bluuebunny/crossref_metadata_2025 huggingface dataset:
Workflows in bioinformatics: meta-analysis and prototype implementation of a workflow generator
Authors: Garcia Castro Alexander , Thoraval Samuel , Garcia Leyla J , Ragan Mark A
Published: April 2005

Background

Computational methods for problem solving need to interleave information access and algorithm execution in a problem-specific workflow. The structures of these workflows are defined by a scaffold of syntactic, semantic and algebraic objects capable of representing them. Despite the proliferation of GUIs (Graphic User Interfaces) in bioinformatics, only some of them provide workflow capabilities; surprisingly, no meta-analysis of workflow operators and components in bioinformatics has been reported.

Results

We present a set of syntactic components and algebraic operators capable of representing analytical workflows in bioinformatics. Iteration, recursion, the use of conditional statements, and management of suspend/resume tasks have traditionally been implemented on an ad hoc basis and hard-coded; by having these operators properly defined it is possible to use and parameterize them as generic re-usable components. To illustrate how these operations can be orchestrated, we present GPIPE, a prototype graphic pipeline generator for PISE that allows the definition of a pipeline, parameterization of its component methods, and storage of metadata in XML formats. This implementation goes beyond the macro capacities currently in PISE. As the entire analysis protocol is defined in XML, a complete bioinformatic experiment (linked sets of methods, parameters and results) can be reproduced or shared among users. Availability:http://if-web1.imb.uq.edu.au/Pise/5.a/gpipe.html (interactive), ftp://ftp.pasteur.fr/pub/GenSoft/unix/misc/Pise/ (download).

Conclusion

From our meta-analysis we have identified syntactic structures and algebraic operators common to many workflows in bioinformatics. The workflow components and algebraic operators can be assimilated into re-usable software components. GPIPE, a prototype implementation of this framework, provides a GUI builder to facilitate the generation of workflows and integration of heterogeneous analytical tools.
Focusing in bioproduction science
Authors: Villaverde Antonio
Published: April 2005

As in other Biotechnological fields, the microbial production of recombinant proteins and other biomolecules can be approached from multiple angles through the help of diverse technologies of increasing complexity. To better reach all the specialized niches in bioproduction, Microbial Cell Factories is now inviting authors to prepare concise Reviews (eventually miniReviews), covering relevant areas that deserve specific and highly focused attention. By the publication of such contributions, the journal will promote the revision of new insights around the Cell Factory concept in a highly comprehensive way, in molecular, cellular and environmental contexts.
Vertical distribution of zooplankton: density dependence and evidence for an ideal free distribution with costs
Authors: Lampert Winfried
Published: April 2005

Background

In lakes with a deep-water algal maximum, herbivorous zooplankton are faced with a trade-off between high temperature but low food availability in the surface layers and low temperature but sufficient food in deep layers. It has been suggested that zooplankton (Daphnia) faced with this trade-off distribute vertically according to an "Ideal Free Distribution (IFD) with Costs". An experiment has been designed to test the density (competition) dependence of the vertical distribution as this is a basic assumption of IFD theory.

Results

Experiments were performed in large, indoor mesocosms (Plankton Towers) with a temperature gradient of 10°C and a deep-water algal maximum established below the thermocline. As expected, Daphnia aggregated at the interface between the two different habitats when their density was low. The distribution spread asymmetrically towards the algal maximum when the density increased until 80 % of the population dwelled in the cool, food-rich layers at high densities. Small individuals stayed higher in the water column than large ones, which conformed with the model for unequal competitors.

Conclusion

The Daphnia distribution mimics the predictions of an IFD with costs model. This concept is useful for the analysis of zooplankton distributions under a large suite of environmental conditions shaping habitat suitability. Fish predation causing diel vertical migrations can be incorporated as additional costs. This is important as the vertical location of grazing zooplankton in a lake affects phytoplankton production and species composition, i.e. ecosystem function.
Why is Violence More Common Where Inequality is Greater?
Authors: WILKINSON RICHARD
Published: April 2005

Abstract:The most well‐established environmental determinant of levels of violence is the scale of income differences between rich and poor. More unequal societies tend to be more violent. If this is a relation between institutional violence and personal violence, how does it work and why is most of the violence a matter of the poor attacking the poor rather than the rich? This paper begins by showing that the tendency for rates of violent crime and homicide to be higher where there is more inequality is part of a more general tendency for the quality of social relations to be poorer in more hierarchical societies. Research on the social determinants of health is used to explore these relationships. It is a powerful source of insights because health is also harmed by greater inequality. Because epidemiological research has gone some way towards identifying the nature of our sensitivity to the social environment and to social status differentials in particular, it provides important insights into why violence is related to inequality. The picture that emerges substantiates and explains the common intuition that inequality is socially corrosive. With an evolutionary slant, and informed by work on ranking systems in non‐human primates, this paper focuses on the sharp distinction between competitive social strategies appropriate to dominance hierarchies and the more affiliative social strategies associated with more egalitarian social structures. The implications for policy seem to echo the importance to the quality of life of the three inter‐related dimensions of the social environment expressed in the demand for “liberty, equality, fraternity.”
Social Stratification, Health, and Violence in the Very Young
Authors: BOYCE W THOMAS
Published: April 2005

Abstract: Inequalities in human social groups contribute in important ways to the initiation and perpetuation of violence. Because both social inequalities and interpersonal aggression emerge in early life, it is important to study their developmental origins in the collective and individual behavior of young children. As young as 2 years of age, children assemble stable, linearly transitive dominance hierarchies when brought together in novel social groups. Just as the consequences of socioeconomic status may be due in part to experiences of social ordering per se, subjective childhood experiences of occupying a lesser or greater position on a scale of social influence may similarly affect health, safety, and behavior in early development. Children's experiences with social ordering may represent a first, formative encounter with the hierarchical social relations that affect health and susceptibility to violence over the human lifespan. We have studied the health correlates of group stressors, dominance positions, and biobehavioral reactivity within cohorts of preschool children and semi free‐ranging rhesus macaques. Social position is ascertained using naturalistic observations of critical dyadic events, and stress‐reactivity is measured using assessments of behavioral and biological responses to standardized challenges. Outcome measures, including indicators of mental and physical health and interpersonal injuries, have been assessed—in the case of children—with parent‐ and teacher‐report questionnaires, child self‐report protocols, and frequent, objective physical examinations of the child and—in the case of rhesus monkeys—with daily observations of violence‐related injuries. Results to date have suggested the following provisional conclusions: (1) Children and monkeys form stable, linearly transitive social hierarchies in which identifiable subgroups of individuals occupy dominant and subordinate social positions. (2) Individuals occupying subordinate positions within the social group show exaggerated adrenocortical and/or autonomic reactivity to challenge and disproportionate rates of chronic medical conditions or violent injuries. (3) Stress‐reactivity, naturally occurring stressors, and social position are interactively predictive of rates of morbidity. Monkeys who displayed high biobehavioral reactivity sustained disproportionate numbers of violent injuries during a confinement stressor. Children who were high in the dominance hierarchy and low in reactivity showed significantly higher rates of externalizing mental health symptoms, while those who were in subordinate social positions and high in reactivity showed higher prevalences of internalizing symptoms. In conclusion, the prevention of youth violence—and other forms of early disorder—will require a deeper, developmental understanding of the “headwaters” of aggression and victimization in early childhood and a stronger accounting of how early social inequalities set trajectories toward healthy or disordered behavior.
The Discrete Character of High‐Lethality Youth Violence
Authors: ZIMRING FRANKLIN E.
Published: April 2005

Abstract:The purpose of this paper is to derive lessons about high‐lethality adolescent violence from study of the extraordinary increase, and then decrease, in youth homicide arrests over the period 1985–2001 in the United States. This effort continues a long tradition of exploring the possible causes of shifts in homicide rates by examining patterns of violence to see whether there are important changes in types of violence. The first section of the paper discusses two dimensions of criminal youth violence over the whole range of reported offenses. The second section shows that one subset of attacks—firearms cases—accounts for the major changes in youth homicide when it increased from 1985–1993 and during the years of decrease, 1994–2001. A third section explores the linkage between rates of adolescent homicide in various cultures and the relative rate of homicide among all ages. My central conclusion is that high‐lethality violence among youth is not representative of the fighting and group assaults that are relatively frequent among adolescents. Instead, the attacks that often lead to death differ with respect to the use of weapons and, to some extent, geography. But there is usually a strong relationship between homicide rates for all ages and youth homicide rates in a particular location.
Epigenetic Programming of Stress Responses through Variations in Maternal Care
Authors: FISH ERIC W. , SHAHROKH DARA , BAGOT ROSE , CALDJI CHRISTIAN , BREDY TIMOTHY , SZYF MOSHE , MEANEY MICHAEL J.
Published: April 2005

Abstract:Early life experiences shape an individual's physical and mental health across the lifespan. Not surprisingly, an upbringing that is associated with adversity can produce detrimental effects on health. A central theme that arises from studies in human and nonhuman species is that the effects of adversity are mediated by the interactions between a mother and her young. In this review we describe some of the long‐term effects of maternal care on the offspring and we focus on the impact of naturally occurring variations in the behavior of female rats. Of particular interest are mothers that engage in high or low amounts of licking/grooming (LG) and arched‐back nursing (ABN) of their pups, but do so within the normal range for this species. Such variations in LG‐ABN can alter the function of the hypothalamic‐pituitary‐adrenal (HPA) axis, and cognitive and emotional development by directly affecting the underlying neural mechanisms. At the heart of these mechanisms is gene expression. By studying the hippocampal glucocorticoid receptor gene, we have identified that maternal care regulates its expression by changing two processes: the acetylation of histones H3‐K9, and the methylation of the NGFI‐A consensus sequence on the exon 17promoter. Sustained “maternal effects” appear elsewhere in biology, including plants, insects, and lizards, and may have evolved to program advantages in the environments that the offspring will likely face as adults. Given the importance of early life and parent‐child interactions to later behavior, prevention and intervention programs should target this critical phase of development.
Cost‐Effective Violence Prevention through Targeted Family Interventions
Authors: GREENWOOD PETER W.
Published: April 2005

Abstract: Efforts in violence prevention can focus on individual youth, their families, their schools, or the communities in which they live. Among the small number of program models that have been proven effective in repeated replications, those that focus on improving family management and child care have been found to be the most cost‐effective. The four model programs include Nurse Home Visitation, Functional Family Therapy, Multi‐systemic Therapy, and Multidimensional Foster Care. All of these programs involve detailed protocols, extensive staff training and supervision, and quality‐assurance procedures. The factors limiting their wider adoption include staff resistance to their structured approach, cost‐sharing issues between local and state levels of government, and the political power of existing programs.
The Role of the Bystander in the Social Architecture of Bullying and Violence in Schools and Communities
Authors: TWEMLOW STUART W. , FONAGY PETER , SACCO FRANK C.
Published: April 2005

Abstract: The bystander is defined as an active and involved participant in the social architecture of school violence, rather than a passive witness. Bullying is redefined from a triadic (bully‐victim‐bystander) rather than dyadic (bully‐victim) perspective. Teachers, including administrators, and students can promote or ameliorate bullying and other forms of violence when in this social role. Cases are used to illustrate this phenomenon, including one in which a teacher is murdered. Data are presented from a study of teachers' perceptions of other teachers who bully students, suggesting that bullying of students by teachers and bullying of teachers by students is a factor in the aggravation of school bullying and violence that needs to be more openly discussed. An intervention in nine elementary schools involving 3,600 students is outlined to illustrate how a focus on reflective mentalizing and awareness of the importance of the helpful bystander role can promote a peaceful school‐learning environment for students and teachers. The paper concludes with an outline for research into how communities and schools adopt bystanding roles when faced with complex problems like youth violence, and how they may avoid facing the problems by blaming law enforcement and educators.
On the Nature and Nurture of Antisocial Behavior and Violence
Authors: VIDING ESSI
Published: April 2005

Abstract: This article focuses on the contribution that behavioral genetic research can make to further the understanding of how antisocial and violent behavior develops. Genetically informative study designs are particularly useful for investigating etiological heterogeneity and can refine the search for developmental pathways to persistent antisocial conduct. While the current data are not yet directly translatable for prevention programs, behavioral genetic research will have far‐reaching implications for prevention and treatment. As we find genes associated with risk for antisocial behavior and develop better understanding of the mechanics of the interplay between genes and the environment, we can expect to tailor prevention and treatment to serve the specific needs of etiologically distinct subgroups of children. Furthermore, researchers involved in sharpening the knowledge base have the responsibility of trying to ensure that such findings are not misused.
Role of Alcohol Consumption in Escalation to Violence
Authors: MICZEK KLAUS A. , FISH ERIC W. , De ALMEIDA ROSA M. M. , FACCIDOMO SARA , DEBOLD JOSEPH F.
Published: April 2005

Abstract:No other drug has been associated with aggressive and violent behavior more than alcohol has. A major characteristic of the link between alcohol and social interactions is the very large variation in who becomes more aggressive while drinking and who does not. Tracing the origins of these individual differences has led to a focus on predispositions, such as the antisocial behavior of Type 2 alcoholics. Successful development of an experimental procedure to model heightened aggressive behavior after voluntary consumption of alcohol has facilitated the neurobiologic analysis of the link between alcohol and aggression. From a pharmacologic perspective, consumption of low to moderate doses of alcohol engenders heightened aggressive behavior in a significant minority of individuals before the circulation of appreciable amounts of the aldehyde metabolite. Ionophoric receptors such as NMDA, 5‐HT3and GABAAhave been identified in the brain as major sites of action for alcohol in the dose range that is relevant for engendering heightened aggression. Actions at the GABAAreceptor complex that depend on particular GABAAsubunits appear to be necessary for alcohol‐heightened aggression. Genes that encode the synthesis of these alpha and gamma subunits are potentially significant markers for those individuals that are prone to engage in heightened aggressive behavior after the consumption of alcohol. Of particular importance are the reciprocal interactions between GABA and serotonin. Activating specific serotonin receptor subtypes such as 5‐HT1Breceptors reduces alcohol‐heightened aggressive behavior. How these GABAergic and serotonergic corticolimbic mechanisms for alcohol‐heightened aggression develop during the adolescent period remains an area of urgent study.
Naive Bidding
Authors: Deltas George , Engelbrecht-Wiggans Richard
Published: April 2005

This paper presents an equilibrium explanation for the persistence of naive bidding. Specifically, we consider a common value auction in which a “naive” bidder (who ignores the winner's curse) competes against a fully rational bidder. We show that the naive bidder earns higher equilibrium profits than the rational bidder when the signal distribution is symmetric and unimodal. We then consider a sequence of such auctions with randomly selected participants from a population of naive and rational bidders, with the proportion of bidder types in the population evolving in response to their relative payoffs in the auctions. We show that the evolutionary equilibrium contains a strictly positive proportion of naive bidders. Finally, we consider more general examples in which a naive bidder matched against a rational bidder does (i) worse than his rational opponent, but (ii) better than a rational bidder matched against another rational bidder. Again, the evolutionary equilibrium contains a strictly positive proportion of naive bidders. The results suggest that overconfident recent entrants in Internet and other low transaction-cost auctions of items that appeal to a mass audience may earn higher payoffs than their experienced competitors and, thus, will not eventually be driven from the market.
A New and Improved Design for Multiobject Iterative Auctions
Authors: Kwasnica Anthony M. , Ledyard John O. , Porter Dave , DeMartini Christine
Published: April 2005

In this paper we present a new improved design for multiobject auctions and report on the results of experimental tests of that design. We merge the better features of two extant but very different auction processes, the Simultaneous Multiple Round (SMR) design used by the FCC to auction the electromagnetic spectrum and the Adaptive User Selection Mechanism (AUSM) of Banks et al. (1989, “Allocating uncertain and unresponsive resources: An experimental approach,” RAND Journal of Economics, Vol. 20, No. 1, pp. 1–25). Then, by adding one crucial new feature, we are able to create a new design, the Resource Allocation Design (RAD) auction process, which performs better than both. Our experiments demonstrate that the RAD auction achieves higher efficiencies, lower bidder losses, higher net revenues, and faster times to completion without increasing the complexity of a bidder's problem.
Iterative Combinatorial Auctions with Bidder-Determined Combinations
Authors: Kwon R. H. , Anandalingam G. , Ungar L. H.
Published: April 2005

In combinatorial auctions, multiple distinct items are sold simultaneously and a bidder may place a single bid on a set (package) of distinct items. The determination of packages for bidding is a nontrivial task, and existing efficient formats require that bidders know the set of packages and/or their valuations. In this paper, we extend an efficient ascending combinatorial auction mechanism to use approximate single-item pricing. The single-item prices in each round are derived from a linear program that is constructed to reflect the current allocation of packages. Introduction of approximate single-item prices allows for endogenous bid determination where bidders can discover packages that were not included in the original bid set. Due to nonconvexities, single-item prices may not exist that are exact marginal values. We show that the use of approximate single-item prices with endogenous bidding always produces allocations that are at least as efficient as those from bidding with a fixed set of packages based on package pricing. A network resource allocation example is given that illustrates the benefits of our endogenous bidding mechanism.
CABOB: A Fast Optimal Algorithm for Winner Determination in Combinatorial Auctions
Authors: Sandholm Tuomas , Suri Subhash , Gilpin Andrew , Levine David
Published: April 2005

Combinatorial auctions where bidders can bid on bundles of items can lead to more economically efficient allocations, but determining the winners is 𝒩𝒫-complete and inapproximable. We present CABOB, a sophisticated optimal search algorithm for the problem. It uses decomposition techniques, upper and lower bounding (also across components), elaborate and dynamically chosen bid-ordering heuristics, and a host of structural observations. CABOB attempts to capture structure in any instance without making assumptions about the instance distribution. Experiments against the fastest prior algorithm, CPLEX 8.0, show that CABOB is often faster, seldom drastically slower, and in many cases drastically faster—especially in cases with structure. CABOB's search runs in linear space and has significantly better anytime performance than CPLEX.

We also uncover interesting aspects of the problem itself. First, problems with short bids, which were hard for the first generation of specialized algorithms, are easy. Second, almost all of the CATS distributions are easy, and the run time is virtually unaffected by the number of goods. Third, we test several random restart strategies, showing that they do not help on this problem—the run-time distribution does not have a heavy tail.
Online Haggling at a Name-Your-Own-Price Retailer: Theory and Application
Authors: Terwiesch Christian , Savin Sergei , Hann Il-Horn
Published: April 2005

We present a formal model of haggling between a name-your-own-price retailer and a set of individual buyers. Rather than posting a price, the retailer waits for potential buyers to submit offers for a given product and then chooses to either accept or reject them. Consumers whose offers have been rejected can invest in additional haggling effort and increment their offers. This pricing model allows the name-your-own-price retailer to engage in price discrimination: As haggling is costly for the potential buyer, customers with a high willingness to haggle will achieve lower transaction prices. However, because haggling is costly, it reduces overall welfare and diminishes the benefits of price discrimination. Our study is motivated by several name-your-own-price retailers that have recently emerged on the Internet. Based on detailed transaction data of a large German name-your-own-price retailer, we present a model of consumer haggling. We then show how this model can be used to improve the decision making of the retailer, who needs to choose a threshold price above which all offers are accepted. Another decision variable for the retailer lies in the user interface design, which allows the retailer to either facilitate or to hinder the haggling of the consumer.
The Landscape of Electronic Market Design
Authors: Anandalingam G. , Day Robert W. , Raghavan S.
Published: April 2005

This paper presents an introductory survey for this special issue of Management Science on electronic markets. We acquaint the reader with some fundamental concepts in the study of electronic market mechanisms, while simultaneously presenting a survey and summary of the essential literature in this area. Along the way, we position each of the papers presented in this special issue within the existing literature, demonstrating the deep impact of these 14 articles on an already broad body of knowledge.
A Method for Staffing Large Call Centers Based on Stochastic Fluid Models
Authors: Harrison J. Michael , Zeevi Assaf
Published: April 2005

We consider a call center model with m input flows and r pools of agents; the m-vector λ of instantaneous arrival rates is allowed to be time dependent and to vary stochastically. Seeking to optimize the trade-off between personnel costs and abandonment penalties, we develop and illustrate a practical method for sizing the r agent pools. Using stochastic fluid models, this method reduces the staffing problem to a multidimensional newsvendor problem, which can be solved numerically by a combination of linear programming and Monte Carlo simulation. Numerical examples are presented, and in all cases the pool sizes derived by means of the proposed method are very close to optimal.
The MSOM Society Student Paper Competition: Extended Abstracts of 2004 Winners
Authors: Levi Retsef , Pál Martin , Roundy Robin O. , Shmoys David B. , Subramanian Ravi , Hu Xinxin , Allon Gad , Caro Felipe , Lutze Holly S.
Published: April 2005

As is our tradition at the journal, we are pleased to publish the extended abstracts from the winners of the 2004 MSOM Student Paper Competition. We do this to celebrate the achievements of these young scholars and provide you with the opportunity to learn about their work in more detail.

The 2004 prize committee was chaired by Professor Phil Kaminsky (University of California, Berkeley). The other committee members were: Naren Agrawal (University of Santa Clara), Hyun-Soo Ahn (University of Michigan), Damian Beil (University of Michigan), Fernando Bernstein (Duke University), Izak Duenyas (University of Michigan), Wedad Elmaghraby (Georgia Institute of Technology), Jeremie Gallien (Massachusetts Institute of Technology), Teck Ho (University of Pennsylvania), Seyed Iravani (Northwestern University), Ananth Iyer (Purdue University), Eric Johnson (Dartmouth College), Roman Kapuscinski (University of Michigan), Pinar Keskinocak (Georgia Institute of Technology), Anton Kleywegt (Georgia Institute of Technology), Özalp Özer (Stanford University), Georgia Perakis (Massachusetts Institute of Technology), Alan Scheller-Wolf (Carnegie Mellon University), Sridhar Seshadri (New York University), Max Shen (University of California, Berkeley), David Simchi-Levi (Massachusetts Institute of Technology), Jay Swaminathan (University of North Carolina), Terry Taylor (Columbia University), Beril Toktay (INSEAD), Scott Webster (Syracuse University), and David Wu (Lehigh University).
In This Issue
Authors: van Ryzin Garrett J.
Published: April 2005

A regular feature of Manufacturing & Service Operations Management, “In This Issue” briefly describes each issue's articles and highlights their contributions.
[18F]fluoro-2-deoxy-d-glucose ([18F]FDG) positron emission tomography imaging of thymic carcinoid tumor presenting with recurrent Cushing’s syndrome
Authors: Markou Athina , Manning Patrick , Kaya Banu , Datta Sam N , Bomanji Jamshed B , Conway Gerard S
Published: April 2005

We report a case of a young woman with Cushing’s syndrome (CS), in whom although endocrine investigations and negative pituitary imaging were suggestive of ectopic ACTH secretion, the results of inferior petrosal sinus (IPS) sampling after coricotropin-releasing hormone (CRH) stimulation were suggestive of pituitary ACTH hypersecretion. 111In-labelled octreotide and high-resolution computer tomography (CT) revealed a lesion possibly responsible for the ACTH source in the thymus. Thymectomy confirmed concomitant ectopic CRH and probable ACTH production by a thymic neuroendocrine carcinoma. After an 8-year remission period the patient developed a clinical and biochemical relapse. A high-resolution computed tomography (CT) scan of the thorax showed a 2-cm nodule in the thymic bed, which was positive on a [18F]fluoro-2-deoxy-d-glucose ([18F]FDG) positron emission tomography (PET) scan. However, a repeated thymectomy did not result in remission. A repeat [18F]FDG PET study showed persistent disease in the thymic bed and also uptake in the adrenals. The patient underwent bilateral adrenalectomy, which resulted in clinical remission. A further [18F]FDG PET scan 8 months later showed no progression of the thymic tumor and confirmed complete excision of the adrenals. This is a rare case of concomitant CRH and ACTH secretion from a thymic carcinoid tumor; the case illustrates the usefulness of functional imaging with [18F]FDG PET in the diagnosis, management and follow-up of neuroendocrine tumors.
Differential effects of all-trans-retinoic acid (RA) on Erk1/2 phosphorylation and cAMP accumulation in normal and malignant human prostate epithelial cells: Erk1/2 inhibition restores RA-induced decrease of cell growth in malignant prostate cells
Authors: Pasquali Daniela , Chieffi Paolo , Deery William J , Nicoletti Gianfranco , Bellastella Antonio , Sinisi Antonio A
Published: April 2005

Objective: All-trans-retinoic acid (RA) regulates cellular growth, differentiation and apoptosis in human prostate by binding to RA receptors. Non-genomic retinoid effects on signal transduction kinases in the cytoplasm are also described in several cells but they are still unknown in prostate cells.

Methods: Using an epithelial cell line derived from normal human prostate (EPN), and normal (NPEC) and malignant (CPEC) epithelial primary cultures of human prostate, we have examined effects of RA on both extracellular signal-regulated kinase 1/2 (Erk1/2) and cAMP accumulation. Then we have verified the effect of the inhibition of Erk1/2 on RA-induced growth arrest and apoptosis in malignant cells.

Results: In NPEC and in EPN treated with RA for up to 24 h, Western blot analyses of Erk1/2 phosphorylation show that RA causes a rapid activation of Erk1/2 within 5 min, which is maintained for 30 min, followed by a return to basal levels. In CPEC, the activated phosphorylation levels persist up to 24 h. While basal cAMP levels are not affected by 30 min treatment with RA in both EPN and NPEC, levels are increased in CPEC. Forskolin-induced cAMP levels are decreased by RA in all cell types. CPEC were incubated for up to 96 h with RA with and without the inhibitor of Erk1/2, UO126. CPEC incubated with RA and UO126 for 72 h showed a significant arrest of cell growth and after 96 h apoptosis in 11% of cells.

Conclusions: We show rapid effects of RA on cytoplasmic messenger pathways in human prostate, and that responses can differ between normal and malignant cells. The inhibition of these pathways could improve the efficiency of RA in prostate cancer growth control.
Norethisterone enanthate has neither a direct effect on the testis nor on the epididymis: a study in adult male cynomolgus monkeys (Macaca fascicularis)
Authors: Junaidi Aris , Luetjens C Marc , Wistuba Joachim , Kamischke Axel , Yeung Ching-Hei , Simoni Manuela , Nieschlag Eberhard
Published: April 2005

Objective: Norethisterone enanthate (NETE) is evaluated in trials of hormonal male contraception. It has been speculated that progestins may exert their contraceptive effects not only by suppressing gonadotropins but also by direct effects on male organs. NETE was given to monkeys in which endogenous gonadotropin secretion was suppressed by a gonadotropin releasing hormone (GnRH) antagonist, and replaced by human follicle-stimulating hormone (FSH) and human chorionic gonadotropin (hCG). If NETE has a direct effect on spermatogenesis and/or epididymal function, some changes in testicular histology, sperm motility and/or morphology should occur soon after exposure to NETE.

Methods: Fifteen adult intact male monkeys were grouped and treated for a 38-day period. Group I received GnRH antagonist, FSH, hCG and NETE while group II received a regime identical to group I without NETE and group III received only NETE and vehicle. Ejaculates, body weight, testicular biopsies and volume, and hormones were evaluated.

Results: There was a similar pattern of serum FSH and testosterone in groups I and II. Testicular volume and the proportion of tubuli exhibiting spermatids was significantly decreased in group III. There were no significant differences between group I and group II in any parameters measured. The forward progression of sperm was not affected by NETE treatment. The consistently low percentages of grade c sperm indicated no sign of hyperactivation. No changes in the gross morphology of the acrosome were detected.

Conclusions: Short-term NETE treatment has neither a direct effect on the testis nor on the epididymis in this nonhuman primate model and its contraceptive effects appear to be exerted exclusively through gonadotropin suppression.
Sheehan’s syndrome: baseline characteristics and effect of 2 years of growth hormone replacement therapy in 91 patients in KIMS – Pfizer International Metabolic Database
Authors: Keleştimur Fahrettin , Jonsson Peter , Molvalilar Senay , Gomez Jose Manuel , Auernhammer Christoph J , Colak Ramiz , Koltowska-Häggström Maria , Goth Miklos I
Published: April 2005

Objective: Sheehan’s syndrome occurs as a result of ischaemic pituitary necrosis due to severe postpartum haemorrhage. It is one of the most important causes of hypopituitarism, and hence growth hormone deficiency (GHD), in developing countries. However, little is known about the effects of growth hormone (GH) replacement therapy in patients with Sheehan’s syndrome.

Design: The demographic background characteristics of 91 GH-deficient patients with Sheehan’s syndrome (mean age ± s.d., 46.3 ± 9.4 years) were compared with those of a group of 156 GH-deficient women (mean age ± s.d., 51.5 ± 13.1 years) with a non-functional pituitary adenoma (NFPA). The baseline characteristics and the effects of 2 years of GH replacement therapy were also studied in the 91 patients with Sheehan’s syndrome and an age-matched group of 100 women with NFPA (mean age ± s.d. 44.5 ± 10.2 years).

Results: All patients were enrolled in KIMS (Pfizer International Metabolic Database). Patients with Sheehan’s syndrome were significantly younger at pituitary disorder onset, diagnosis of GHD and at entry into KIMS than patients with NFPA (P < 0.01), and had significantly lower insulin-like growth factor I levels (P < 0.001). At baseline, quality of life (QoL) was significantly (P < 0.05) reduced in patients with Sheehan’s syndrome compared with those with NFPA (P < 0.001). With regard to treatment effects, lean body mass increased significantly (P < 0.05), QoL improved significantly (P < 0.05) and total and low-density lipoprotein-cholesterol decreased significantly (P < 0.05) in patients with Sheehan’s syndrome after 1 year of GH replacement therapy. Similar significant changes in QoL and lipid profiles occurred in patients with NFPA after 2 years of GH replacement. Blood pressure remained unchanged in patients with Sheehan’s syndrome, but decreased significantly (P < 0.01) in the group with NFPA after 1 year, before returning to pretreatment levels at 2 years.

Conclusions: In conclusion, patients with Sheehan’s syndrome have more severe GHD compared with individuals with NFPA. GH replacement therapy in patients with Sheehan’s syndrome may have beneficial effects on QoL, body composition and lipid profile.
The GHRH/GHRP-6 test for the diagnosis of GH deficiency in elderly or severely obese men
Authors: Haijma Sander V , van Dam P Sytze , de Vries Wouter R , Maitimu-Smeele Inge , Dieguez Carlos , Casanueva Felipe F , Koppeschaar Hans P F
Published: April 2005

Objective and design: Ageing and obesity result in decreased activity of the GH/IGF-I axis and concomitant impaired GH responses to secretory stimuli. We therefore determined the validity of the GH cut-off value of 15.0 μg/l in the GH-releasing hormone (GHRH)/GH releasing peptide-6 (GHRP-6) test for the diagnosis of GH deficiency in elderly or severely obese men.

Methods: We performed a combined GHRH/GHRP-6 test in ten elderly men (mean age 74 years; mean body mass index (BMI) 24.6 kg/m2), nine obese men (mean age 47 years; mean BMI 40.6 kg/m2) and seven healthy male controls (mean age 51 years, mean BMI 24.3 kg/m2). After assessment of fasting plasma GH, IGF-I and IGF-binding protein-3 (IGFBP-3), GHRH (100 μg) and GHRP-6 (93 μg) were given intravenously as a bolus injection. Repeated GH measurements were performed for two hours. Results: Both peak GH levels and areas under the curve (AUC) were significantly lower in the obese than in the controls (peak 13.2 vs 53.4 μg/l, P = 0.001; AUC 707 vs 3250 μg/l × 120 min; P = 0.001). Mean GH response in the elderly was lower than in the controls (peak 35.0 μg/l; AUC 2274 μg/l × 120 min), but this was not statistically significant. In contrast, GH peak levels in seven obese men remained below the cut-off level of 15.0 μg/l associated with severe GH deficiency. All others had GH peak levels exceeding this threshold. IGFBP-3 levels were significantly lower in the elderly than in the controls (1.35 vs 2.05 mg/l, P = 0.001). Baseline GH or IGF-I did not differ significantly between groups.

Conclusions: GH responses following GHRH/GHRP-6 administration were significantly reduced in severely obese men, but were not significantly reduced in elderly men, despite a negative trend. Our data indicate that the cut-off GH level of 15.0 μg/l after GHRH + GHRP-6 administration for the diagnosis of severe GH deficiency cannot be used in severely obese men.
Effectiveness of adding dopamine agonist therapy to long-acting somatostatin analogues in the management of acromegaly
Authors: Selvarajah Dinesh , Webster Jonathan , Ross Richard , Newell-Price John
Published: April 2005

Background: The excess mortality and morbidity associated with acromegaly are secondary to prolonged elevation of GH and IGF-I. Vigorous control of these biochemical parameters results in improved morbidity and mortality. Somatostatin analogues (SAs) allow adequate control of GH and IGF-I in approximately 65% of subjects, leaving a significant cohort uncontrolled. Dopamine agonists (DAs), a cheap alternative to SAs, allow control of GH and IGF-I in less than 20% of patients with acromegaly.

Aims: To assess the effectiveness of adding DA therapy to SA in the biochemical control of acromegaly.

Subjects: One hundred and twenty cases from the Sheffield Acromegaly Register were reviewed; 24 (20%) did not require medical treatment following pituitary surgery alone; 16 (13%) had safe GH levels following surgery and radiotherapy; and 58 (48%) required medical treatment despite having had surgery, radiotherapy or both. The remaining 22 (18%) received only medical treatment.

Methods: In nine subjects a DA (three bromocriptine, six cabergoline) was added to an SA to control active disease. GH day curves and IGF-I levels were compared before and after the addition of a DA to existing SA treatment. All were on stable maximum-dose treatment with an SA, with inadequate biochemical control prior to addition of DA therapy. Mean duration of treatment on a DA before biochemical assessments were made was 10.3 months. Six subjects had previously been treated with either transsphenoidal surgery, radiotherapy or both. In three subjects SA was the primary therapy.

Results: All subjects exhibited a fall in median GH and IGF-I levels. Introduction of a DA resulted in a 36.1% reduction in median GH levels (8.3 vs 5.3 mIU/l; P = 0.008) on a GH day curve and a 35.2% reduction in IGF-I levels (387.2 vs 251.0 μg/l; P = 0.018). Only four subjects had elevated prolactin levels prior to the addition of a DA (>368 mIU/l).

Conclusion: Addition of DAs to SAs is of benefit in the biochemical control of acromegaly and should be considered in those inadequately controlled. Furthermore, the beneficial effects of DAs occur even when pre-treatment prolactin levels are within the normal range.
CXCR6 within T-helper (Th) and T-cytotoxic (Tc) type 1 lymphocytes in Graves’ disease (GD)
Authors: Aust G , Kamprad M , Lamesch P , Schmücking E
Published: April 2005

Objective: In Graves’ disease (GD), stimulating anti-TSH receptor antibodies are responsible for hyperthyroidism. T-helper 2 (Th2) cells were expected to be involved in the underlying immune mechanism, although this is still controversial. The aim of this study was to examine the expression of CXCR6, a chemokine receptor that marks functionally specialized T-cells within the Th1 and T-cytotoxic 1 (Tc1) cell pool, to gain new insights into the running immune processes.

Methods: CXCR6 expression was examined on peripheral blood lymphocytes (PBLs) and thyroid-derived lymphocytes (TLs) of GD patients in flow cytometry. CXCR6 cDNA was quantified in thyroid tissues affected by GD (n = 16), Hashimoto’s thyroiditis (HT; n = 2) and thyroid autonomy (TA; n = 11) using real-time reverse transcriptase PCR.

Results: The percentages of peripheral CXCR6+ PBLs did not differ between GD and normal subjects. CXCR6 was expressed by small subsets of circulating T-cells and natural killer (NK) cells. CXCR6+ cells were enriched in thyroid-derived T-cells compared with peripheral CD4+ and CD8+ T-cells in GD. The increase was evident within the Th1 (CD4+ interferon-γ+ (IFN-γ+)) and Tc1 (CD8+IFN-γ+) subpopulation and CD8+ granzyme A+ T-cells (cytotoxic effector type). Thyroid-derived fibro-blasts and thyrocytes were CXCR6−. There was no significant difference between the CXCR6 mRNA levels in GD compared with HT and normal TA tissues. The lowest CXCR6 mRNA levels were obtained from thyroid nodules from TA patients and GD patients with low thyroid peroxidase autoantibody levels.

Conclusions: CXCR6 was overexpressed in Th1 and Tc1 TLs compared with PBLs in GD. CXCR6 could be a marker for lymphocytes that have migrated into the thyroid and assist in the thyroid, independently of the bias of the underlying disease.
Increased risk of affective disorder following hospitalisation with hyperthyroidism – a register-based study
Authors: Thomsen Anders F , Kvist Tine K , Andersen Per K , Kessing Lars V
Published: April 2005

Objective: The pattern of comorbidity between thyroid disorders and affective disorder is not fully known. We assessed whether hospitalisation with hyperthyroidism was a risk factor for hospitalisation with affective disorder and evaluated the temporal relationship between these events.

Design: A historical prospective cohort study comparing patients with hyperthyroidism with patients with non-toxic goitre or osteoarthritis, using existing data from Danish registers. The observational period was from 1 January 1977 to 31 December 1999.

Methods: Three study cohorts were identified by their International Classification of Diseases (ICD) diagnoses at discharge from hospital and consisted of all patients with a first hospital admission with the index diagnoses of hyperthyroidism, osteoarthritis, or non-toxic goitre. Later admissions to psychiatric hospital wards with discharge ICD diagnoses of affective disorder were used as events of interest. Rates of re-admission were estimated using competing risks models in survival analyses. Age, sex, substance abuse, and calendar time were included as co-variables.

Results: A study sample of 183 647 patients discharged with an index diagnosis was identified. In total 1374 events occurred in the observational period. An index diagnosis of hyperthyroidism was associated with an increased risk of hospitalisation with affective disorder for both sexes and for all age-bands investigated, compared with the other index diagnoses. The risk was greatest in the first six months after index hospitalisation (rate ratio, 95% confidence interval: 3.60 (2.58–5.04)).

Conclusions: Patients hospitalised with hyperthyroidism are at greater risk of re-admission with depressive disorder or bipolar disorder than control patients. This suggests that hyperthyroidism is associated with long-term mood disturbances.
Cardiac function in borderline hypothyroidism: a study by pulsed wave tissue Doppler imaging
Authors: Zoncu Sandra , Pigliaru Francesca , Putzu Claudia , Pisano Lorella , Vargiu Sara , Deidda Martino , Mariotti Stefano , Mercuro Giuseppe
Published: April 2005

Objective: In subclinical hypothyroidism (SH), impaired diastolic function has been documented at rest and on effort, while systolic dysfunction has only been assessed on effort.

Design: The aim of the present study was: (a) to further assess systolic function at rest in SH; and (b) to ascertain whether cardiac dysfunction could precede TSH increase in euthyroid patients with a high risk of developing SH.

Methods: We studied 32 patients with classical Hashimoto’s thyroiditis (22 with increased serum TSH (> 3 mU/ml – group A), and 10 with normal serum TSH (< 3 mU/ml – group B)); a third group (C), which included 13 healthy controls. All subjects underwent pulsed wave tissue Doppler imaging (PWTDI) to accurately quantify the global and regional left ventricular function.

Results: When compared with group C, PWTDI indices showed that in both groups A and B there was a significant impairment of systolic ejection (P < 0.001 and P < 0.05, respectively), a delay in diastolic relaxation (P < 0.001 and P < 0.05, respectively) and a decrease in the compliance to the ventricular filling (P < 0.05). Several significant correlations were found between PWTDI parameters and serum-free T3 and T4 and TSH concentrations.

Conclusion: PWTDI is a sensitive technique that allows detection of both diastolic and systolic abnormalities, not only in patients with SH, but also in euthyroid subjects with a high risk of developing thyroid failure. Futhermore, the significant correlations of several PWTDI indices with serum FT3 and TSH concentrations strongly support the concept of a continuum spectrum of a slight thyroid failure in autoimmune thyroiditis extending to subjects with serum TSH still within the normal range.