bluuebunny/crossref_metadata_2025 huggingface dataset:
The WT1 Wilms' tumor suppressor gene is a downstream target for insulin‐like growth factor‐I (IGF‐I) action in PC12 cells
Authors: Sarfstein Rive , Werner Haim
Published: August 2006

The biological actions of the insulin‐like growth factors, IGF‐I and IGF‐II, are mediated by the ligand‐induced activation of the IGF‐I receptor (IGF‐IR), a transmembrane heterotetramer linked to the ras–raf–mitogen‐activated protein kinase (MAPK) and phosphatidyl inositol 3 kinase (PI3K)–protein kinase B (PKB)/Akt signal transduction cascades. The Wilms' tumor suppressor gene (wt1) encodes a zinc finger transcription factor, WT1, which has been implicated in various cellular processes including proliferation, differentiation and apoptosis. In the present study we demonstrated that IGF‐I modulates the WT1 gene expression in neurally derived PC12 cells in a dose‐ and time‐dependent manner. This effect was mediated through both the MAPK and PI3‐kinase signaling pathways, as shown by the ability of the specific inhibitors UO126 and LY294002 to abrogate IGF‐I action. Moreover, using RT‐PCR and transient transfection assays, we demonstrated that the IGF‐I effect was associated with corresponding changes in WT1 mRNA levels and WT1 promoter activity. In addition, the results of the present study revealed that high WT1 levels were associated with the induction of apoptosis, whereas low WT1 levels were correlated with the inhibition of apoptosis, as demonstrated by poly ADP ribose polymerase (PARP) cleavage, Bax expression, Annexin V‐FITC staining, and by the use of antisense oligonucleotides against WT1. In summary, our results show that the wt1 gene is a novel target for IGF‐I action in neurally derived cells.
Stimulation of excitatory amino acid release from adult mouse brain glia subcellular particles by high mobility group box 1 protein
Authors: Pedrazzi Marco , Raiteri Luca , Bonanno Giambattista , Patrone Mauro , Ledda Sabina , Passalacqua Mario , Milanese Marco , Melloni Edon , Raiteri Maurizio , Pontremoli Sandro , Sparatore Bianca
Published: August 2006

The multifunctional protein high mobility group box 1 (HMGB1) is expressed in hippocampus and cerebellum of adult mouse brain. Our aim was to determine whether HMGB1 affects glutamatergic transmission by monitoring neurotransmitter release from glial (gliosomes) and neuronal (synaptosomes) re‐sealed subcellular particles isolated from cerebellum and hippocampus. HMGB1 induced release of the glutamate analogue [3H]d‐aspartate form gliosomes in a concentration‐dependent manner, whereas nerve terminals were insensitive to the protein. The HMGB1‐evoked release of [3H]d‐aspartate was independent of modifications of cytosolic Ca2+ , but it was blocked by dl‐threo‐β‐benzyloxyaspartate (dl‐TBOA), an inhibitor of glutamate transporters. HMGB1 also stimulated the release of endogenous glutamate in a Ca2+‐independent and dl‐TBOA‐sensitive manner. These findings suggest the involvement of carrier‐mediated release. Moreover, dihydrokainic acid, a selective inhibitor of glutamate transporter 1 (GLT1), does not block the effect of HMGB1, indicating a role for the glial glutamate‐aspartate transporter (GLAST) subtype in this response. We also demonstrate that HMGB1/glial particles association is promoted by Ca2+. Furthermore, although HMGB1 can physically interact with GLAST and the receptor for advanced glycation end products (RAGE), only its binding with RAGE is promoted by Ca2+. These results suggest that the HMGB1 cytokine could act as a modulator of glutamate homeostasis in adult mammal brain.
Isolation and characterization of microsatellite loci in Santalum insulare, Santalaceae
Authors: EMELINE LHUILLIER , ALEXANDRE VAILLANT , JEAN‐FRANÇOIS BUTAUD , JEAN‐MARC BOUVET
Published: August 2006

The forest tree Santalum insulare is endemic to the archipelagos of eastern Polynesia and is threatened by important anthropic pressures. In order to investigate the genetic diversity and structure of this species, we developed eight pairs of primers for nuclear microsatellites. One hundred and sixty‐two individuals distributed in 10 islands were analysed. These loci were all polymorphic and displayed three to 15 alleles per locus. Significant Hardy–Weinberg deviation was detected and interpreted as a result of Wahlund effect. These markers constitute an efficient tool in investigating the genetic patterns of S. insulare populations.
Development of six microsatellite loci for black mangrove (Avicennia germinans)
Authors: CERÓN‐SOUZA IVANIA , RIVERA‐OCASIO ELSIE , FUNK STEPHAN M. , MCMILLAN W. OWEN
Published: August 2006

We developed six new microsatellite loci for the black mangrove (Avicennia germinans), an important member of wetland communities worldwide. Loci showed moderate to high polymorphism and a survey of four locations [Puerto Rico (Jobos Bay and Luquillo), Mexico, French Guyana] revealed clear regional (and local) population structure. All populations were genetically distinct and the two continental populations showed much higher diversity than the two insular Puerto Rican locations. These loci complement those recently published by Nettel et al. (2005) and promise to be valuable for characterizing local and regional population dynamics in the black mangrove.
Development of microsatellite markers in the toxic dinoflagellate Alexandrium minutum (Dinophyceae)
Authors: NAGAI S. , MCCAULEY L. , YASUDA N. , ERDNER D. L. , KULIS D. M. , MATSUYAMA Y. , ITAKURA S. , ANDERSON D. M.
Published: August 2006

Outbreaks of paralytic shellfish poisoning caused by the toxic dinoflagellate Alexandrium minutum (Dinophyceae) are a worldwide concern from both the economic and human health points of view. For population genetic studies of A. minutum distribution and dispersal, highly polymorphic genetic markers are of great value. We isolated 12 polymorphic microsatellites from this cosmopolitan, toxic dinoflagellate species. These loci provide one class of highly variable genetic markers, as the number of alleles ranged from four to 12, and the estimate of gene diversity was from 0.560 to 0.862 across the 12 microsatellites; these loci have the potential to reveal genetic structure and gene flow among A. minutum populations.
New microsatellite resources for groupers (Serranidae)
Authors: RAMÍREZ MANUEL ALEJANDRO , PATRICIA‐ACEVEDO JENNY , PLANAS SILVIA , CARLIN JOEL L. , FUNK STEPHAN M. , MCMILLAN W. OWEN
Published: August 2006

We characterized nine microsatellite loci and identified an additional 60 genomic regions containing microsatellites in the red hind grouper, Epinephelus guttatus. The nine loci were highly polymorphic, and primers designed from red hind genomic DNA produced a strong amplification product in a test panel of 16 other groupers in the genera Epinephelus and Mycteroperca collected from across the world. Most of the amplified regions were homologous to the red hind locus and a well‐defined microsatellite repeat was generally evident. The nine loci, together with the 60 uncharacterized microsatellite‐containing regions, provide a powerful tool for ecological and evolutionary studies in groupers.
Development and characterization of microsatellite markers for the endangered northern riffleshell mussel Epioblasma torulosa rangiana (Bivalvia: Unionidae)
Authors: ZANATTA DAVID T. , MURPHY ROBERT W.
Published: August 2006

Primers for six polymorphic microsatellite loci were developed for the endangered northern riffleshell Epioblasma torulosa rangiana from the Sydenham River, Ontario, Canada. These loci along with an additional nine microsatellite loci, developed from other unionoid species, available in the literature, were tested and characterized on individuals from two populations in the Allegheny River; one population in French Creek, PA, USA, and one population from the Sydenham River. Allelic diversity ranged from two to 28 alleles per locus and averaged 13.7 per locus. These primers are being used in a rangewide study on the conservation genetics of remaining extant populations of the northern riffleshell.
Isolation of polymorphic tetranucleotide microsatellite markers for the green‐eyed tree frog (Litoria genimaculata)
Authors: GRAY MELISSA M. , HOSKIN CONRAD J. , BARDELEBEN CAROLYNE
Published: August 2006

We have isolated 16 polymorphic microsatellite markers for the green‐eyed tree frog, Litoria genimaculata, from genomic libraries enriched for (AAGG)n and (AAAG)n repetitive elements. The number of alleles ranges from four to 14 per locus with the observed heterozygosity ranging from 0.36 to 1.00. These markers will be useful for analysis of questions concerning population genetic structure and speciation.
POWSIM: a computer program for assessing statistical power when testing for genetic differentiation
Authors: RYMAN NILS , PALM STEFAN
Published: August 2006

Knowledge of statistical power is essential for sampling design and data evaluation when testing for genetic differentiation. Yet, such information is typically missing in studies of conservation and evolutionary genetics, most likely because of complex interactions between the many factors that affect power. powsim is a 32‐bit Windows/DOS simulation‐based computer program that estimates power (and α error) for chi‐square and Fisher's exact tests when evaluating the hypothesis of genetic homogeneity. Optional combinations include the number of samples, sample sizes, number of loci and alleles, allele frequencies, and degree of differentiation (quantified as FST). powsim is available at http://www.zoologi.su.se/~ryman.
Isolation of microsatellite markers in the tiger mosquito Aedes albopictus (Skuse)
Authors: PORRETTA D. , GARGANI M. , BELLINI R. , CALVITTI M. , URBANELLI S.
Published: August 2006

Among the numerous molecular markers available in population genetics, microsatellites are one of the most powerful tools developed in recent years. This paper describes the isolation of six polymorphic microsatellite loci in the tiger mosquito Aedes albopictus using an enriched genomic library technique. Such loci should be an efficient tool in population genetic studies for this mosquito species.
Isolation of polymorphic tetranucleotide microsatellite markers for the ornate nursery frog Cophixalus ornatus
Authors: BARDELEBEN CAROLYNE , GRAY MELISSA M. , HOSKIN CONRAD J.
Published: August 2006

We have isolated 18 polymorphic microsatellite loci for Cophixalus ornatus from genomic libraries enriched for (AAAG)n, (AACC)n and (AAGG)n repetitive elements. The number of alleles ranges from five to 22 per locus with the observed heterozygosity ranging from 0.10 to 0.92. These markers will be useful for the analysis of population structure in C. ornatus and testing alternative models of speciation.
Development and localization of microsatellite markers for the sibling species Chironomus riparius and Chironomus piger (Diptera: Chironomidae)
Authors: NOWAK CARSTEN , HANKELN THOMAS , SCHMIDT ERWIN R. , SCHWENK KLAUS
Published: August 2006

Five variable microsatellite loci are reported for the nonbiting midge species Chironomus riparius and Chironomus piger. All loci show considerable intraspecific variation and species‐specific alleles, which allow to discriminate among the two closely related species and their interspecific hybrids, and to estimate genetic diversity within and between populations. Additionally, the loci were localized on C. riparius polytene chromosomes to verify their single copy status and investigate possible chromosomal linkage. The described markers are used in different studies with regard to population and ecological genetics and evolutionary ecotoxicology of Chironomus.
THE PERSPECTIVES OF RESEARCHERS ON OBTAINING INFORMED CONSENT IN DEVELOPING COUNTRIES
Authors: NEWTON SAM K. , APPIAH‐POKU JOHN
Published: August 2006

Background:  The doctrine of informed consent (IC) exists to protect individuals from exploitation or harm. This study into IC was carried out to investigate how different researchers perceived the process whereby researchers obtained consent. It also examined researchers’ perspectives on what constituted IC, and how different settings influenced the process.

Methods:  The study recorded in‐depth interviews with 12 lecturers and five doctoral students, who had carried out research in developing countries, at a leading school of public health in the United Kingdom. A purposive, snowballing approach was used to identify interviewees.

Results:  Although the concept and application of the doctrine of IC should have been the same, irrespective of where the research was carried out, the process of obtaining it had to be different. The setting had to be taken into consideration and the autonomy of the subject had to be respected at all times. In areas of high illiteracy, and where understanding of the subject was likely to be a problem, there was an added responsibility placed on the researcher to devise innovative ways of carrying out the study, taking into consideration the peculiarities of the environment.

Conclusion:  The ethical issues for IC were the same, irrespective of where the research was conducted. However, because the backgrounds, setting, and knowledge of populations differed, there was the need to be similarly sensitive in obtaining consent. The problems of obtaining genuine IC were not limited to developing countries.
SHARING THE BENEFITS OF GENETIC RESOURCES: FROM BIODIVERSITY TO HUMAN GENETICS1
Authors: SCHROEDER DORIS , LASÉN‐DÍAZ CAROLINA
Published: August 2006

Benefit sharing aims to achieve an equitable exchange between the granting of access to a genetic resource and the provision of compensation. The Convention on Biological Diversity (CBD), adopted at the 1992 Earth Summit in Rio de Janeiro, is the only international legal instrument setting out obligations for sharing the benefits derived from the use of biodiversity. The CBD excludes human genetic resources from its scope, however, this article considers whether it should be expanded to include those resources, so as to enable research subjects to claim a share of the benefits to be negotiated on a case‐by‐case basis. Our conclusion on this question is: ‘No, the CBD should not be expanded to include human genetic resources.’ There are essential differences between human and non‐human genetic resources, and, in the context of research on humans, an essentially fair exchange model is already available between the health care industry and research subjects. Those who contribute to research should receive benefits in the form of accessible new health care products and services, suitable for local health needs and linked to economic prosperity (e.g. jobs). When this exchange model does not apply, as is often the case in developing countries, individually negotiated benefit sharing agreements between researchers and research subjects should not be used as ‘window dressing’. Instead, national governments should focus their finances on the best economic investment they could make; the investment in population health and health research as outlined by the World Health Organization’s Commission on Macroeconomics and Health; whilst international barriers to such spending need to be removed.
NORTH–SOUTH BENEFIT SHARING ARRANGEMENTS IN BIOPROSPECTING AND GENETIC RESEARCH: A CRITICAL ETHICAL AND LEGAL ANALYSIS
Authors: SCHÜKLENK UDO , KLEINSMIDT ANITA
Published: August 2006

Most pharmaceutical research carried out today is focused on the treatment and management of the lifestyle diseases of the developed world. Diseases that affect mainly poor people are neglected in research advancements in treatment because they cannot generate large financial returns on research and development costs. Benefit sharing arrangements for the use of indigenous resources and genetic research could only marginally address this gap in research and development in diseases that affect the poor. Benefit sharing as a strategy is conceptually problematic, even if one, as we do, agrees that impoverished indigenous communities should not be exploited and that they should be assisted in improving their living conditions. The accepted concept of intellectual property protection envisages clearly defined originators and owners of knowledge, whereas the concept of community membership is fluid and indigenous knowledge is, by its very nature, open, with the originator(s) lost in the mists of time. The delineation of ‘community’ presents serious conceptual and practical difficulties as few communities form discrete, easily discernable groups, and most have problematic leadership structures. Benefit sharing is no substitute for governments’ responsibility to uplift impoverished communities. Benefit sharing arrangements may be fraught with difficulties but considerations of respect and equity demand that prior informed consent and consultation around commercialisation of knowledge take place with the source community and their government.1
EXPLORING DISPARITIES BETWEEN GLOBAL HIV/AIDS FUNDING AND RECENT TSUNAMI RELIEF EFFORTS: AN ETHICAL ANALYSIS
Authors: CHRISTIE TIMOTHY , ASRAT GETNET A. , JIWANI BASHIR , MADDIX THOMAS , MONTANER JULIO S.G.
Published: August 2006

Objective:  To contrast relief efforts for the 26 December 2004 tsunami with current global HIV/AIDS relief efforts and analyse possible reasons for the disparity.

Methods:  Literature review and ethical analysis.

Results:  Just over 273,000 people died in the tsunami, resulting in relief efforts of more than US$10 bn, which is sufficient to achieve the United Nation’s long‐term recovery plan for South East Asia. In contrast, 14 times more people died from HIV/AIDS in 2004, with UNAIDS predicting a US$8 bn funding gap for HIV/AIDS in developing nations between now and 2007. This disparity raises two important ethical questions. First, what is it that motivates a more empathic response to the victims of the tsunami than to those affected by HIV/AIDS? Second, is there a morally relevant difference between the two tragedies that justifies the difference in the international response?

The principle of justice requires that two cases similarly situated be treated similarly. For the difference in the international response to the tsunami and HIV/AIDS to be justified, the tragedies have to be shown to be dissimilar in some relevant respect. Are the tragedies of the tsunami disaster and the HIV/AIDS pandemic sufficiently different, in relevant respects, to justify the difference in scope of the response by the international community?

Conclusion:  We detected no morally relevant distinction between the tsunami and the HIV/AIDS pandemic that justifies the disparity. Therefore, we must conclude that the international response to HIV/AIDS violates the fundamental principles of justice and fairness.
POPULATION AGING AND INTERNATIONAL DEVELOPMENT: ADDRESSING COMPETING CLAIMS OF DISTRIBUTIVE JUSTICE
Authors: ENGELMAN MICHAL , JOHNSON SUMMER
Published: August 2006

To date, bioethics and health policy scholarship has given little consideration to questions of aging and intergenerational justice in the developing world. Demographic changes are precipitating rapid population aging in developing nations, however, and ethical issues regarding older people’s claim to scarce healthcare resources must be addressed. This paper posits that the traditional arguments about generational justice and age‐based rationing of healthcare resources, which were developed primarily in more industrialized nations, fail to adequately address the unique challenges facing older persons in developing nations. Existing philosophical approaches to age‐based resource allocation underemphasize the importance of older persons for developing countries and fail to adequately consider the rights and interests of older persons in these settings. Ultimately, the paper concludes that the most appropriate framework for thinking about generational justice in developing nations is a rights‐based approach that allows for the interests of all age groups, including the oldest, to be considered in the determination of health resource allocation.
ETHICAL AND REGULATORY ISSUES SURROUNDING AFRICAN TRADITIONAL MEDICINE IN THE CONTEXT OF HIV/AIDS
Authors: NYIKA ACEME
Published: August 2006

It has been estimated that more than 80% of people in Africa use traditional medicine (TM). With the HIV/AIDS epidemic claiming many lives in Africa, the majority of people affected rely on TM mainly because it is relatively affordable and available to the poor populations who cannot afford orthodox medicine. Whereas orthodox medicine is practiced under stringent regulations and ethical guidelines emanating from The Nuremburg Code,1 African TM seems to be exempt from such scrutiny. Although recently there have been calls for TM to be incorporated into the health care system, less emphasis has been placed on ethical and regulatory issues.

In this paper, an overview of the use of African TM in general, and for HIV/AIDS in particular, is given, followed by a look at: (i) the relative laxity in the application of ethical standards and regulatory requirements with regards to TM; (ii) the importance of research on TM in order to improve and demystify its therapeutic qualities; (iii) the need to tailor‐make intellectual property laws to protect traditional knowledge and biodiversity. A framework of partnerships involving traditional healers’ associations, scientists, policy makers, patients, community leaders, members of the communities, and funding organizations is suggested as a possible method to tackle these issues. It is hoped that this paper will stimulate objective and constructive debate that could enhance the protection of patients’ welfare.
GLOBAL BIOETHICS: UTOPIA OR REALITY?
Authors: HELLSTEN SIRKKU K.
Published: August 2006

This article discusses what ‘global bioethics’ means today and what features make bioethical research ‘global’. The article provides a historical view of the development of the field of ‘bioethics’, from medical ethics to the wider study of bioethics in a global context. It critically examines the particular problems that ‘global bioethics’ research faces across cultural and political borders and suggests some solutions on how to move towards a more balanced and culturally less biased dialogue in the issues of bioethics. The main thesis is that we need to bring global and local aspects closer together, when looking for international guidelines, by paying more attention to particular cultures and local economic and social circumstances in reaching a shared understanding of the main values and principles of bioethics, and in building ‘biodemocracy’.
Hospice Enrollment and Evaluation of Its Causal Effect on Hospitalization of Dying Nursing Home Patients
Authors: Gozalo Pedro L. , Miller Susan C.
Published: August 2006

Objective.To examine the patient, nursing home (NH), hospice provider, and local market factors associated with the selection of the Medicare hospice benefit by eligible NH residents, and evaluate the causal effect of hospice on end‐of‐life hospitalization rates.

Data Sources/Study Setting.Secondary data for 1995–1997 for NH residents.

Study Design.This retrospective cohort study includes NH residents in five states (Kansa, Maine, New York, Ohio, South Dakota) who died in the years 1995–1997. Medicare claims identified hospice enrollment and hospitalizations. Geocoding of NHs, hospice providers, and hospitals was used to identify local markets. The two outcome measures are hospice enrollment and hospitalization of NH residents in their last 30 days of life.

Data Collection/Extraction Method.A file was constructed linking MDS assessments to Medicare claims and denominator files, NH provider files (OSCAR), hospice provider of service files, and the area resource file.

Principal Findings.Twenty‐six percent of hospice and 44 percent of nonhospice residents were hospitalized in their last 30 days of life (odds ratio [OR] 0.45; 95 percent confidence interval [CI]: 0.42–0.48). Adjusting for confounders, hospice patients were less likely than nonhospice residents to be hospitalized (OR 0.47; 95 percent CI: 0.45–0.50). Adding inverse propensity score weighting, hospice patients were still less likely than nonhospice residents to be hospitalized (OR 0.56; 95 percent CI: 0.53–0.61).

Conclusions.Hospice selection introduces some bias in the evaluation of the causal effect of hospice on end‐of‐life hospitalization rates. However, even after adjusting for selection bias, hospice does have a powerful effect in reducing end‐of‐life hospitalization rates.
Reflection on a patient’s airway management during a ward‐based resuscitation
Authors: Shepherd Carolyn
Published: August 2006

Background: The bag‐valve‐mask (BVM) system is a common adjunct used during adult resuscitation to ventilate the lungs and deliver oxygen to patients in cardiopulmonary arrest. Gastric inflation, regurgitation and aspiration are well‐documented complications of BVM ventilation, which can have serious consequences for patients. Aim: The aim of this paper is to review the cause of gastric inflation, regurgitation and aspiration during BVM ventilation and to consider techniques that have been suggested to reduce these problems.Method: Using a reflective model, the author revisits an actual cardiac arrest, and within a structured framework considers the event itself, the context of the event and looks at ways in which practice could be improved in future.Results: It is clear from the evidence that a reduction in peak airway pressure can reduce the risk of gastric inflation, regurgitation and aspiration. A review of the available research strongly suggests that in expert hands, the most effective means of reducing peak airway pressure is by reducing tidal volume by using a smaller bag.Conclusion: Although the evidence, as presented, for a reduction in bag size is convincing, there appears to be a problem that less regular users do not appear to be able to produce effective tidal volumes when using a smaller bag. If a reduced bag size is standardized, further research using a diverse group of health care workers with the BVM is required before a clear policy can be achieved. It is likely that training and practice will be shown to be important for nursing staff expected to use the smaller BVM.
The effect of music listening on older adults undergoing cardiovascular surgery
Authors: Twiss Elizabeth , Seaver Jean , McCaffrey Ruth
Published: August 2006

The purpose of this study was to determine the effect of music listening on postoperative anxiety and intubation time in patients undergoing cardiovascular surgery. Coronary artery disease and valvular heart disease affect approximately 15 million Americans and 5 million persons in the UK annually, with the majority of these patients being older adults. The anxiety experienced before, during and after surgery increases cardiovascular workload, thereby prolonging recovery time. Music listening as a nursing intervention has shown an ability to reduce anxiety. The study used a randomized control trial design. Sixty adults older than 65 years were randomly assigned to the control and the experimental groups. The experimental group listened to music during and after surgery, while the control group received standard postoperative care. The Spielberger State Trait Anxiety Inventory was administered to both groups before surgery and 3 days postoperatively. The mean of the differences between scores was compared using analysis of variance. Differences in mean intubation time were measured in both groups. Older adults who listened to music had lower scores on the state anxiety test (F= 5·57, p = ·022) and had significantly fewer minutes of postoperative intubation (F = 5·45, p = ·031) after cardiovascular surgery. Older adults undergoing cardiovascular surgery who listen to music had less anxiety and reduced intubation time than those who did not.
Correcting arterial blood gases for temperature: (when) is it clinically significant?
Authors: Bisson Jamie , Younker Jackie
Published: August 2006

Interpreting arterial blood gases (ABGs) is a common practice in intensive care units. The use of the temperature correction facility, however, is not standardized, and the effects of temperature correction on the ABG result may affect the overall management of the patient. The aim of this study was to discuss the significance of temperature correction. Current practice in the UK and Australia is discussed along with a review of physiological principles of oxygenation and acid‐base balance. The alpha‐stat and pH‐stat methods of blood gas analysis are presented, with arguments for and against using the temperature correction facility for blood gas analysis. The study concludes with recommendations for practice.
Critical care outreach 1: an exploration of fundamental philosophy and underpinning knowledge
Authors: Durham Lesley , Hancock Helen C
Published: August 2006

Critical care outreach (Outreach) is central to the effective management of critically ill patients. Its recent, expedited and somewhat uncoordinated introduction has, however, resulted in a lack of understanding about the fundamental philosophical theories and sources of knowledge that underpin it. Furthermore, there is a lack of understanding of the context in which these are applied. It is important that we understand and are able to provide sound rationale and guidance for current and future Outreach practice, for the education of practitioners and in order to evaluate and show the impact of Outreach on patient care. The need for this is heightened in the context of current changes in roles and role boundaries, in which there are significant pressures and expectations from organizations for Outreach teams to demonstrate their effectiveness. The authors argue that the complex situations encountered and managed by Outreach are not amenable to traditional forms of measurement and that its impact on patient care is, therefore, not readily acknowledged by those external to the service. This study explores the philosophical underpinnings and types of knowledge inherent in the practice of Outreach. In doing so, it illuminates how they apply and contribute to the practice and impact of Outreach.
Critical care outreach 2: uncovering the underpinning philosophy and knowledge through collaborative reflection
Authors: Durham Lesley , Hancock Helen C
Published: August 2006

Critical care outreach (Outreach) was introduced as part of a government strategy to address increasing demands on limited intensive care (level 3) and high‐dependency (level 2) resources. The discipline of Outreach developed rapidly and, as a result, the fundamental philosophical theories and sources of knowledge that underpin its practice remain, at least to some extent, unexplored, and their contribution to practice overlooked. It is important that we understand these philosophical theories and sources of knowledge so that we are able to provide sound rationale and guidance for practice and address the increasing pressure to demonstrate effectiveness. The authors argue that the complex situations encountered and managed by Outreach are not entirely amenable to traditional forms of measurement, and that its impact on patient care is, therefore, not readily acknowledged. In applying a model of collaborative reflection, this study analyses the management of a clinical case by a nurse consultant in Outreach. In doing so, it explores the realities of practice by deconstructing the complexity of a particular situation and highlights the variety of knowledge that contributes to effective Outreach practice.
Glutamate‐Dopamine Cotransmission and Reward Processing in Addiction
Authors: Lapish Christopher C. , Seamans Jeremy K. , Judson Chandler L.
Published: August 2006

While Dale's principle of “one neuron, one neurotransmitter” has undergone revisions to incorporate evidence of the corelease of atypical neurotransmitters such as neuropeptides, the corelease of classical neurotransmitters has only recently been realized. Surprisingly, numerous studies now indicate that the corelease of neurotransmitters in the mammalian central nervous system is not an obscure and rare phenomenon but is widespread and involves most classical neurotransmitters systems. However, the suggestion that glutamate can be coreleased with dopamine (DA) has remained controversial. Furthermore, glutamate‐DA cotransmission has not yet been seriously considered in the context of the neurocircuitry of addiction. If glutamate is in fact coreleased with DA as some evidence now suggests, this may have significant implications for advancing our understanding of the interactive role that these 2 neurotransmitters play in cognitive and reward processes. In this commentary, we review the evidence for and against glutamate as a cotransmitter and discuss the potential role of glutamate‐DA corelease in addiction. In particular, we describe a recently proposed model in which coreleased glutamate transmits a temporally precise prediction error signal of reward described by Schultz et al., whereas the function of coreleased DA is to exert prolonged modulatory influences on neuronal activity. In addition, we suggest that as alcohol consumption transitions from recreational use to addiction, there is a corresponding transition in the reward valence signal from better than predicted to worse than predicted.
The Alcoholism Generator
Authors: Miller Michael W. , Spear Linda P.
Published: August 2006

Alcohol exposure largely affects 3 populations: fetuses, adolescents, and adults. These 3 developmental stages are inextricably intertwined such that elevated alcohol exposure at any time increases the probability of exposure at the others. This circular interdependency is called the alcoholism generator. Furthermore, exposure to large amounts of alcohol at these 3 times can cause cognitive dysfunction, largely through mechanisms of alcohol‐induced perturbations in neurogenesis and synaptogenesis. Breaking this cycle is key to reducing problem alcohol drinking and the associated sequelae.
Associations of Variations in Alcohol Dehydrogenase Genes With the Level of Response to Alcohol in Non‐Asians
Authors: Duranceaux Nicole C. E. , Schuckit Marc A. , Eng Mimy Y. , Robinson Shannon K. , Carr Lucinda G. , Wall Tamara L.
Published: August 2006

Background: Risk and protective factors for alcohol use disorders (AUDs) are complex and reflect both environmental and genetic factors. Genetic components account for about 50% of the variation and influence several phenotypes, including the level of response (LR) to alcohol as well as alcohol‐metabolizing enzyme polymorphisms. Variations in the ADH1B and ADH1C genes may influence the LR to alcohol by increasing levels of acetaldehyde during alcohol metabolism, although most data on this question come from Asian populations.

Methods: This study evaluated associations of ADH1B and ADH1C genotypes in a non‐Asian sample. Participants (N=117, 69.2% female) were 18‐ to 29‐year‐old men and women, primarily Caucasian (70.1%) and black (26.5%), recruited in San Diego, California. The Semi‐Structured Assessment for the Genetics of Alcoholism Interview was used to assess demographic, substance use, and psychiatric history information, and the Family History Assessment Module was used to determine first‐degree family history of alcohol dependence. An alcohol challenge paradigm was used to gather data on the LR to alcohol over 210 minutes.

Results: Participants with the ADH1B*1/*2 genotype had a higher LR to alcohol early in the alcohol challenge (i.e., 30, 60, and 90 minutes after drinking) as measured by both alcohol‐related changes in subjective feelings of intoxication and body sway, even when controlling for sex and Russian/Eastern European ancestry. A similar trend was seen for ADH1C*1/*1 genotype, although the results were not significant.

Conclusions: These findings suggest that studies searching for genes relating to the LR to alcohol as a vulnerability factor for AUDs should consider controlling for ADH1B genotype, as the ADH1B*2 allele could obscure the impact of other genetic polymorphisms.
Effects of Acamprosate on Sleep During Alcohol Withdrawal: A Double‐Blind Placebo‐Controlled Polysomnographic Study in Alcohol‐Dependent Subjects
Authors: Luc Staner , Peter Boeijinga , Thierry Danel , Isabelle Gendre , Muriel Muzet , Frédéric Landron , Rémy Luthringer
Published: August 2006

Background:Sleep disturbances are frequently encountered in alcohol‐dependent patients. Drugs improving sleep during abstinence from alcohol may play an important role in the recovery process.

Methods:In the present study, the effects of acamprosate, a drug successfully used in maintaining abstinence following alcohol withdrawal, were assessed by polysomnographic recordings. A parallel double‐blind placebo‐controlled study was conducted in 24 male DSM‐IV alcohol‐dependent subjects aged 35.9±1.2 years. Treatments (2 tablets of 333 mg acamprosate vs placebo t.i.d.) were initiated 8 days before alcohol withdrawal and continued during the 15 days following alcohol withdrawal. Polysomnographic assessments were recorded during acute withdrawal (the first 2 nights following withdrawal) and during postwithdrawal abstinence (the last 2 nights of the trial).

Results:Results show that, compared with placebo, acamprosate decreased wake time after sleep onset and increased stage 3 and REM sleep latency (all treatment effects with ap<0.05 significance). Withdrawal effects themselves were also demonstrated as sleep efficiency (p<0.01) and total sleep time (p<0.05) were lower in abstinence nights versus withdrawal nights, whereas no significant treatment × withdrawal effect could be evidenced. Acamprosate was well tolerated during the entire course of the study.

Conclusions:The present study shows that acamprosate ameliorates both sleep continuity and sleep architecture parameters classically described as disturbed in alcohol‐dependent patients. From a clinical perspective, it suggests that an 8‐day acamprosate prewithdrawal treatment is well tolerated and can attenuate the sleep disturbances engendered by alcohol withdrawal in alcohol‐dependent subjects.
Enzymatic Mechanisms of Ethanol Oxidation in the Brain
Authors: Zimatkin Sergey M. , Pronko Sergey P. , Vasiliou Vasilis , Gonzalez Frank J. , Deitrich Richard A.
Published: August 2006

Background: The exact enzymatic mechanisms of ethanol oxidation in the brain are still unclear. The catalase‐mediated oxidation of ethanol was demonstrated in rat brain using incubation of brain homogenates with catalase inhibitors. The role of the alcohol dehydrogenase (ADH) or cytochrome P450–dependent system in this process is possible, but has not been confirmed. The objective of the study was to determine the contribution of the different enzymatic pathways to ethanol oxidation in brain homogenates from mice and rats.

Methods: Three approaches were used to investigate the enzymatic mechanisms of ethanol oxidation in the brain of rats and mice: (1) preincubation of brain homogenates with inhibitors of the ethanol‐metabolizing enzymes (catalase, CYP2E1, ADH, and ALDH); (2) utilization of mice with genetic deficiency in ethanol‐metabolizing enzymes (catalase, CYP2E1, or both enzymes); and (3) determination of ethanol oxidation in brain subcellular fractions known to have differential activity of ethanol‐metabolizing enzymes. The ethanol‐derived acetaldehyde (AC) and acetate were determined in brain samples by gas chromatography.

Results: The catalase inhibitors sodium azide (5 mM) and aminotriazole (5 mM) as well as CYP2E1 inhibitors diallyl sulfide (2 mM) and β‐phenethyl isothiocyanate (0.1 mM) lowered significantly the accumulation of the ethanol‐derived AC and acetate in brain homogenates. The ADH inhibitor 4‐methyl pyrazole (5 mM) significantly decreased the acetate but not the AC accumulation. Ethanol‐derived AC accumulation in brain homogenates of acatalasemic mice was 47% of the control value, 91% in CYP2E1‐null mice, and 24% in double mutants (with deficiency of both catalase and CYP2E1). The highest levels of ethanol oxidation were found in microsomal and peroxisomal subcellular brain fractions, where CYP2E1 and catalase are located, respectively.

Conclusions: Catalase is the key enzyme of ethanol oxidation in the brain of rodents: it may be responsible for about 60% of the process. CYP2E1 plays an important role in ethanol oxidation in the rodent brains. Alcohol dehydrogenase plays a minor role, if any, in this process. Aldehyde dehydrogenase plays the crucial role in the further oxidation of ethanol‐derived AC in the brain homogenates.
Infantile Sensitivity to Ethanol's Motivational Effects: Ethanol Reinforcement During the Third Postnatal Week
Authors: Molina Juan Carlos , Ponce Luciano Federico , Truxell Eric , Spear Norman E.
Published: August 2006

Background: Although tests specific to newborn rats have frequently verified their susceptibility to the reinforcing properties of ethanol, demonstration of comparable reinforcing effects in older infants has been elusive. Using a second‐order conditioning procedure, the present study assessed in preweanling rats whether pairing with early postabsorptive effects of ethanol would render intraorally delivered gustatory stimuli capable of positive reinforcement for association with a salient texture. Direct reinforcing effects of ethanol were also evaluated through intake tests of gustatory stimuli previously paired with the drug. Blood ethanol levels (BELs) were determined for each of the ethanol doses used.

Methods: Pups (14 days old) were stimulated with intraoral infusion of sucrose (10% v/v), water, or quinine (0.0045% w/v) 5 minutes after being intragastrically (i.g.) administered 0.00, 0.25, 0.50, or 2.00 g/kg ethanol (Experiments 1 and 2). These stimuli were then briefly presented while pups experienced a rough texture (sandpaper). Rats were subsequently evaluated in a 2‐way texture location test (sandpaper vs smooth surface). In Experiment 3, sucrose, water, or quinine was paired with early postabsorptive effects of ethanol (0.00, 0.50, or 2.0 g/kg). Consumption of these stimuli was later assessed. Motor activity patterns during the intake test were also evaluated. In Experiment 4, BELs corresponding to 0.25, 0.50, or 2.0 g/kg ethanol were determined 5 and 20 minutes after i.g. administration (time periods were in accord with the onset and offset of intraoral stimulation used in the previous experiments).

Results: Intraoral infusion of sucrose, water, or quinine, while under a state of sobriety and paired with sandpaper, resulted in roughly 50% preference for this texture. Sandpaper preferences were significantly elevated in pups that had experienced sucrose or water in a nonsober state—while under the effects of ethanol (Experiments 1 and 2). This indicated reinforcing effects of the ethanol intoxication. Pairing ethanol intoxication directly with consumption of sucrose, water, or quinine did not affect their later consumption. Yet, there were clear indications that this pairing resulted in conditioned behavioral activity patterns. Blood ethanol levels corresponding to the ethanol doses used here ranged between 10 and 150 mg%.

Conclusions: Infants appear sensitive to pharmacological reinforcing properties of low and relatively high ethanol doses. This sensitivity was revealed indirectly, by pairing gustatory stimuli with ethanol intoxication and then allowing these stimuli to act as second‐order reinforcement for a quite different (tactile) stimulus. Behavioral activation elicited by the gustatory stimuli previously paired with a state of intoxication seems to compete with the expression of ethanol's motivational properties as assessed through intake tests.
Barriers to Treatment of Hepatitis C in HIV/HCV‐Coinfected Adults with Alcohol Problems
Authors: Nunes David , Saitz Richard , Libman Howard , Cheng Debbie M. , Vidaver John , Samet Jeffrey H.
Published: August 2006

Background:Alcohol use and human immune deficiency virus (HIV) infection are both associated with accelerated progression of hepatitis C virus (HCV) disease and reduced response rates to interferon therapy. In this study, we assessed the prevalence of barriers to interferon treatment in a population of HIV/HCV‐coinfected patients with current or past alcohol problems and the extent to which they received treatment to address the barriers.

Methods:This is a cross‐sectional, descriptive analysis of baseline data from a prospective study assessing the impact of HCV and alcohol use on HIV disease progression. Using consensus guidelines, subjects were categorized as having absolute, relative, or no contraindications to interferon therapy for HCV. Absolute contraindications to treatment included heavy alcohol use, decompensated liver disease, CD4 cell count <100 cells/μL, recent needle sharing, and suicidal ideation. Relative contraindications included moderate alcohol use, recent injection drug use, depressive symptoms, and CD4 cell count from 100 to 199 cells/μL.

Results:Of 401 HIV‐infected subjects, 200 were HCV RNA‐positive. Fifty‐three percent had an absolute contraindication to interferon therapy, 35% a relative but no absolute contraindication, and only 12% had no contraindication. Of those with an absolute contraindication, 61% reported heavy drinking and the majority (88%) had multiple contraindications. These contraindications were present despite the fact that over 50% were in receipt of substance abuse and mental health treatment.

Conclusions:Continued alcohol and drug use as well as depressive symptoms are the major barriers to interferon therapy in HCV/HIV‐coinfected subjects and these barriers persist despite high treatment rates for these problems. Therefore, more intensive treatments of alcohol, drug, and mental health issues are needed to improve HCV treatment eligibility in HCV/HIV‐coinfected persons.