bluuebunny/crossref_metadata_2025 huggingface dataset:
Histone H1x is highly expressed in human neuroendocrine cells and tumours
Authors: Warneboldt Julia , Haller Florian , Horstmann Olaf , Danner Bernhard C , Füzesi László , Doenecke Detlef , Happel Nicole
Published: December 2008

Background

Histone H1x is a ubiquitously expressed member of the H1 histone family. H1 histones, also called linker histones, stabilize compact, higher order structures of chromatin. In addition to their role as structural proteins, they actively regulate gene expression and participate in chromatin-based processes like DNA replication and repair. The epigenetic contribution of H1 histones to these mechanisms makes it conceivable that they also take part in malignant transformation.

Methods

Based on results of a Blast data base search which revealed an accumulation of expressed sequence tags (ESTs) of H1x in libraries from neuroendocrine tumours (NETs), we evaluated the expression of H1x in NETs from lung and the gastrointestinal tract using immunohistochemisty. Relative protein and mRNA levels of H1x were analysed by Western blot analysis and quantitative real-time RT-PCR, respectively. Since several reports describe a change of the expression level of the replacement subtype H1.0 during tumourigenesis, the analysis of this subtype was included in this study.

Results

We found an increased expression of H1x but not of H1.0 in NET tissues in comparison to corresponding normal tissues. Even though the analysed NETs were heterogenous regarding their grade of malignancy, all except one showed a considerably higher protein amount of H1x compared with corresponding non-neoplastic tissue. Furthermore, double-labelling of H1x and chromogranin A in sections of pancreas and small intestine revealed that H1x is highly expressed in neuroendocrine cells of these tissues.

Conclusion

We conclude that the high expression of histone H1x in NETs is probably due to the abundance of this protein in the cells from which these tumours originate.
Ephrin-B2 expression critically influences Nipah virus infection independent of its cytoplasmic tail
Authors: Thiel Lena , Diederich Sandra , Erbar Stephanie , Pfaff Dennis , Augustin Hellmut G , Maisner Andrea
Published: December 2008

Background

Cell entry and cell-to-cell spread of the highly pathogenic Nipah virus (NiV) requires binding of the NiV G protein to cellular ephrin receptors and subsequent NiV F-mediated fusion. Since expression levels of the main NiV entry receptor ephrin-B2 (EB2) are highly regulated in vivo to fulfill the physiological functions in axon guidance and angiogenesis, the goal of this study was to determine if changes in the EB2 expression influence NiV infection.

Results

Surprisingly, transfection of increasing EB2 plasmid concentrations reduced cell-to-cell fusion both in cells expressing the NiV glycoproteins and in cells infected with NiV. This effect was attributed to the downregulation of the NiV glycoproteins from the cell surface. In addition to the influence on cell-to-cell fusion, increased EB2 expression significantly reduced the total amount of NiV-infected cells, thus interfered with virus entry. To determine if the negative effect of elevated EB2 expression on virus entry is a result of an increased EB2 signaling, receptor function of a tail-truncated and therefore signaling-defective ΔcEB2 was tested. Interestingly, ΔcEB2 fully functioned as NiV entry and fusion receptor, and overexpression also interfered with virus replication.

Conclusion

Our findings clearly show that EB2 signaling does not account for the striking negative impact of elevated receptor expression on NiV infection, but rather that the ratio between the NiV envelope glycoproteins and surface receptors critically influence cell-to-cell fusion and virus entry.
Altered ATP Release and Metabolism in Dorsal Root Ganglia of Neuropathic Rats
Authors: Matsuka Yoshizo , Ono Takeshi , Iwase Hirotate , Mitrirattanakul Somsak , Omoto Kevin S , Cho Ting , Lam Yan Yan N , Snyder Bradley , Spigelman Igor
Published: December 2008

Background:

Adenosine 5′-triphosphate (ATP) has a ubiquitous role in metabolism and a major role in pain responses after tissue injury. We investigated the changes in basal and KCl-evoked ATP release from rat dorsal root ganglia (DRG) after peripheral neuropathy induction by unilateral sciatic nerve entrapment (SNE).

Results:

After SNE, rats develop long-lasting decreases in ipsilateral hindpaw withdrawal thresholds to mechanical and thermal stimulation. At 15–21 days after neuropathy induction, excised ipsilateral L4–L5 DRG display significantly elevated basal extracellular ATP levels compared to contralateral or control (naive) DRG. However, KCl-evoked ATP release is no longer observed in ipsilateral DRG. We hypothesized that the differential SNE effects on basal and evoked ATP release could result from the conversion of extracellular ATP to adenosine with subsequent activation of adenosine A1 receptors (A1Rs) on DRG neurons. Adding the selective A1R agonist, 2-chloro-N6-cyclopentyladenosine (100 nM) significantly decreased basal and evoked ATP release in DRG from naïve rats, indicating functional A1R activation. In DRG ipsilateral to SNE, adding a selective A1R antagonist, 8-cyclopentyl-1,3-dipropylxanthine (30 nM), further increased basal ATP levels and relieved the blockade of KCl-evoked ATP release suggesting that increased A1R activation attenuates evoked ATP release in neurons ipsilateral to SNE. To determine if altered ATP release was a consequence of altered DRG metabolism we compared O2 consumption between control and neuropathic DRG. DRG ipsilateral to SNE consumed O2 at a higher rate than control or contralateral DRG.

Conclusion:

These data suggest that peripheral nerve entrapment increases DRG metabolism and ATP release, which in turn is modulated by increased A1R activation.
Nestin and CD133: valuable stem cell-specific markers for determining clinical outcome of glioma patients
Authors: Zhang Mingyu , Song Tao , Yang Liang , Chen Ruokun , Wu Lei , Yang Zhuanyi , Fang Jiasheng
Published: December 2008

Aim

Gliomas represent the most frequent neoplasm of the central nervous system. Unfortunately, surgical cure of it is practically impossible and their clinical course is primarily determined by the biological behaviors of the tumor cells. The aim of this study was to investigate the correlation of the stem cell markers Nestin and CD133 expression with the grading of gliomas, and to evaluate their prognostic value.

Methods

The tissue samples consisted of 56 low- (WHO grade II), 69 high- (WHO grade III, IV) grade gliomas, and 10 normal brain tissues. The expression levels of Nestin and CD133 proteins were detected using SABC immunohistochemical analysis. Then, the correlation of the two markers' expression with gliomas' grading of patients and their prognostic value were determined.

Results

Immunohistochemical analysis with anti-Nestin and anti-CD133 antibodies revealed dense and spotty staining in the tumor cells and their expression levels became significantly higher as the glioma grade advanced (p < 0.05). There was a positive correlation between the two markers' expression in different gliomas tissues (rs = 0.89). The low expression of the two markers significantly correlated with long survival of the glioma patients (p < 0.05). The survival rate of the patients with Nestin+/CD133+ expression was the lowest (p < 0.01), and the multivariate analysis confirmed that conjoined expression of Nestin+/CD133+ and Nestin-/CD133- were independent prognostic indicators of gliomas (both p < 0.01, Cox proportional hazard regression model).

Conclusion

These results collectively suggest that Nestin and CD133 expression may be an important feature of human gliomas. A combined detection of Nestin/CD133 co-expression may benefit us in the prediction of aggressive nature of this tumor.
Growth Differentiation Factor 9 Is a Germ Cell Regulator of Sertoli Cell Function
Authors: Nicholls Peter K. , Harrison Craig A. , Gilchrist Robert B. , Farnworth Paul G. , Stanton Peter G.
Published: December 2008

Oocyte-secreted growth differentiation factor (GDF) 9 and bone morphogenetic protein (BMP) 15 are critical regulatory factors in female reproduction. Together, they promote granulosa cell proliferation and stimulate the maturation of preovulatory follicles. Despite their importance in female fertility, GDF9 and BMP15 expression patterns and function during spermatogenesis have not been investigated. In this study we show that the expression and stage-specific localization of both factors are limited to the germ cells of the rat seminiferous epithelium, with GDF9 being principally localized in round spermatids and BMP15 in gonocytes and pachytene spermatocytes. To identify potential cellular targets for GDF9 actions, cells of the seminiferous tubule were isolated and screened for the expression of signaling receptors [activin-like kinase (ALK) 5, ALK6, and BMP receptor, type II)]. Individual receptor types were expressed throughout the seminiferous epithelium, but coexpression of ALK5 and BMP receptor, type II was limited to Sertoli cells and round spermatids. Based on the reproductive actions of related TGFβ ligands in the ovary and testis, GDF9 was assessed for its ability to regulate tight junction function and inhibin B production in rat Sertoli cell cultures. When recombinant mouse GDF9 was added to immature Sertoli cell cultures, it inhibited membrane localization of the junctional proteins claudin-11, occludin, and zonula occludens-1, thereby disrupting tight junction integrity. Concomitantly, GDF9 up-regulated inhibin subunit expression and significantly stimulated dimeric inhibin B protein production. Together, these results demonstrate that GDF9 and BMP15 are germ cell-specific factors in the rat testis, and that GDF9 can modulate key Sertoli cell functions.
Role of the Rho-ROCK (Rho-Associated Kinase) Signaling Pathway in the Regulation of Pancreatic β-Cell Function
Authors: Hammar Eva , Tomas Alejandra , Bosco Domenico , Halban Philippe A.
Published: December 2008

Extracellular matrix has a beneficial impact on β-cell spreading and function, but the underlying signaling pathways have yet to be fully elucidated. In other cell types, Rho, a well-characterized member of the family of Rho GTPases, and its effector Rho-associated kinase (ROCK), play an important role as downstream mediators of outside in signaling from extracellular matrix. Therefore, a possible role of the Rho-ROCK pathway in β-cell spreading, actin cytoskeleton dynamics, and function was investigated. Rho was inhibited using a new cell-permeable version of C3 transferase, whereas the activity of ROCK was repressed using the specific ROCK inhibitors H-1152 and Y-27632. Inhibition of Rho and of ROCK increased spreading and improved both short-term and prolonged glucose-stimulated insulin secretion but had no impact on basal secretion. Inhibition of this pathway led to a depolymerization of the actin cytoskeleton. Furthermore, the impact of the inhibition of ROCK on stimulated insulin secretion was acute and reversible, suggesting that rapid signaling such as phosphorylation is involved. Finally, quantification of the activity of RhoA indicated that the extracellular matrix represses RhoA activity. Overall these results show for the first time that the Rho-ROCK signaling pathway contributes to the stabilization of the actin cytoskeleton and inhibits glucose-stimulated insulin secretion in primary pancreatic β-cells. Furthermore, they indicate that inhibition of this pathway might be one of the mechanisms by which the extracellular matrix exerts its beneficial effects on pancreatic β-cell function.
Palatable Foods, Stress, and Energy Stores Sculpt Corticotropin-Releasing Factor, Adrenocorticotropin, and Corticosterone Concentrations after Restraint
Authors: Foster Michelle T. , Warne James P. , Ginsberg Abigail B. , Horneman Hart F. , Pecoraro Norman C. , Akana Susan F. , Dallman Mary F.
Published: December 2008

Previous studies have shown reduced hypothalamo-pituitary-adrenal responses to both acute and chronic restraint stressors in rats allowed to ingest highly palatable foods (32% sucrose ± lard) prior to restraint. In this study we tested the effects of prior access (7 d) to chow-only, sucrose/chow, lard/chow, or sucrose/lard/chow diets on central corticotropin-releasing factor (CRF) expression in rats studied in two experiments, 15 and 240 min after onset of restraint. Fat depot, particularly intraabdominal fat, weights were increased by prior access to palatable food, and circulating leptin concentrations were elevated in all groups. Metabolite concentrations were appropriate for values obtained after stressors. For unknown reasons, the 15-min experiment did not replicate previous results. In the 240-min experiment, ACTH and corticosterone responses were inhibited, as previously, and CRF mRNA in the hypothalamus and oval nucleus of the bed nuclei of the stria terminalis were reduced by palatable foods, suggesting strongly that both neuroendocrine and autonomic outflows are decreased by increased caloric deposition and palatable food. In the central nucleus of the amygdala, CRF was increased in the sucrose-drinking group and decreased in the sucrose/lard group, suggesting that the consequence of ingestion of sucrose uses different neural networks from the ingestion of lard. The results suggest strongly that ingestion of highly palatable foods reduces activity in the central stress response network, perhaps reducing the feeling of stressors.
Migraineurs' perceptions of and interactions with pharmacists: a qualitative study
Authors: Skomo Monica L , Desselle Shane P , Shah Neel
Published: December 2008

Aims and objectives

Migraine is an underdiagnosed and undertreated condition. Diagnosed and undiagnosed migraineurs come into frequent contact with pharmacists, who are in a unique position to intervene and potentially improve the therapeutic outcomes of migraineurs; however, little is known about migraineurs' attitudes towards pharmacists' roles and the experiences they have shared with pharmacists. The purpose of this study was to evaluate migraineurs' perceptions of the roles that pharmacists may play in helping them manage their disease.

Setting

Duquesne University, Pittsburgh, Pennsylvania, USA.

Method

The study employed the use of two focus groups of migraineurs from a university population, approached from a phenomenologic perspective. Focus-group sessions were conducted using a flexible interview guide. Focus-group content was digitally recorded, then transcribed, verified for accuracy and content analysed according to established criteria, employing the use of a formal coding procedure. Inductive analysis was performed to establish patterns, themes and categories in the data.

Key findings

Six principal themes emerged. Among the most important findings were that (1) migraineurs were concerned about managing their headaches and the impact migraine has on their lives and their families' lives, (2) migraineurs did not discuss their headaches or migraine therapy with pharmacists and (3) migraineurs believe that many communication barriers exist in their pharmacistpatient relationship.

Conclusion

Community pharmacists have an opportunity to impact the level of care provided to migraine sufferers. As such, community pharmacists should strive to remove communication barriers and be more proactive during interactions with these patients. Further study may examine how pharmacists can elicit more social support for migraineurs and to help migraineurs cope with their condition.
Identifying criteria for assessing the quality of medicines use review referral documentation by community pharmacists
Authors: James Delyth H , Hatten Sarah , Roberts Debra , John Dai N
Published: December 2008

Aims and objectives

The medicines use review (MUR) service was introduced in April 2005 for England and Wales as part of the new community pharmacy contractual framework. Following a MUR, community pharmacists are required to document their interventions and refer any unresolved issues to the patient's general medical practitioner using a structured template. The patient also receives a copy of this form. Anecdotal feedback suggests that there is considerable variation in the quality of this documentation. The aim of this study was to develop explicit criteria against which the quality of MUR referral documentation can be assessed.

Setting

This study forms part of the Welsh School of Pharmacy's ongoing monitoring and evaluation of its MUR accreditation assessment.

Method

A two-round electronic Delphi technique was used to develop a consensus of the key quality indicators to assess the quality of MUR referral documentation. Statements were generated following a systematic review of the literature plus interviews. Sixteen panellists who responded to an invitation to participate in the study were involved in the Delphi process (these were 10 out of 14 MUR accreditation tutors who were invited to take part and six pharmacy practitioners from a possible 22 primary care organisations in Wales) to rate the usefulness of these statements as a measure of pharmacists' referral skills. Consensus was defined a priori as > 70% of participants scoring the statement as 1–3 on an ordinal scale from 1–9 (where 1 is definitely and 9 is definitely not).

Key findings

The first round of the electronic Delphi survey comprised 30 statements of which consensus was gained for 19. Following the second round, consensus was achieved for 20 statements.

Conclusion

These criteria could be used to assess the quality of referral documentation following MUR and to provide feedback to pharmacists on their referral skills. However, further studies are needed to test the validity of the MUR quality indicators with community pharmacists and GPs and the feasibility of using this tool in practice.
The impact of an electronic prescribing and administration system on the safety and quality of medication administration
Authors: Franklin Bryony Dean , Jacklin Ann , Barber Nick
Published: December 2008

Objective

To assess the effect of an electronic prescribing and administration system on the safety and quality of medication administration in a UK hospital.

Setting

Surgical ward in a teaching hospital.

Method

Data were collected before and after introducing a closed-loop system comprising electronic prescribing, automated dispensing, barcode patient identification and electronic medication administration records (ServeRx, MDG Medical). We observed medication administration during drug rounds and assessed medication administration error (MAE) rates for ward-stock and non-ward-stock drugs, accuracy of medication administration documentation, timeliness of administration, administration of medication from unlocked areas and supervision of patients taking oral medication by nursing staff.

Key findings

Pre- and post-intervention MAE rates were 6.4 and 2.3% respectively for ward-stock drugs (95% confidence interval for the difference (CI) −5.8 to −2.4%), and 14.6 and 13.7% for non-ward-stock drugs (CI −6.5 to 4.7%). Excluding omissions due to unavailability, pre- and post-intervention MAE rates were 6.2 and 2.2% respectively for ward-stock drugs (CI −5.7 to −2.3%), and 9.2 and 3.5% for non-ward-stock drugs (CI −9.3 to −2.1%). Pre-intervention, 2086 doses (96.3%) were documented correctly and 1557 (95.9%) post-intervention (CI −1.6 to 0.8%). There were five clinically significant documentation discrepancies pre-intervention (0.2%), and 33 (2.0%) afterwards (CI 1.1 to 2.5%). Timeliness of administration improved post-intervention (P < 0.001; Chi-square test), as did administration of medication from unlocked areas (CI 4.7 to 7.3%) and supervision of patients taking oral medication (CI 17 to 23%).

Conclusion

Reductions in MAEs, excluding omissions due to unavailability, occurred for both ward-stock and non-ward-stock drugs. The system also improved timeliness and security of drug administration. However, there was an increase in potentially significant documentation discrepancies.
The social life of chemotherapy protocols in a UK cancer network
Authors: Hibbert Derek , Ryan-Woolley Bernadette , Amir Ziv
Published: December 2008

Aims and objectives

This paper explores the development of chemotherapy protocols in a UK NHS cancer network, using data from a study of a Macmillan-funded cancer network pharmacist post.

Setting

A UK NHS cancer network.

Method

Qualitative case study drawing mainly on interviews with stakeholders.

Key findings

The paper outlines the importance of protocols in addressing problems associated with service variability in cancer networks. It explores the development of a set of network-level chemotherapy protocols co-ordinated by a network pharmacist. The work to establish common protocols is seen in light of the congruent and conflicting agendas of constituent organisations. The potential for protocols to embody organisational interests is considered in the context of the network's particular political landscape. Whereas protocols could represent the interests of the network organisation, the latter also offered a bureaucratic process through which protocols might transcend their specific organisational origins. This depended on the democratic engagement of locality (hospital trust) specialist and generalist pharmacists in the network-level enterprise. The need for protocols to convince as network and locality documents entailed an ongoing process of negotiation, particularly around the extent to which documents could acknowledge and incorporate local practices.

Conclusion

The development of chemotherapy protocols in the cancer network was outlined as a complex and ongoing process, requiring collaborative work from a range of stakeholders. We note the relevance of Timmermans and Berg's analysis of the ‘local’ and ‘universal’ dimensions of protocols. The development process, co-ordinated by the network pharmacist, involved the negotiation of these two aspects with the aim of achieving standardisation in local contexts. Network structures and the network pharmacist served to promote a dialogue between local and universal domains. This enabled the network to embody local interests, while also encouraging adoption of an ‘extralocal’ perspective by locality stakeholders.
Evaluation of multi-dose repackaging for individual patients in long-term care institutions: savings from the perspective of statutory health insurance in Germany
Authors: Gerber Andreas , Stollenwerk Björn , Lauterbach Karl W , Stock Stephanie , Büscher Guido , Rath Thomas , Lungen Markus
Published: December 2008

Aims and objectives

Elderly people often have difficulty adhering to multi-drug medication regimens. The current study aimed to evaluate whether multi-dose repackaging for individual patients reduces medication expenses from the perspective of statutory health insurance in Germany.

Setting

A total of 307 residents, mean age 76.8 years, median age 80 years, from four long-term care facilities were included in the prospective pre—post study conducted from September 2004 to December 2005. Minimum periods of 9 months prior to and 9 months following the introduction of multi-dose packaging were compared at the individual level with respect to the expenses for medications that were repackaged in weekly blister packs.

Method

The main outcome measure was savings in medication expenses. Statistical evaluation was carried out using the program Rversion 2.1.0. Adjustments were made for effects of age and con currently increasing morbidity in so far as number of prescriptions were held constant at the individual level.

Key findings

In the subset of 181 people included in this analysis, approximately 6.0% (95% confidence interval, 5.1–7.0%; P < 0.001) of expenses for medication were saved: 2.0% (1.6–2.3%; P < 0.001) was due to price differences and 4.1% (3.2–5.0%; P < 0.001) to reduced wastage of prescribed medication. The probability of being prescribed a generic compared with a brand-name medication was significantly lower prior to the introduction of repackaging (0.92, 0.89–0.94; P < 0.01), although this did not have any effect on turnover of medications (0.996, 0.988–1.005; P < 0.01).

Conclusion

Significant savings in medication expenses were found. Nonetheless, cost savings should not be the sole objective in reorganising drug dispensing.
Exploring the role of clinical self-audits as a professional development tool
Authors: Newby David , Robertson Jane , Higgins Gwen
Published: December 2008

Aims and objectives

To explore the knowledge, attitudes and practices of pharmacists towards continuing education and continuing professional development (CPD) in general and clinical self-audits specifically as a CPD tool.

Setting

Newcastle, New South Wales, Australia.

Method

Two focus groups were used, involving 22 hospital and community pharmacists, with a range of professional experience. The focus groups explored the barriers and enablers to participating in continuing education and professional development activities, and clinical self-audits in particular.

Key findings

Participants indicated support for CPD, although sometimes found it difficult to distinguish between CPD and continuing education. Not all pharmacists supported CPD being compulsory for continuing registration. The barriers to involvement in educational activities included time, cost and lack of locums. The main barriers to involvement in clinical self-audits were lack of time, and a lack of awareness of what they involved. Once explained, there was support for the concept of clinical self-audits as a professional development tool.

Conclusion

Pharmacists want professional development activities suitable for the variety of practice settings in which they now work. Clinical self-audits appear to address many of the limitations of current educational activities, being practice-focused, flexible, able to be accommodated within working routines and available at low cost. However, better promotion and increased exposure to them is required to improve their uptake.
Off-label promotion of drugs in Bangladesh: evidence from promotional brochures circulated among general practioners by pharmaceutical companies
Authors: Islam Mohammad Saidul
Published: December 2008

Aims and objectives

To gauge the incidences and nature of off-label promotion of drugs in the promotional brochures circulated among general practioners (GPs) in Bangladesh.

Setting

A single district town of Bangladesh.

Methods

Pharmaceutical promotional brochures were obtained from the ten GPs seeing the most patients using convenience sampling. Data sheets for both proprietary and generic products were used to identify off-label promotion in the brochures. This was done because drug formulations as well as other scientific information are copied from the original brands in Bangladesh. Data management and statistical analysis were performed using Microsoft Excel.

Key findings

Of the total promotional claims, 32% were found to be off-label while the rest were as per the approved indications. Brochures for drugs used in cases of diabetes contained the highest rates (66.7%) of off-label claims followed by centrally acting drugs (56.3%). Among the centrally acting drugs, clonazepam was found to have the highest (44%) level of off-label claims. Brochures on vitamin and mineral preparations were reported to promote off-label use with mecobalamin alone having 50% off-label claims. Brochures on flucloxacillin were reported to have the highest (19%) level of off-label claims among the antibiotics. Significant levels (35%) of off-label claims were found in brochures for anti-ulcerant drugs, with ranitidine having about 58%. Promotional brochures on cardiovascular drugs and non-steroidal anti-inflammatory drugs (NSAIDs) showed 29.7% and 19.4% off-label claims respectively.

Conclusion

In this study, a high level of off-label promotional claims was reported in the pharmaceutical promotional brochures distributed among GPs in Bangladesh.
Linear system identification of a cold flow circulating fluidized bed
Authors: Panday R , Woerner B D , Ludlow J C , Shadle L J , Boyle E J
Published: December 2008

Knowledge of the solids circulation rate (SCR) is essential to the control and improved performance of a circulating fluidized bed system. In the present work, the noise model is derived using the prediction error method considering process and measurement noises acting on the cold flow circulating fluidized bed (CFCFB) with a cork particulate material. The outputs of the initial model are the total pressure drop across the riser, the pressure drop across the crossover, the pressure drop across the primary cyclone, the total pressure drop across the stand-pipe, the pressure drop across the loop seal, and the SCR. The stochastic estimate of SCR is determined from the noise model using the stochastic pressure drop estimates. The deterministic estimate is obtained through the inputs taken as move air flow, riser aeration, and loop seal fluidization air that are all independent variables of the given setup and under the control of the user. The theory has been developed to convert a complete blackbox model to a grey box model through the output-to-state transformation such that both the models of the CFCFB consists of all these output variables as the states of the system, and only pressure drops across the system as the output measurements. Thus, the final models do not include any fictitious terms and they are defined only in terms of physical parameters of the given system. Both components of SCR are separately analysed. The combined SCR response of both the noise model and deterministic model is compared with the validation data set of this state variable in terms of modelfit, and the results are shown.
A numerical investigation of the flow structures and losses for turbulent flow in 90° elbow bends
Authors: Crawford N , Spence S , Simpson A , Cunningham G
Published: December 2008

Computational fluid dynamic modelling was carried out on a series of pipe bends having R/ r values of 1.3, 5, and 20, with the purpose of determining the accuracy of numerical models in predicting pressure loss data from which to inform one-dimensional loss models. Four separate turbulence models were studied: the standard k—ε model, realizable k—ε model, k—ω model, and a Reynolds stress model (RSM). The results are presented for each bend in the form of upstream and downstream pressure profiles, pressure distributions along the inner and outer walls, detailed pressure and velocity fields as well as overall loss values. In each case, measured data were presented to evaluate the predictive ability of each model. The RSM was found to perform the best, producing accurate pressure loss data for bends with R/ r values of 5 and 20. For the tightest bend with an R/ r value of 1.3, however, predictions were significantly worse due to the presence of flow separation, stronger pressure gradients, and high streamline curvature.
Is the Obesity Epidemic a Public Health Problem? A Review of Zoltan J. Acs and Alan Lyles's Obesity, Business and Public Policy
Authors: Philipson Tomas J , Posner Richard A
Published: December 2008

We review the recent but growing economic literature on the worldwide growth of obesity, relating the review to a recent anthology of articles—Obesity, Business and Public Policy. We discuss the competing explanations for the growth of obesity as well as the role of governments in attempting to limit it.
Mesolimbic Functional Magnetic Resonance Imaging Activations during Reward Anticipation Correlate with Reward-Related Ventral Striatal Dopamine Release
Authors: Schott Björn H. , Minuzzi Luciano , Krebs Ruth M. , Elmenhorst David , Lang Markus , Winz Oliver H. , Seidenbecher Constanze I. , Coenen Heinz H. , Heinze Hans-Jochen , Zilles Karl , Düzel Emrah , Bauer Andreas
Published: December 2008

The dopaminergic mechanisms that control reward-motivated behavior are the subject of intense study, but it is yet unclear how, in humans, neural activity in mesolimbic reward-circuitry and its functional neuroimaging correlates are related to dopamine release. To address this question, we obtained functional magnetic resonance imaging (fMRI) measures of reward-related neural activity and [11C]raclopride positron emission tomography measures of dopamine release in the same human participants, while they performed a delayed monetary incentive task. Across the cohort, a positive correlation emerged between neural activity of the substantia nigra/ventral tegmental area (SN/VTA), the main origin of dopaminergic neurotransmission, during reward anticipation and reward-related [11C]raclopride displacement as an index of dopamine release in the ventral striatum, major target of SN/VTA dopamine neurons. Neural activity in the ventral striatum/nucleus accumbens itself also correlated with ventral striatal dopamine release. Additionally, high-reward-related dopamine release was associated with increased activation of limbic structures, such as the amygdala and the hippocampus. The observed correlations of reward-related mesolimbic fMRI activation and dopamine release provide evidence that dopaminergic neurotransmission plays a quantitative role in human mesolimbic reward processing. Moreover, the combined neurochemical and hemodynamic imaging approach used here opens up new perspectives for the investigation of molecular mechanisms underlying human cognition.
Signaling through cGMP-Dependent Protein Kinase I in the Amygdala Is Critical for Auditory-Cued Fear Memory and Long-Term Potentiation
Authors: Paul Cindy , Schöberl Florian , Weinmeister Pascal , Micale Vincenzo , Wotjak Carsten T. , Hofmann Franz , Kleppisch Thomas
Published: December 2008

Long-term potentiation (LTP) of inputs relaying sensory information from cortical and thalamic neurons to principal neurons in the lateral amygdala (LA) is thought to serve as a cellular mechanism for associative fear learning. Nitric oxide (NO), a messenger molecule widely implicated in synaptic plasticity and behavior, has been shown to enhance LTP in the LA as well as consolidation of associative fear memory. Additional evidence suggests that NO-induced enhancement of LTP and amygdala-dependent learning requires signaling through soluble guanylyl cyclase (sGC) and cGMP-dependent protein kinase (cGK). Mammals possess two genes for cGK: theprkg1gene gives rise to the cGK type I isoforms, cGKIα and cGKIβ, and theprkg2gene encodes the cGK type II. Reportedly, both cGKI and cGKII are expressed in the amygdala, and cGKII is involved in controlling anxiety-like behavior. Because selective pharmacological tools for individual cGK isoforms are lacking, we used different knock-out mouse models to examine the function of cGKI and cGKII for LTP in the LA and pavlovian fear conditioning. We found robust expression of the cGKI specifically in the LA with cGKIβ as the prevailing isoform. We further show a marked reduction of LTP at both thalamic and cortical inputs to the LA and a selective impairment of auditory-cued fear memory in cGKI-deficient mutants. In contrast, cGKII null mutants lack these phenotypes. Our data suggest a function of cGKI, likely the β isoform, in the LA, supporting synaptic plasticity and consolidation of fear memory.
Distinct Roles for Onset and Sustained Activity in the Neuronal Code for Temporal Periodicity and Acoustic Envelope Shape
Authors: Zheng Yi , Escabí Monty A.
Published: December 2008

Auditory neurons are selective for temporal sound information that is important for rhythm, pitch, and timbre perception. Traditional models assume that periodicity information is represented either by the discharge rate of tuned modulation filters or synchrony in the discharge pattern. Compelling evidence for an invariant rate or synchrony code, however, is lacking and neither of these models account for how the sound envelope shape is encoded. We examined the neuronal representation for envelope shape and periodicity in the cat central nucleus of the inferior colliculus (CNIC) with modulated broadband noise that lacks spectral cues and produces a periodicity pitch percept solely based on timing information. The modulation transfer functions of CNIC neurons differed dramatically across stimulus conditions with identical periodicity but different envelope shapes implying that shape contributed significantly to the neuronal response. We therefore devised a shuffled correlation procedure to quantify how periodicity and envelope shape contribute to the temporal discharge pattern. Sustained responses faithfully encode envelope shape at low modulation rates but deteriorate and fail to account for timing and envelope information at high rates. Surprisingly, onset responses accurately entrained to the stimulus and provided a means of encoding repetition information at high rates. Finally, we demonstrate that envelope shape information is accurately reflected in the population discharge pattern such that shape is readily discriminated for repetition frequencies up to ∼100 Hz. These results argue against conventional rate- or synchrony-based codes and provide two complementary temporal mechanisms by which CNIC neurons can encode envelope shape and repetition information in natural sounds.
Id2 Is Required for Specification of Dopaminergic Neurons during Adult Olfactory Neurogenesis
Authors: Havrda Matthew C. , Harris Brent T. , Mantani Akio , Ward Nora M. , Paolella Brenton R. , Cuzon Verginia C. , Yeh Hermes H. , Israel Mark A.
Published: December 2008

Understanding the biology of adult neural stem cells has important implications for nervous system development and may contribute to our understanding of neurodegenerative disorders and their treatment. We have characterized the process of olfactory neurogenesis in adult mice lacking inhibitor of DNA binding 2−/−(Id2−/−). We found a diminished olfactory bulb containing reduced numbers of granular and periglomerular neurons with a distinct paucity of dopaminergic periglomerular neurons. While no deficiency of the stem cell compartment was detectable, migrating neuroblasts inId2−/−mutant mice prematurely undergo astroglial differentiation within a disorganized rostral migratory stream. Further, when evaluatedin vitroloss ofId2results in decreased proliferation of neural progenitors and decreased expression of theHes1andAscl1 (Mash1)transcription factors, known mediators of neuronal differentiation. These data support a novel role for sustainedId2expression in migrating neural progenitors mediating olfactory dopaminergic neuronal differentiation in adult animals.
Four Excitatory Postsynaptic Ionotropic Receptors Coactivated at the Motoneuron–Renshaw Cell Synapse
Authors: Lamotte d'Incamps Boris , Ascher Philippe
Published: December 2008

Renshaw cells (RCs) are spinal interneurons excited by collaterals of the axons of motoneurons (MNs). They respond to a single motoneuronal volley by a surprisingly long (tens of milliseconds) train of action potentials. We have analyzed this synaptic response in spinal cord slices of neonatal mice in light of recent observations suggesting that the MN axons release both acetylcholine and glutamate. We found that the RC synaptic current involves four components of similar amplitudes mediated by two nicotinic receptors (nAChRs, tentatively identified as α7homomers and α4β2heteromers) and two glutamate receptors (AMPARs and NMDARs). The decay time constants of the four components cover a wide range: from 3.6 ± 2.2 ms (α7nAChRs) to 54.6 ± 19.5 ms (NMDARs, at −45 mV). The RC discharge can be separated into an initial doublet of high-frequency action potentials followed by later spikes with a variable latency and longer interspike intervals. The initial doublet involves the four ionotropic receptors as well as endogenous voltage-dependent conductances. The late discharge depends on NMDARs, but these receptors must be primed by the initial depolarization. The activation of the NMDARs is prolonged by the fact that their slow deactivation is further slowed by depolarization. The formation of the initial doublet is favored by hyperpolarization, whereas the late discharge is favored by depolarization. This suggests that in physiological conditions the pattern of discharge of the RC in response to a MN input may alternate between a phasic and a tonic response.
Multiple Molecular Interactions Determine the Clustering of Caspr2 and Kv1 Channels in Myelinated Axons
Authors: Horresh Ido , Poliak Sebastian , Grant Seth , Bredt David , Rasband Matthew N. , Peles Elior
Published: December 2008

Clustering of Kv1 channels at the juxtaparanodal region (JXP) in myelinated axons depends on their association with the Caspr2/TAG-1 adhesion complex. The interaction between these channels and Caspr2 was suggested to depend on PDZ (PSD-95/Discs large/zona occludens-1) scaffolding proteins. Here, we show that at a subset of the JXP, PSD-93 colocalizes with Caspr2, K+channels and its related protein postsynaptic density protein-95 (PSD-95). The localization of PSD-93 and PSD-95 depends on the presence of Caspr2, as both scaffolding proteins failed to accumulate at the JXP in mice lacking either Caspr2 or TAG-1. In contrast, Caspr2 and K+channels still colocalized and associated inPSD-93,PSD-95or doublePSD-93/PSD-95null mice. To directly evaluate the role of PDZ domain proteins in the function of Caspr2, we examined the ability of transgenic Caspr2 molecules lacking either their cytoplasmic domain (Caspr2dCT), or their PDZ-binding sequence (Caspr2dPDZ), to restore Kv1 channel clustering inCaspr2null mice. We found that while Kv1 channels were distributed throughout internodes in nerves expressing Caspr2dCT, they were clustered at the JXP in axons expressing a full-length Caspr2 (Caspr2FL) or the Caspr2dPDZ transgene. Further proteomic analysis revealed that Caspr2 interacts with a distinct set of scaffolding proteins through its PDZ- and protein 4.1-binding sequences. These results demonstrate that while the molecular assembly of the JXP requires the cytoplasmic domain of Caspr2, its carboxy-terminal PDZ-binding motif is dispensable for Kv1 channel clustering. This mechanism is clearly distinct from the one operating at the axon initial segment, which requires PSD-93 for Kv1 channel clustering.
Control of Motoneuron Survival by Angiogenin
Authors: Kieran Dairín , Sebastia Jordi , Greenway Matthew J. , King Matthew A. , Connaughton Dervla , Concannon Caoimhin G. , Fenner Beau , Hardiman Orla , Prehn Jochen H. M.
Published: December 2008

Mutations in the hypoxia-inducible factor angiogenin (ANG) have been identified in Amyotrophic Lateral Sclerosis (ALS) patients, but the potential role ofANGin ALS pathogenesis was undetermined. Here we show that angiogenin promotes motoneuron survival bothin vitroandin vivo. Angiogenin protected cultured motoneurons against excitotoxic injury in a PI-3-kinase/Akt kinase-dependent manner, whereas knock-down of angiogenin potentiated excitotoxic motoneuron death. Expression of wild-typeANGprotected against endoplasmic reticulum (ER) stress-induced and trophic-factor-withdrawal-induced cell deathin vitro, whereas the ALS-associatedANGmutant K40I exerted no protective activity and failed to activate Akt-1. InSOD1G93Amice angiogenin delivery increased lifespan and motoneuron survival, restored the disease-associated decrease in Akt-1 survival signaling, and reversed a pathophysiological increase in ICAM-1 expression. Our data demonstrate that angiogenin is a key factor in the control of motoneuron survival.
Relationship of Striatal Dopamine Synthesis Capacity to Age and Cognition
Authors: Braskie Meredith N. , Wilcox Claire E. , Landau Susan M. , O'Neil James P. , Baker Suzanne L. , Madison Cindee M. , Kluth Jennifer T. , Jagust William J.
Published: December 2008

Past research has demonstrated that performance on frontal lobe-dependent tasks is associated with dopamine system integrity and that various dopamine system deficits occur with aging. The positron emission tomography (PET) radiotracer 6-[18F]fluoro-l-m-tyrosine (FMT) is a substrate of the dopamine-synthesizing enzyme, aromatic amino acid decarboxylase (AADC). Studies using 6-[18F]fluorodopa (FDOPA) (another AADC substrate) to measure how striatal PET signal and age relate have had inconsistent outcomes. The varying results occur in part from tracer processing that renders FDOPA signal subject to aspects of postrelease metabolism, which may themselves change with aging. In contrast, FMT remains a purer measure of AADC function. We used partial volume-corrected FMT PET scans to measure age-related striatal dopamine synthesis capacity in 21 older (mean, 66.9) and 16 younger (mean, 22.8) healthy adults. We also investigated how striatal FMT signal related to a cognitive measure of frontal lobe function. Older adults showed significantly greater striatal FMT signal than younger adults. Within the older group, FMT signal in dorsal caudate (DCA) and dorsal putamen was greater with age, suggesting compensation for deficits elsewhere in the dopamine system. In younger adults, FMT signal in DCA was lower with age, likely related to ongoing developmental processes. Younger adults who performed worse on tests of frontal lobe function showed greater FMT signal in right DCA, independent of age effects. Our data suggest that higher striatal FMT signal represents nonoptimal dopamine processing. They further support a relationship between striatal dopamine processing and frontal lobe cognitive function.
Nociceptors Are Interleukin-1β Sensors
Authors: Binshtok Alexander M. , Wang Haibin , Zimmermann Katharina , Amaya Fumimasa , Vardeh Daniel , Shi Lin , Brenner Gary J. , Ji Ru-Rong , Bean Bruce P. , Woolf Clifford J. , Samad Tarek A.
Published: December 2008

A cardinal feature of inflammation is heightened pain sensitivity at the site of the inflamed tissue. This results from the local release by immune and injured cells of nociceptor sensitizers, including prostaglandin E2, bradykinin, and nerve growth factor, that reduce the threshold and increase the excitability of the peripheral terminals of nociceptors so that they now respond to innocuous stimuli: the phenomenon of peripheral sensitization. We show here that the proinflammatory cytokine interleukin-1β (IL-1β), in addition to producing inflammation and inducing synthesis of several nociceptor sensitizers, also rapidly and directly activates nociceptors to generate action potentials and induce pain hypersensitivity. IL-1β acts in a p38 mitogen-activated protein kinase (p38 MAP kinase)-dependent manner, to increase the excitability of nociceptors by relieving resting slow inactivation of tetrodotoxin-resistant voltage-gated sodium channels and also enhances persistent TTX-resistant current near threshold. By acting as an IL-1β sensor, nociceptors can directly signal the presence of ongoing tissue inflammation.