bluuebunny/crossref_metadata_2025 huggingface dataset:
Roadmap for patient safety research: approaches and roadforks
Authors: Hofoss Dag , Deilkås Ellen
Published: November 2008

Patient safety improvement is a healthcare priority worldwide. Pioneer research reports include the 1984 Harvard Medical Practice Study, and the 1999 report "To err is human''. Patient safety research is expanding rapidly. Among the Scandinavian countries, Denmark is the patient safety improvement leader, and Norway is the laggard, having only recently institutionalized safety research and then having started with industrial safety research, and only recently having expanded into patient safety research. Aims: To produce a roadmap for patient safety research, indicationg three main roadforks. Patient safety research can be conducted along a number of lines. To identify patient safety problems and come up with ideas for patient safety improvement one can investigate 1) particular cases of adverse events, 2) the design of healthcare delivery systems, or 3) the culture of the care-giving institutions. The study of safety culture can be subdivided into the study of organization culture in general (and in particular of leadership culture) and the study of patient safety culture. The article provides a number of references to existing instruments of patient safety research. Methods: Qualitative interpretation of the referenced literature. Results: Scrutinizing adverse events for errors is health care's traditional way of improving patient safety. The idea of rethinking the design of care delivery systems has been accompanied by claims of modernity. The study of patient safety culture is the most recent approach. The three approaches are discussed in separate sub-chapters. Conclusions: Although chronology suggests a developmental trend, the three approaches should not necessarily be seen as steps up the ladder of evolution. Each approach does have its merits.
Reconstructing reefs: qualitative research and the environmental history of the Great Barrier Reef, Australia
Authors: Daley Ben , Griggs Peter , Marsh Helene
Published: November 2008

Given recent concerns about the degradation of coral reef ecosystems world-wide, we investigated the environmental history of the Great Barrier Reef of Australia using qualitative methods. In particular, we used archival and oral history sources to reconstruct changes in coral reefs, islands and marine wildlife species for the period 1860—1970 and we evaluated the potential of qualitative methods to inform marine environmental research. Here, we argue that qualitative research offers a valuable means of reconstructing environmental changes, their drivers and their historical contexts. However, we found that qualitative methods also had important limitations. Hence we identify strategies for addressing those challenges and we suggest criteria for ensuring the accuracy and rigor of qualitative sources in marine environmental research. Overall, we argue that qualitative methods offer distinctive insights into the environmental history of the Great Barrier Reef, and that qualitative reconstructions can act as important triggers for conservation of marine ecosystems.
Observing places: using space and material culture in qualitative research
Authors: O'Toole Paddy , Were Prisca
Published: November 2008

A significant amount of qualitative research takes place in the field. Yet the notion of analysing the place and material objects that contribute to the interactions and in situ behaviour of the participants is often overlooked. This article shows how an analysis of space and material culture contributes to an understanding of social and structural relationships in qualitative research. We use examples from a study of a technology company to demonstrate how an analysis of space and material culture added insights into power, identity and status. We conclude that the tacit insights derived from space and material culture analysis, when synthesized with analysis of other data enable researchers to gain new perspectives on the social world.
General practice-based intervention for suspecting and detecting dementia in France
Authors: Rondeau Virginie , Allain Hervé , Bakchine Serge , Bonet Philippe , Brudon Frédérique , Chauplannaz Guy , Dubois Bruno , Gallarda Thierry , Lepine Jean-Pierre , Pasquier Florence , Pouchain Denis , Ritchie Karen , Robert Philippe , Touchon Jacques , Vellas Bruno , Vercelletto Martine , Verny Marc , Carcaillon Laure , Duveau Françoise , Millet Véronique , Tonelli Isabelle , Schuck Stéphane , Dartigues Jean-François
Published: November 2008

The study evaluated the impact of a general practice-based intervention on 3021 patients in France aged 75 years and above with spontaneous memory complaints. The objective was to identify evocative signs of Alzheimer's disease through a cluster randomized controlled trial. The study involved 681 general practitioners (GPs), randomly selected and assigned to an intervention ( n = 352) or a control group ( n = 329), and 214 specialists. The intervention group participated in training sessions relating to dementia diagnosis and the use of brief neuropsychological tests suited to general practice. The control group dispensed usual general practitioner care. The primary outcome was suspicion of dementia by GPs. The secondary outcome was accurate detection of dementia by the GPs. Most patients (96%) were already followed by the GPs (mean follow-up duration 10.8 years, similar in both groups). Suspicion of dementia was two-fold higher for GPs in the intervention group (adjusted OR = 1.99, p < 0.0001). Probability of suspected dementia increased with patient age and decreased with educational level. However the positive predictive value was not significantly different between the two groups (60.9% vs. 64.4%, p = 0.41). GPs from the intervention group also had a higher probability (adjusted OR = 2.24, p = 0.01) of correctly detecting demented patients (intervention did not increase the number of diagnosed cases of dementia, but increased the number of suspected cases that were later confirmed by specialists). The study showed that information on dementia and application of simple psychometric tests could improve the precision of a GP's diagnosis without changing the efficacy of detection of dementia.
Forgetting and the memory of forgetting
Authors: Kelly Angela
Published: November 2008

In death-driven narratives of AIDS, phenomenological losses experienced as a result of changes to memory with AIDS dementia remain uncharted. Traditionally in the field of dementia, memory has been viewed as a neurological skill to be measured and charted, categorized into short-term or long-term memory loss. In this article, a relationship-based approach to memory is taken where memory is understood to play an important material and symbolic role in the lives of people with AIDS dementia and their relationships with significant others. Through ethnographic description, this article details how for two informants — Diane and Andrew — forgetting and the memory of forgetting was central to how they made sense of who they were in relationship to others and others in relationship to them. For them, memory was more than an individual cerebral activity. Memory, and loss of memory, was instrumental to intersubjective life and formed part of a social space of living loss, characterized by liminality.
A systematic review of the use of contingent valuation in Alzheimer's disease research
Authors: Oremus Mark , Tarride Jean-Eric
Published: November 2008

This systematic review was conducted to examine the use of an economic evaluation strategy called `contingent valuation' in Alzheimer's disease (AD). Several scholarly and internet databases were searched for relevant citations. Articles were included in the review if they contained an original report of the use of contingent valuation in AD. Six articles — all of which assessed contingent valuation defined as willingness-to-pay (WTP) — met this criterion. Overall, caregivers' and patients' WTP for medications was higher when outcomes were better (e.g. cure versus stability). Cost-benefit analyses in two articles indicated that cholinesterase inhibitors, caregiver training, diagnostic testing, and publicly funded AD research would have net benefits for society. The articles were difficult to compare because of differences in methodology and setting. The articles also had a mix of methodological problems pertaining to study population, survey design, and elicitation of WTP. WTP is a useful means of conducting socioeconomic and policy research in AD, provided researchers are careful to address potential problems with comparability and methodology.
The meaning of everyday technology as experienced by people with dementia who live alone
Authors: Nygård Louise
Published: November 2008

This study explored how people with dementia who live alone experienced the meaning of their everyday technology, such as telephones and electronic equipment, and the use of it. Eight participants with mild to moderate stage dementia were included. Repeated interviews and observations were undertaken in each participant's home and surroundings. A phenomenological, interpretative method was adopted in the analysis. In summary, the participants experienced their everyday technology to be embedded with both practical and existential meaning, as it could assist them in different ways in daily life as well as support their perception and presentation of themselves. Although important, habit and familiarity did not seem to provide them with enough support to continue using technology, unless the technology was experienced as very significant and incorporated in a bodily experience through continuous and very frequent practice. The abundance of experienced meanings and the significance of the technology in the participants' lives call for further studies in order to better understand the conditions for managing everyday technology in home and society and, when relevant, to facilitate technology use in people with dementia.
Telephone-delivered psychosocial intervention reduces burden in dementia caregivers
Authors: Tremont Geoffrey , Duncan Davis Jennifer , Bishop Duane S. , Fortinsky Richard H.
Published: November 2008

The objective of this study was to examine the preliminary efficacy of Family Intervention: Telephone Tracking — Dementia (FITT-D), a multi-component intervention that is delivered in 23 telephone contacts over 12 months. Thirty-three dementia caregivers were randomly assigned to receive either FITT-D ( n = 16) or standard care ( n = 17) using urn randomization to balance the groups on dementia severity, caregiver gender and relationship type (spouse versus other). Inclusion criteria included formal dementia diagnosis, caregiving for at least six months, residing with the care recipient, and providing at least four hours of direct supervision per day. Master's-level therapists contacted caregivers by telephone over 12 months. Each contact followed a standardized treatment manual, involving assessment and individualized application of interventions to address mood, family functioning, social support and health. Outcomes included Zarit Burden Interview, Revised Memory and Behavior Problem Checklist, and the Geriatric Depression Scale at baseline and 12 months (end of treatment). Caregivers receiving FITT-D exhibited significantly lower burden scores and less severe reactions to memory and behavior problems than caregivers in the standard care condition. Findings provide preliminary evidence for the efficacy of FITT-D, a potentially highly accessible, low-cost intervention for dementia caregivers.
Lay and professional expectations of cholinesterase inhibitor treatment in the early stage of Alzheimer's disease
Authors: Andersen Elizabeth , Silvius James , Slaughter Susan , Dalziel William , Drummond Neil
Published: November 2008

The objectives of the study were to identify, compare and contrast the expectations of key stakeholders regarding cholinesterase inhibitor treatments prescribed to people with Alzheimer's Disease (AD), and to examine those expectations in the light of recent findings regarding the efficacy and effectiveness of this class of drug. Participants were four older women diagnosed with early stage AD, their lay caregivers, their professional healthcare providers, and pharmacists and policy makers, making a total of 23 participants. Semi-structured interviews were performed in a conversational style designed to elicit accounts of expectations of cholinesterase inhibitors in relation to diagnosis and treatment for AD. The interviews were carried out in the participants' own homes, their places of work or by telephone. A five-member, multidisciplinary team taped, transcribed and coded the interviews using qualitative software in order to identify overarching themes.

The study found that although the policy makers and physicians harbored more skeptical or negative expectations, the majority of stakeholders expected that people diagnosed with AD would reap beneficial effects through the use of cholinesterase inhibitors. The study concludes that there is still controversy about the use of cholinesterase inhibitors, particularly in terms of their cost-effectiveness. A clear and ethical argument exists in support of attempts to both modify unrealistic patient expectations where they exist, and to enhance the knowledge base of prescribers. Greater concordance between physicians', patients' and caregivers' treatment goals, and appropriate prescription of these agents in line with available research will require more complete patient and caregiver information on the one hand, and potentially a shift in emphasis to more individualized, clinically focused outcomes, on the other.
The Albanian and Post-Soviet Business of Trafficking Women for Prostitution
Authors: Leman Johan , Janssens Stef
Published: November 2008

We studied 62 court files relating to East European networks, which were handled as cases of human trafficking by the Belgian courts between 1995 and 2003. The goal was to uncover the profiles and developments in the network structure and their financial modus operandi. We discovered two initial profiles (an Albanian and a post-Soviet profile), which are gradually changing into a multi-ethnic and transnational profile. This is not because there is some mastermind at work, but results from the fact that some traffickers want to extend their field and have learned from past experiences. The financial modus operandi is adapting to these developments.
Adolescent Substance Use in Germany and the United States
Authors: Link Tanja C.
Published: November 2008

Theories of substance use highlight the importance of the sociocultural environment in understanding and explaining the prevalence and patterns of adolescent substance use. The likelihood to engage in substance use is said to be influenced by key social, structural and economic forces associated with the adolescents' demographic and socioeconomic background. Even though the need for cross-cultural applications of existing theoretical frameworks is apparent, the relationships posited by existing theories have mostly been tested with US samples. In the current article, data from the 2003 waves of the Monitoring the Future (MTF) survey and the European School Survey Project on Alcohol and Other Drugs (ESPAD) are used to investigate and assess the relationships between theoretically grounded measures and adolescent substance use in Germany and the United States.
Leadership as Practice: Challenging the Competency Paradigm
Authors: Carroll Brigid , Levy Lester , Richmond David
Published: November 2008

Competency frameworks, models, instruments and thinking have long been ingrained and utilized in management and organizational life. Not surprisingly they have been transplanted both swiftly and seemingly easily into the leadership domain. While there certainly have been discomfort and critique from academic and practitioner sources, nothing has emerged strongly enough to date that would provide an alternative mode of framing and translating both leadership and leadership development in the different contexts that seek to make it visible. In this article, consequently, we submit leadership and its development to the `practice turn' to enable a radically different perspective from a competency orientated one. The ontology, epistemology and methodologies of practice are examined and translated to the leadership field. We argue that a focus on praxis, practitioner and practice offers both challenge and transformation to the ways that leadership is bounded and constrained by current organizational and managerial conventions.
Negotiating Gender Role Expectations: Rhetorical Leadership and Women in the US Senate
Authors: Bligh Michelle C. , Kohles Jeffrey C.
Published: November 2008

The historical paucity of US women senators has provided little opportunity to study women at one of the highest and most prestigious leadership levels. Through a content analysis of 12 months of public discourse in a variety of media, we explore the rhetorical leadership of women senators as they carry out their elected roles. Results indicate that women senators use significantly less aggressive and more ambivalent speech when compared to political norms, and are less likely to use terms denoting accomplishment, praise and human interest. Overall, our results suggest that women continue to feel the effects of gender stereotypes and expectations in higher levels of political office, and these effects may have important negative implications for perceptions of their leadership and effectiveness.
What Are We Measuring? Convergence of Leadership with Interpersonal and Non-interpersonal Personality
Authors: de Vries Reinout E.
Published: November 2008

Since leadership styles have been most commonly defined in terms of interpersonal influence, one would assume that they have their main projections on the interpersonal circumplex. In this study, the relations between leadership styles from the Multifactor Leadership Questionnaire and Leader Behaviour Description Questionnaire and both interpersonal and HEXACO personality scales are investigated. As expected, charismatic leadership and leader's consideration have strong projections on the interpersonal circumplex, with main projections on the warm-agreeable octant. Transactional leadership, passive leadership, and task-oriented leadership have considerably weaker or no projections on the circumplex. Leader's consideration is most strongly related to interpersonal personality while both transactional and passive leadership are most strongly related to non-interpersonal personality. It is concluded that especially charismatic leadership and leader's consideration are captured almost fully by the HEXACO personality inventory.
Ethical Integrity in Leadership and Organizational Moral Culture
Authors: Thoms John C.
Published: November 2008

Ethical integrity and moral culture are defined, and ethical integrity in leadership, ethical dilemmas and failures, and organizational moral culture are examined. These views are measured against a number of case studies to determine whether there are linkages between organizational moral culture and the ethical or unethical integrity of leadership. A number of conclusions are drawn from the case studies. There appears to be a direct link between ethical leadership and organizational moral culture, although in some cases, considerable time may be needed to change the moral culture of an organization. Shareholders and the public appreciate and reward organizations with high ethical principles and moral culture whereas regulators are increasingly taking legal action against companies which flout share-holders' and the public's trust. The article questions whether codes of conduct, regular performance and audit reviews or other mechanisms to maintain ethics inhibit employees' right to moral autonomy. Finally, it is noted that inconsistencies exist in correlating private standards and behaviour as important predictors or determinants of ethical business conduct.
Inter-leadership: Why and How Should We Think of Leadership and Followership Integrally?
Authors: Küpers Wendelin , Weibler Jürgen
Published: November 2008

This article raises questions about and provides meta-paradigmatic perspectives on an integral understanding of leadership. In view of the various shortcomings of conventional leadership discourse, an integral orientation considers that leadership research demands a comprehensive framework and multi-level approach suited for investigating the complex, interrelated processes involved. Correspondingly, the outlined integral framework of leadership covers the interdependent subjective, intersubjective and objective dimensions of leaders and leadership. Furthermore, developmental levels and lines — classified in a dynamic cycle — open up a processual understanding of leadership. Finally, theoretical and methodological implications are discussed and some avenues for future research and perspectives of integral leadership presented.
Blood diffusion and Th1-suppressive effects of galectin-9–containing exosomes released by Epstein-Barr virus–infected nasopharyngeal carcinoma cells
Authors: Klibi Jihène , Niki Toshiro , Riedel Alexander , Pioche-Durieu Catherine , Souquere Sylvie , Rubinstein Eric , Le Moulec Sylvestre , Guigay Joël , Hirashima Mitsuomi , Guemira Fethi , Adhikary Dinesh , Mautner Josef , Busson Pierre
Published: November 2008

Epstein-Barr virus (EBV)–associated nasopharyngeal carcinoma (NPC) is the third most frequent virus-associated human malignancy. How this tumor escapes immune recognition despite the expression of several viral antigens has remained poorly understood. Our previous in vitro studies have shown that NPC cells release exosomes containing high amounts of galectin-9, a ligand of the membrane receptor Tim-3, which is able to induce apoptosis in mature Th1 lymphocytes. Here, we sought to determine whether galectin-9–carrying exosomes were produced in NPC patients and whether such exosomes might play a role in the immune evasion of NPC cells. We report that galectin-9–containing exosomes are selectively detected in plasma samples from NPC patients and mice xenografted with NPC tumors. The incorporation into exosomes protects galectin-9 against proteolytic cleavage but retains its Tim-3–binding capacity. Importantly, NPC exosomes induce massive apoptosis in EBV-specific CD4+ cells used as a model of target T cells. This effect is inhibited by both anti–Tim-3 and antigalectin-9 blocking antibodies. These results indicate that blocking galectin-9/Tim-3 interaction in vivo might alleviate the Th1-suppressive effect of NPC exosomes and sustain antitumoral T-cell responses and thereby improve clinical efficacy of immunotherapeutic approaches against NPC.
Expression and Functional Role of Urotensin-II and Its Receptor in the Adrenal Cortex and Medulla: Novel Insights for the Pathophysiology of Primary Aldosteronism
Authors: Giuliani Luisa , Lenzini Livia , Antonello Michele , Aldighieri Enrico , Belloni Anna S. , Fassina Ambrogio , Gomez-Sanchez Celso , Rossi Gian Paolo
Published: November 2008

Context: The involvement of urotensin II, a vasoactive peptide acting via the G protein-coupled urotensin II receptor, in arterial hypertension remains contentious.

Objective: We investigated the expression of urotensin II and urotensin II receptor in adrenocortical and adrenomedullary tumors and the functional effects of urotensin II receptor activation.

Design: The expression of urotensin II and urotensin II receptor was measured by real time RT-PCR in aldosterone-producing adenoma (n = 22) and pheochromocytoma (n = 10), using histologically normal adrenocortical (n = 6) and normal adrenomedullary (n = 5) tissue as control. Urotensin II peptide and urotensin II receptor protein were investigated with immunohistochemistry and immunoblotting. To identify urotensin II-related and urotensin II receptor-related pathways, a whole transcriptome analysis was used. The adrenocortical effects of urotensin II receptor activation were also assessed by urotensin II infusion with/without the urotensin II receptor antagonist palosuran in rats.

Results: Urotensin II was more expressed in pheochromocytoma than in aldosterone-producing adenoma tissue; the opposite was seen for the urotensin II receptor expression. Urotensin II receptor activation in vivo in rats enhanced (by 182 ± 9%; P < 0.007) the adrenocortical expression of immunoreactive aldosterone synthase.

Conclusions: Urotensin II is a putative mediator of the effects of the adrenal medulla and pheochromocytoma on the adrenocortical zona glomerulosa. This pathophysiological link might account for the reported causal relationship between pheochromocytoma and primary aldosteronism.
Prostaglandin E2 Via Steroidogenic Factor-1 Coordinately Regulates Transcription of Steroidogenic Genes Necessary for Estrogen Synthesis in Endometriosis
Authors: Attar Erkut , Tokunaga Hideki , Imir Gonca , Yilmaz M. Bertan , Redwine David , Putman Michael , Gurates Bilgin , Attar Rukset , Yaegashi Nobuo , Hales Dale B. , Bulun Serdar E.
Published: November 2008

Context: Products of at least five specific steroidogenic genes, including steroidogenic acute regulatory protein (StAR), which facilitates the entry of cytosolic cholesterol into the mitochondrion, side chain cleavage P450 enzyme, 3β-hydroxysteroid-dehydrogenase-2, 17-hydroxylase/17-20-lyase, and aromatase, which catalyzes the final step, are necessary for the conversion of cholesterol to estrogen. Expression and biological activity of StAR and aromatase were previously demonstrated in endometriosis but not in normal endometrium. Prostaglandin E2 (PGE2) induces aromatase expression via the transcriptional factor steroidogenic factor-1 (SF1) in endometriosis, which is opposed by chicken-ovalbumin upstream-transcription factor (COUP-TF) and Wilms’ tumor-1 (WT1) in endometrium.

Objective: The aim of the study was to demonstrate a complete steroidogenic pathway leading to estrogen biosynthesis in endometriotic cells and the transcriptional mechanisms that regulate basal and PGE2-stimulated estrogen production in endometriotic cells and endometrium.

Results: Compared with normal endometrial tissues, mRNA levels of StAR, side chain cleavage P450, 3β-hydroxysteroid-dehydrogenase-2, 17-hydroxylase/17-20-lyase, aromatase, and SF1 were significantly higher in endometriotic tissues. PGE2 induced the expression of all steroidogenic genes; production of progesterone, estrone, and estradiol; and StAR promoter activity in endometriotic cells. Overexpression of SF1 induced, whereas COUP-TFII or WT1 suppressed, StAR promoter activity. PGE2 induced coordinate binding of SF1 to StAR and aromatase promoters but decreased COUP-TFII binding in endometriotic cells. COUP-TFII or WT1 binding to both promoters was significantly higher in endometrial compared with endometriotic cells.

Conclusion: Endometriotic cells contain the full complement of steroidogenic genes for de novo synthesis of estradiol from cholesterol, which is stimulated by PGE2 via enhanced binding of SF1 to promoters of StAR and aromatase genes in a synchronous fashion.
Fresh-Frozen Plasma as a Source of Exogenous Insulin-Like Growth Factor-I in the Extremely Preterm Infant
Authors: Hansen-Pupp Ingrid , Engström Eva , Niklasson Aimon , Berg Ann-Cathrine , Fellman Vineta , Löfqvist Chatarina , Hellström Ann , Ley David
Published: November 2008

Context: Preterm birth is followed by a decrease in circulatory levels of IGF-I and IGF binding protein (IGFBP)-3, proteins with important neurogenic and angiogenic properties.

Objective: Our objective was to evaluate the effects of iv administration of fresh-frozen plasma (FFP) from adult donors on circulatory levels of IGF-I and IGFBP-3 in extremely preterm infants.

Design, Setting, and Patients: A prospective cohort study was performed in 20 extremely preterm infants [mean (sd) gestational age 25.3 (1.3) wk] with clinical requirement of FFP during the first postnatal week. Sampling was performed before initiation of transfusion, directly after, and at 6, 12, 24, and 48 h after completed FFP transfusion.

Main Outcome Measures: Concentrations of IGF-I and IGFBP-3 before and after transfusion of FFP were determined.

Results: FFP with a mean (sd) volume of 11 ml/kg (3.1) was administered at a median postnatal age of 2 d (range 1–7). Mean (sd) IGF-I and IGFBP-3 concentrations in administered FFP were 130 (39) and 2840 μg/liter (615), respectively. Immediately after FFP transfusion, mean (sd) concentrations of IGF-I increased by 133% from 11 (6.4) to 25 μg/liter (9.3) (P < 0.001) and IGFBP-3 by 61% from 815 (451) to 1311 μg/liter (508) (P < 0.001). Concentrations of IGF-I and IGFBP-3 remained higher at 6 (P < 0.001, P = 0.009) and 12 h (P = 0.017, P = 0.018), respectively, as compared with concentrations before FFP transfusion. Typical half-life of administrated IGF-I was 3.4 h for a 1-kg infant.

Conclusion: Transfusion of FFP to extremely preterm infants during the first postnatal week elevates levels of IGF-I and IGFBP-3.
Differential Effects of Octreotide and Pasireotide on Somatostatin Receptor Internalization and Trafficking in Vitro
Authors: Lesche Sarah , Lehmann Diana , Nagel Falko , Schmid Herbert A. , Schulz Stefan
Published: November 2008

Objective: The clinically used somatostatin analogs, octreotide and lanreotide, act primarily by binding to somatostatin receptor 2 (sst2). In contrast, the novel multireceptor ligand pasireotide (SOM230) binds with high affinity to somatostatin receptor subtypes sst1, sst2, sst3, and sst5. SOM230 is currently under clinical evaluation for treatment of acromegaly, Cushing’s disease, and octreotide-resistant carcinoid tumors. However, the effects of SOM230 on internalization and postendosomal sorting of individual human somatostatin receptor subtypes have not been determined so far.

Results: Here we show that SOM230 was less potent than octreotide in inducing internalization and signaling of sst2 receptors expressed in human embryonic kidney cells. In contrast, SOM230 was more potent than octreotide in inducing internalization and signaling of sst3 and sst5 receptors. Both SOM230 and octreotide stimulated a rapid down-regulation of sst3 but not of sst2 or sst5 receptors. SOM230 and octreotide profoundly differed in their patterns of sst2-stimulated β-arrestin mobilization. Whereas octreotide-mediated receptor activation led to the formation of stable complexes facilitating the internalization of sst2 and β-arrestin-2 into the same endocytic vesicles, SOM230-mediated receptor activation led to the formation of unstable complexes that dissociated at or near the plasma membrane. Consequently, sst2 receptors recycled rapidly to the plasma membrane after endocytosis in SOM230-treated cells, but not in octreotide-treated cells.

Conclusion: We show that SOM230 modulates somatostatin receptor trafficking in a manner clearly distinct from octreotide and somatostatin. These findings may provide an explanation for the differential regulation of somatostatin receptor responsiveness during long-term administration of stable somatostatin analogs.
Two distinct regions of Mto1 are required for normal microtubule nucleation and efficient association with the γ-tubulin complex in vivo
Authors: Samejima Itaru , Miller Victoria J. , Groocock Lynda M. , Sawin Kenneth E.
Published: November 2008

Cytoplasmic microtubule nucleation in the fission yeast Schizosaccharomyces pombe involves the interacting proteins Mto1 and Mto2, which are thought to recruit the γ-tubulin complex (γ-TuC) to prospective microtubule organizing centres. Mto1 contains a short amino-terminal region (CM1) that is conserved in higher eukaryotic proteins implicated in microtubule organization, centrosome function and/or brain development. Here we show that mutations in the Mto1 CM1 region generate mutant proteins that are functionally null for cytoplasmic microtubule nucleation and interaction with the γ-TuC (phenocopying mto1Δ), even though the Mto1-mutant proteins localize normally in cells and can bind Mto2. Interestingly, the CM1 region is not sufficient for efficient interaction with the γ-TuC. Mutation within a different region of Mto1, outside CM1, abrogates Mto2 binding and also impairs cytoplasmic microtubule nucleation and Mto1 association with the γ-TuC. However, this mutation allows limited microtubule nucleation in vivo, phenocopying mto2Δ rather than mto1Δ. Further experiments suggest that Mto1 and Mto2 form a complex (Mto1/2 complex) independent of the γ-TuC and that Mto1 and Mto2 can each associate with the γ-TuC in the absence of the other, albeit extremely weakly compared to when both Mto1 and Mto2 are present. We propose that Mto2 acts cooperatively with Mto1 to promote association of the Mto1/2 complex with the γ-TuC.
Rash Associated with Pregabalin Use
Authors: Smith Timothy L , Baldwin Aaron , Cunningham Larry L , Cook Aaron M
Published: November 2008

Objective:

To report a case of extensive rash induced by orally administered pregabalin in a patient with neuropathic pain.

Case Summary:

A 35-year-old white female with a diffuse, erythematous, maculopapular rash localized to her back and extremities presented to the preoperative holding area for planned exploratory nerve surgery. Prior to presentation, she had been receiving oral pregabalin 50 mg 3 times a day for approximately 2 weeks to treat her neuropathy. Prior to pregabalin therapy, the patient indicated that she had taken gabapentin for approximately 3 weeks for the pain, but had discontinued it due to adverse effects and perceived lack of efficacy. Pregabalin was discontinued and diphenhydramine and methylprednisolone were given to treat the rash. The rash almost completely resolved one week after pregabalin was discontinued.

Discussion:

Pregabalin-induced rash was rarely reported in Phase 3 trials, and a clinical description of such events has not been published. Pregabalin exhibits pharmacokinetics different from those of most other antiepileptic agents. Presently, there are no clear mechanisms known for rash associated with pregabalin. The Naranjo probability scale indicates a probable relationship between the development of rash and use of pregabalin by our patient.

Conclusions:

There are currently no other available reports of the development of a rash coinciding with the use of pregabalin. As both Food and Drug Administration–approved and off-label use of this drug increases, further consideration of risk factors associated with the development of rash is needed.
Perspectives on Health Care of Adults With Developmental Disabilities
Authors: Parish Susan L. , Moss Kathryn , Richman Erica L.
Published: November 2008

A focus group study was conducted with individuals with developmental disabilities to understand their perspectives on their health status, health promotion behaviors, and health care services they receive. The majority of participants reported good to excellent health, and all had some form of medical insurance. However, participants reported notable gaps in dental and reproductive health care and age-specific cancer screening. Some adults had good access to medical care, particularly those with a family member or friend who served as their health advocate. Some adults had a sound understanding of their health and health care needs. Program and policy implications are discussed and recommendations are presented to ensure adequate health care for adults with disabilities, including health advocacy training for caregivers.
Emergency Psychiatric Services for Individuals With Intellectual Disabilities: Perspectives of Hospital Staff
Authors: Lunsky Yona , Gracey Carolyn , Gelfand Sara
Published: November 2008

Strains on the mainstream mental health system can result in inaccessible services that force individuals with intellectual disabilities into the emergency room (ER) when in psychiatric crisis. The purpose of this study was to identify clinical and systemic issues surrounding emergency psychiatry services for people with intellectual disabilities, from the perspective of hospital staff. Focus groups were conducted with emergency psychiatry staff from 6 hospitals in Toronto, Canada. Hospital staff reported a lack of knowledge regarding intellectual disabilities and a shortage of available community resources. Hospital staff argued that caregivers need more community and respite support to feel better equipped to deal with the crisis before it escalates to the ER and that hospital staff feel ill prepared to provide the necessary care when the ER is the last resort. Input from hospital staff pointed to deficiencies in the system that lead caregivers to use the ER when other options have been exhausted. Both staff and caregivers need support and access to appropriate services if the system is to become more effective at serving the psychiatric needs of this complex population.
Distribution of Label-retaining Cells in the Limbal Epithelium of a Mouse Eye
Authors: Zhao Jin , Mo Victoria , Nagasaki Takayuki
Published: November 2008

Corneal epithelial stem cells are believed to be localized in the limbus, an annular zone between the cornea and the conjunctiva, but it has not been possible to identify individual stem cells in situ because of the lack of specific molecular markers. Description of stem cell distribution has also been ambiguous because limbal boundaries are ill defined. In this study, we investigated whether distribution of slow cycling, label-retaining cells (LRCs) could be determined precisely against a definable anatomical structure of an eye. We found that a boundary between the cornea and the limbus could be determined reliably by distinct epithelial nuclear staining patterns. Using this boundary line as a fiduciary marker, we determined that LRCs were located exclusively in the basal epithelium at the limbal side of the cornea-limbus boundary line along the entire circumference, within an annular zone of 100–200 μm wide. LRC density was highest in the superior temporal quadrant and lowest in the inferior nasal quadrant. These results show that LRCs are present asymmetrically in a narrow zone within the limbus that can be defined precisely in reference to a newly defined anatomical boundary line between the cornea and the limbus.
Histopathological Study of Healing After Allogenic Mesenchymal Stem Cell Delivery in Myocardial Infarction in Dogs
Authors: Vela Deborah C. , Silva Guilherme V. , Assad Joao A.R. , Sousa Andre L.S. , Coulter Stephanie , Fernandes Marlos R. , Perin Emerson C. , Willerson James T. , Buja L. Maximilian
Published: November 2008

In this histological study, we assessed the role of mesenchymal stem cells (MSCs) in the healing process that takes place during the subacute phase of myocardial infarction in dogs. Seven days after occlusion of the left anterior descending coronary artery, adult mongrel dogs received 100 × 106 4′-6-diamidino-2-phenylindole (DAPI)-labeled allogenic bone marrow-derived MSCs by the transendocardial (TE, n = 6) and intracoronary (IC, n = 4) routes; control dogs ( n = 6) received no infusion. The dogs were euthanized at 21 days after occlusion. Hearts were excised and sliced from apex to base into four transverse sections, which were divided into nine segments. Paraffin sections from each segment were stained with hematoxylin and eosin, trichrome, picrosirius red, and antibodies against several extracellular matrix components. Frozen sections were immunostained for host cardiac phenotypical markers and analyzed by epifluorescence and deconvolution fluorescence microscopy (DFM). We found less unresolved necrotic myocardium and more extracellular matrix deposition in MSC-treated dogs than in controls 2 weeks after cell delivery. By DFM, no DAPI+ MSC nuclei were observed within native cardiac cells. MSCs delivered during the subacute phase of acute myocardial infarction positively affect healing, apparently by mechanisms other than differentiation into mature native cardiac cells.
Choice of Fixative Is Crucial to Successful Immunohistochemical Detection of Phosphoproteins in Paraffin-embedded Tumor Tissues
Authors: Burns Janine A. , Li Yuan , Cheney Carol A. , Ou Yangsi , Franlin-Pfeifer Laura L. , Kuklin Nelly , Zhang Zhi-Qiang
Published: November 2008

Protein phosphorylation is frequently used as an indicator of cellular signaling activity. Elevated phosphorylation of tyrosine kinase receptors plays an important role in cancer pathogenesis. However, phosphoproteins are usually poorly preserved in clinical tissue samples that are routinely fixed in 10% formalin. Nonetheless, in oncology clinical trials, use of phosphoproteins as biomarkers has been considered to be of great value in evaluating the effectiveness of a given drug candidate. Therefore, it is worthy of investigating whether alternative fixatives would improve the preservation of phosphoproteins in tissue. We compared the IHC staining of a number of phosphoproteins in xenograft and human surgical tumor tissues fixed in three different fixatives: 10% formalin, 4% paraformaldehyde (PFA), and Streck's tissue fixative (STF). We found that STF significantly enhanced the staining intensity of phosphoproteins compared with 10% formalin or 4% PFA. STF fixative also showed superiority of preservation of phosphoproteins in human surgical samples. Our results indicate that the choice of fixative could significantly affect the usability of clinical tissue samples for evaluating phosphoprotein by IHC.
The HMGB1 Receptor RAGE Mediates Ischemic Brain Damage
Authors: Muhammad Sajjad , Barakat Waleed , Stoyanov Stoyan , Murikinati Sasidhar , Yang Huan , Tracey Kevin J. , Bendszus Martin , Rossetti Grazisa , Nawroth Peter P. , Bierhaus Angelika , Schwaninger Markus
Published: November 2008

In ischemic stroke, the necrotic core is surrounded by a zone of inflammation, in which delayed cell death aggravates the initial insult. Here, we provide evidence that the receptor for advanced glycation end products (RAGE) functions as a sensor of necrotic cell death and contributes to inflammation and ischemic brain damage. The RAGE ligand high mobility group box 1 (HMGB1) was elevated in serum of stroke patients and was released from ischemic brain tissue in a mouse model of cerebral ischemia. A neutralizing anti-HMGB1 antibody and HMGB1 box A, an antagonist of HMGB1 at the receptor RAGE, ameliorated ischemic brain damage. Interestingly, genetic RAGE deficiency and the decoy receptor soluble RAGE reduced the infarct size.In vitro, expression of RAGE in (micro)glial cells mediated the toxic effect of HMGB1. Addition of macrophages to neural cultures further enhanced the toxic effect of HMGB1. To test whether immigrant macrophages in the ischemic brain mediate the RAGE effect, we generated chimeric mice by transplanting RAGE−/−bone marrow to wild-type mice. RAGE deficiency in bone marrow-derived cells significantly reduced the infarct size. Thus, HMGB1–RAGE signaling links necrosis with macrophage activation and may provide a target for anti-inflammatory therapy in stroke.
Maternal High-Fat Diet and Fetal Programming: Increased Proliferation of Hypothalamic Peptide-Producing Neurons That Increase Risk for Overeating and Obesity
Authors: Chang Guo-Qing , Gaysinskaya Valeriya , Karatayev Olga , Leibowitz Sarah F.
Published: November 2008

Recent studies in adult and weanling rats show that dietary fat, in close association with circulating lipids, can stimulate expression of hypothalamic peptides involved in controlling food intake and body weight. In the present study, we examined the possibility that a fat-rich diet during pregnancy alters the development of these peptide systemsin utero, producing neuronal changes in the offspring that persist postnatally in the absence of the diet and have long-term consequences. The offspring of dams on a high-fat diet (HFD) versus balanced diet (BD), from embryonic day 6 to postnatal day 15 (P15), showed increased expression of orexigenic peptides, galanin, enkephalin, and dynorphin, in the paraventricular nucleus and orexin and melanin-concentrating hormone in the perifornical lateral hypothalamus. The increased density of these peptide-expressing neurons, evident in newborn offspring as well as P15 offspring cross-fostered at birth to dams on the BD, led us to examine events that might be occurringin utero. During gestation, the HFD stimulated the proliferation of neuroepithelial and neuronal precursor cells of the embryonic hypothalamic third ventricle. It also stimulated the proliferation and differentiation of neurons and their migration toward hypothalamic areas where ultimately a greater proportion of the new neurons expressed the orexigenic peptides. This increase in neurogenesis, closely associated with a marked increase in lipids in the blood, may have a role in producing the long-term behavioral and physiological changes observed in offspring after weaning, including an increase in food intake, preference for fat, hyperlipidemia, and higher body weight.
Group I Metabotropic Glutamate Receptors Control Metaplasticity of Spinal Cord Learning through a Protein Kinase C-Dependent Mechanism
Authors: Ferguson Adam R. , Bolding Kevin A. , Huie J. Russell , Hook Michelle A. , Santillano Daniel R. , Miranda Rajesh C. , Grau James W.
Published: November 2008

Neurons within the spinal cord can support several forms of plasticity, including response–outcome (instrumental) learning. After a complete spinal transection, experimental subjects are capable of learning to hold the hindlimb in a flexed position (response) if shock (outcome) is delivered to the tibialis anterior muscle when the limb is extended. This response-contingent shock produces a robust learning that is mediated by ionotropic glutamate receptors (iGluRs). Exposure to nociceptive stimuli that are independent of limb position (e.g., uncontrollable shock; peripheral inflammation) produces a long-term (>24 h) inhibition of spinal learning. This inhibition of plasticity in spinal learning is itself a form of plasticity that requires iGluR activation and protein synthesis. Plasticity of plasticity (metaplasticity) in the CNS has been linked to group I metabotropic glutamate receptors (subtypes mGluR1 and mGluR5) and activation of protein kinase C (PKC). The present study explores the role of mGluRs and PKC in the metaplastic inhibition of spinal cord learning using a combination of behavioral, pharmacological, and biochemical techniques. Activation of group I mGluRs was found to be both necessary and sufficient for metaplastic inhibition of spinal learning. PKC was activated by stimuli that inhibit spinal learning, and inhibiting PKC activity restored the capacity for spinal learning. Finally, a PKC inhibitor blocked the metaplastic inhibition of spinal learning produced by a group I mGluR agonist. The data strongly suggest that group I mGluRs control metaplasticity of spinal learning through a PKC-dependent mechanism, providing a potential therapeutic target for promoting use-dependent plasticity after spinal cord injury.
Light-Induced Rescue of Breathing after Spinal Cord Injury
Authors: Alilain Warren J. , Li Xiang , Horn Kevin P. , Dhingra Rishi , Dick Thomas E. , Herlitze Stefan , Silver Jerry
Published: November 2008

Paralysis is a major consequence of spinal cord injury (SCI). After cervical SCI, respiratory deficits can result through interruption of descending presynaptic inputs to respiratory motor neurons in the spinal cord. Expression of channelrhodopsin-2 (ChR2) and photostimulation in neurons affects neuronal excitability and produces action potentials without any kind of presynaptic inputs. We hypothesized that after transducing spinal neurons in and around the phrenic motor pool to express ChR2, photostimulation would restore respiratory motor function in cervical SCI adult animals. Here we show that light activation of ChR2-expressing animals was sufficient to bring about recovery of respiratory diaphragmatic motor activity. Furthermore, robust rhythmic activity persisted long after photostimulation had ceased. This recovery was accomplished through a form of respiratory plasticity and spinal adaptation which is NMDA receptor dependent. These data suggest a novel, minimally invasive therapeutic avenue to exercise denervated circuitry and/or restore motor function after SCI.