners of presentation are consistent with key direct‐realist claims about the structure of visual awareness.
Desires as Reasons1
Authors: SHEMMER YONATAN
Published: October 2007

Humeans believe that at least some of our desires give us reasons for action. This view is widely accepted by social scientists and has some following among philosophers. In recent years important objections were raised against this position by Scanlon, Dancy, and others. The foundations of the Humean view have never been properly defended.

In the first part of the paper I discuss some objections to the Humean position. In the second part I attempt to provide an argument for the claim that the Humean view gives us a plausible, even if not exclusive, understanding of our notion of reasons. The particular version of the Humean view I set out to defend is that only desires that the agent is not alienated from, and that are not impulses, are reason giving.
Knowing the Answer
Authors: SCHAFFER JONATHAN
Published: October 2007

“ev’ry gambler knows that the secret to survivin’ is knowin’ what to throw away and knowing what to keep.” (Kenny Rogers)

How should one understand knowledge‐whascriptions? That is, how should one understand claims such as “I know where the car is parked,” which feature an interrogative complement? The received view is that knowledge‐whreduces to knowledge thatp, wherephappens to be the answer to the questionQdenoted by thewh‐clause. I will argue that knowledge‐whincludes the question—to know‐whis to know thatp,as the answer to Q. I will then argue that knowledge‐thatincludes a contextually implicit question. I will conclude thatknowledge is a question‐relative state. Knowing is knowing the answer, and whether one knows the answer depends (in part) on the question.