bluuebunny/crossref_metadata_2025 huggingface dataset:
Alteration in the Sensitivity of GABAAReceptors to Allosteric Modulatory Drugs in Rat Hippocampus After Chronic Intermittent Ethanol Treatment
Authors: Kang Maeng‐Hee , Spigelman Igor , Olsen Richard W.
Published: February 2008

Chronicintermittentethanol (CIE)‐treated rats exhibited a kindlinglike persistent increase in withdrawal hyperexcitability. The alteration of GABAAreceptor (QABAAR) function in the hippocampus was suggested as a possible mechanism underlying the hyperexcitability observed in CIE rats, because (1) GABAAR agonist (muscimol)‐evoked38Cl‐ efflux was decreased; (2) paired‐pulse inhibition in the CA1 area, predominantly due to GABAAR‐mediated recurrent inhibition, was persistently decreased; and (3) GABAAR subunit expression was altered in the hippocampus from CIE rats. To further characterize the functional alteration of GABAAR after CIE treatment, their sensitivity to acute ethanol, a steroid anesthetic (alphaxalone), and a benzodiazepine inverse agonist (DMCM; methyl‐6, 7‐dimethoxy‐4‐ethyl‐β‐carboline‐3‐carboxylate) were studied using either synaptically evoked GABAAR responses or exogenously applied muscimol‐evoked responses in hippocampal slices. Bath application of ethanol (60 mM) enhanced the area of GABAAR‐mediated inhibitory postsynaptic potentials in the hippocampal CA1 region from control and CIE rats, and this potentiation was significantly (p = 0.027) greater in CIE rats (98%) than in control rats (53%). The positive modulatory effect of alphaxalone (1 μM) on GABAAR‐inhibitory postsynaptic potentials was not significantly different between control and CIE rats (p = 0.375), whereas alphaxalone allosterically increased [3H]flunitrazepam binding in the CA1 area only in CIE rats (by 20 to 25%, p < 0.01), but not in controls. On the other hand, the negative modulatory effect of DMCM (1 μM) on muscimol‐evoked responses was significantly larger in CIE rats (p = 0.002). These results suggest that the sensitization of GABAAR to acute ethanol and benzodiazepine inverse agonists, and possibly neurosteroids, may underlie ethanol dependence after multiple ethanol withdrawal episodes. These altered pharmacological properties are most consistent with changes in the subunit composition in the CA1 area of this rat model of alcohol dependence.
The Opioid Receptor Antagonist Nalmefene Reduces Responding Maintained by Ethanol Presentation: Preclinical Studies in Ethanol‐Preferring and Outbred Wistar Rats
Authors: June Harry L , Grey Collette , Warren‐Reese Connease , Durr La Franze , Ricks‐Cord Anila , Johnson Amanda , McCane Shannan , Williams LaShone , Mason Dynesha , Cummings Rancia , Lawrence Amanda
Published: February 2008

Nalmefene, the 6‐methylene derivative of naltrexone, was examined after subcutaneous (s.c.) (0.0001 to 8.0 mg/kg) and oral (10 to 80.0 mg/kg) administration in ethanol (EtOH)‐preferring rats whose responding (i.e., lever pressing) was maintained by the presentation of EtOH. Naltrexone (0.01 to 40 mg/kg) was used as a reference opioid antagonist. EtOH (10% v/v) and saccharin (0.025 to 0.1% w/v) solutions were concurrently available for 1 hr each day under a two‐lever, fixed‐ratio schedule in which four responses on one lever produced the EtOH solution and four responses on the other lever produced the saccharin solution. When basal response rates for saccharin were 10% that of EtOH, all routes of nalmefene administration reduced control levels of responding maintained by EtOH by 38 to 84%. When basal response rates for saccharin‐maintained responding were 60% or 82% that of EtOH, only lower s.c. naltrexone (e.g., 0.01 to 0.025 mg/kg) and nalmefene (e.g., 0.01 to 0.10 mg/kg) doses produced a selective dose‐dependent suppression of EtOH‐maintained responding. Higher nalmefene (0.25 to 8.0 mg/kg) and naltrexone (1.0 to 20.0 mg/kg) doses failed to produce a dose‐dependent suppression on EtOH or saccharin maintained responding. Both antagonists suppressed responding maintained by EtOH primarily during the initial 10‐min period, with little additional suppression occurring across the remainder of the 60‐min period. Subcutaneous nalmefene was 3200‐ to 6400‐fold more potent than oral nalmefene, suggesting bioavailability was optimized using the s.c. route. Nalmefene (0.5 mg/kg, s.c.) treatment for 10 consecutive days produced mild tolerance development, whose effects dissipated by day 8. Naltrexone (10 to 40 mg/kg) and nalmefene (1.5 to 3.0 mg/kg), given 8 to 24 hr before the test session, reduced control levels of responding maintained by EtOH by 82%. Thus, immediate opioid receptor occupancy was not required to observe antagonism. These data demonstrate that, under a variety of experimental conditions, nalmefene is an effective antagonist of responding maintained by EtOH and lend support to clinical reports that nalmefene may function as an alternative pharmacotherapy to naltrexone to reduce EtOH‐motivated behavior and prevent relapse.
Clearance of dengue virus in the plasma‐derived therapeutic proteins
Authors: Xie Yi‐Wu , Chan Paul K.S. , Szeto Chi Kit , Kwok Sui Yi , Chu Ida M.T. , Chu Shirley S.L. , Cheung Jo L.K. , Wong Sai Wah , Ali Mahommed B. , Wong Bing‐Lou
Published: February 2008

BACKGROUND: Viral safety is of paramount importance for human plasma–derived therapeutic proteins. Recent reports of blood‐associated transmission and continuous regional outbreaks of dengue fever have prompted a validation of clearance of dengue virus in the manufacture processes of the plasma‐derived products.

STUDY DESIGN AND METHODS: A high titer of cultured dengue virus serotype 2 was spiked into process samples before individual steps of albumin and immunoglobulin manufacture processes, including cold ethanol precipitation, cation‐exchange chromatography, pasteurization, solvent/detergent treatment, and virus filtration. Clearance of dengue virus was quantified with TCID50 assays in the culture of Vero E6 cells and, when appropriate, real‐time polymerase chain reaction (RT‐PCR) assays.

RESULTS: The individual process steps were all effective in the inactivation and/or removal of dengue virus, and the data obtained clearly demonstrate that the risk of dengue virus transmission was reduced cumulatively by at least 10.12 and at least 14.24 log in the albumin and immunoglobulin manufacture processes, respectively.

CONCLUSION: The dedicated viral inactivation and/or removal approaches currently implemented in the manufacture of plasma‐derived products provide a good safety margin with regard to the transmission of dengue virus.
New Health Risks and Sociocultural Contexts: Bird Flu Impacts on Consumers and Poultry Businesses in Lao PDR
Authors: Suder Gabriele , Inthavong Saynakhone
Published: February 2008

Avian flu has been identified as one of the most challenging new risks, global in impact due to the “highly interconnected and integrated world economy along with other unpredictable events such as the Asian financial crisis and global terrorism.” We have chosen the case of Lao PDR to shed light on an area in which local people consume chicken as one of their staple foods. Our research analyzes consumer behavior, poultry business modification patterns in a high‐risk country, and government reaction for business resilience. The geographic choice is motivated by the 2006 EIU report on Catastrophe Risk Management that indicated that Asian‐Pacific companies are better prepared for such risks as bird flu than European business is, despite the many cases found in both regions.
Individual‐ and Community‐Level Effects on Risk Perception in Cancer Cluster Investigations
Authors: Trumbo Craig W. , McComas Katherine A. , Besley John C.
Published: February 2008

This article focuses on the relative influence of individual versus community effects on risk perception. The study is grounded in literature examining how individuals manage information and make risk judgments in the context of suspected environmental cancer threats. We focus on three individual‐level perspectives: the psychometric model of risk perception, an adaptation of the heuristic‐systematic information processing model, and cancer anxiety. We also evaluate five sets of community‐level variables that frame cancer cluster investigations: demographic, epidemiologic, sociologic, etiologic, and pathologic. Data were collected through a mail survey of 30 communities in which cancer cluster investigations were being conducted. Response rates averaged 43%, with 1,111 records in the final data set. Through multilevel modeling and other techniques, the results show that the individual‐level model developed in previous work remains a robust description of risk perception in these cases. However, the analysis also shows that the community‐level measures neither improve the individual‐level model nor offer any substantial explanatory power of their own. We provisionally conclude that, within the context of cancer cluster investigations, risk perception is a phenomenon located in a common psychological dimension that is substantially independent of contextual influences. We also suggest that risk communication efforts in this specific context might successfully draw from a common approach informed more by individual than community factors.
Societal Risk Perception Among African Villagers Without Access to the Media
Authors: Kpanake Lonzozou , Chauvin Bruno , Mullet Etienne
Published: February 2008

The impact of the media on people's risk perception was assessed by comparing risk ratings obtained from African villagers without access to the media with risk ratings obtained from African city‐dwellers with access to the media and risk ratings obtained from French participants. The overall mean risk judgment observed among the Togolese villagers was lower than the mean rating observed among the Togolese city‐dwellers, and lower than the mean rating observed among the French. The linear association observed between the Togolese villagers' ratings and the Togolese city‐dweller ratings and the French ratings was moderate. The impact of the media on risk perception was estimated to be an increase of about 15% of the overall mean ratings, and to about 31% of the variance of the mean ratings. This impact was independent of educational level.
A Flexible Count Data Regression Model for Risk Analysis
Authors: Guikema Seth D. , Goffelt Jeremy P.
Published: February 2008

In many cases, risk and reliability analyses involve estimating the probabilities of discrete events such as hardware failures and occurrences of disease or death. There is often additional information in the form of explanatory variables that can be used to help estimate the likelihood of different numbers of events in the future through the use of an appropriate regression model, such as a generalized linear model. However, existing generalized linear models (GLM) are limited in their ability to handle the types of variance structures often encountered in using count data in risk and reliability analysis. In particular, standard models cannot handle both underdispersed data (variance less than the mean) and overdispersed data (variance greater than the mean) in a single coherent modeling framework. This article presents a new GLM based on a reformulation of the Conway‐Maxwell Poisson (COM) distribution that is useful for both underdispersed and overdispersed count data and demonstrates this model by applying it to the assessment of electric power system reliability. The results show that the proposed COM GLM can provide as good of fits to data as the commonly used existing models for overdispered data sets while outperforming these commonly used models for underdispersed data sets.
The Perceived Health Risks of Indoor Radon Gas and Overhead Powerlines: A Comparative Multilevel Approach
Authors: Poortinga Wouter , Cox Patrick , Pidgeon Nick F.
Published: February 2008

Radon and overhead powerlines are two radiation risk cases that have raised varying levels of concern among the general public and experts. Despite both involving radiation—a typically feared and unseen health hazard—individuals' perceptions of the two risk cases may invoke rather different factors. We examined individual and geographic‐contextual factors influencing public perceptions of the health risks of indoor radon gas and overhead powerlines in a comparative research design, utilizing a postal questionnaire with 1,528 members of the general public (response rate 28%) and multilevel modeling techniques. This study found that beliefs about the two risk cases mainly differed according to the level of “exposure”—defined here in terms of spatial proximity. We argue that there are two alternative explanations for this pattern of findings: that risk perception itself varies directly with proximity, or that risk is more salient to concerned people in the exposed areas. We also found that while people living in high radon areas are more concerned about the risks of indoor radon gas, they find these risks more acceptable and have more trust in authorities. These results might reflect the positive effects of successive radon campaigns in high radon areas, which may have raised awareness and concern, and at the same time may have helped to increase trust by showing that the government takes the health risks of indoor radon gas seriously, suggesting that genuine risk communication initiatives may have positive impacts on trust in risk management institutions.
The Bible and Gender Troubles: American Evangelicals Debate Scripture and Submission
Authors: Padgett Alan G.
Published: February 2008

Abstract:  This article surveys the recent debates about gender roles and submissions in American evangelical theology since the 1960's. It argues that the so‐called “complementarian” viewpoint, in which women are equal in being but submissive to men in gender roles, is not the same as the traditional Christian patriarchal viewpoint. Both biblical equality and complementarian views are thus revisionist. This article introduces the “return to the Trinity” in this debate as one of the more interesting moves in recent years, and suggests some lessons for mainline Protestants.
Beyond Strategy, Towards the Kingdom of God: The Post‐Critical Reconstructionist Mission of the Emerging Church
Authors: Moritz Joshua M.
Published: February 2008

Abstract:  The Emerging Church is a diverse global phenomenon which envisions a radical reforming of the theology and praxis of the broader Christian church in light of the philosophical and cultural shift from modernism to post‐modernism. Differing from the evangelical New Paradigm seeker‐sensitive Church's generational focus, and the organizational unity and routines of Mainline Protestant denominations the Emerging Church conversation endeavors to create committed, authentic, day‐to‐day communities that embrace ecumenical and ancient Christian theology and practices in order to live out the reality of the in‐breaking kingdom of God. Though precise systemic theological unity within the Emerging movement is recognized as an elusive goal that is generally not even sought, the movement as a whole finds much in common with post‐conservative and post‐liberal theology, and shares a joint mission with those who have been called to the task of post‐critical reconstruction.
Rethinking the Human Being in Light of Evolutionary Biology
Authors: Jersild Paul
Published: February 2008

Abstract:  For the sake of its own enrichment and relevance, Christian anthropology today must be informed by what we are learning from the biosciences, including the theory of biological evolution. The two quite different paradigms of theology and biology should be seen as complementary to each other, with theology recognizing the biological foundation of human nature. This necessitates a repudiation of the traditional body/soul dualism and re‐conceptualizing the concept of soul as a metaphorical expression rather than a spiritual entity. It affirms the spiritual dimension of human life that relates us to God and neighbor. Biblical scholarship affirms this psychosomatic, holistic view of the human being.
Should We Dispense with Sola Scriptura? Scripture, Tradition and Postmodern Theology
Authors: George Awad Najeeb
Published: February 2008

Abstract:  This essay deals with Kevin Vanhoozer's warning that the central attention that sola scriptura had once enjoyed is being paid instead to a sola traditio principle in postmodern theology. It argues that the emphasis on tradition does not necessitate a dispensation with sola scriptura. It points to Martin Luther's and Friedrich Scheliermacher's understanding of the role of Scripture in faith, and to Hans‐George Gadamer's hermeneutic understanding of tradition, to show that the original content of sola scriptura proves its principal value for today's interest in the tradition(s) of performance in the church. Sola scriptura both takes the text and its enactment into consideration and postulates that neither Scripture nor tradition alone work as a criterion for doing theology.
Microstructural Evolution of Calcium Aluminate Cements Hydration with Silica Fume and Fly Ash Additions by Scanning Electron Microscopy, and Mid and Near‐Infrared Spectroscopy
Authors: Hidalgo López Ana , García Calvo José Luis , García Olmo Juan , Petit Sabine , Alonso Marìa Cruz
Published: February 2008

Calcium aluminate cement (CAC) is less commonly used as ordinary Portland cements (OPCs) for structural concrete, is relatively expensive, but may have certain advantages when used for solidification of wastes; it introduces rapid strength gain and has a higher resistance to chemical attack than OPC. However, the most widely identified degradation process suffered by CAC is the so‐called conversion of hexagonal calcium aluminate hydrate to a cubic form. Mixes of CAC with silica fume (SF) or fly ash (FA) represent an interesting alternative for the stabilization of CAC hydrates, which might be attributed to a microstructure based mainly on aluminosilicates. This paper deals with the microstructure of cement pastes fabricated with binders of CAC–SF and CAC–FA, and their evolution over time. Mid infrared and near infrared spectroscopy have been used to assess the microstructure of these formulations. Microstructural characterization was completed by backscattering electron microscopy observation and microanalysis.
State of the Dispersant and Particle Surface During Wet‐Jet Milling for Preparation of a Stable Slurry
Authors: Hotta Yuji , Yilmaz Huseyin , Shirai Takashi , Ohota Kazutoku , Sato Kimiyasu , Watari Koji
Published: February 2008

Wet‐jet‐milled alumina slurries exhibited distinctly different stability behavior compared with ball‐milled ones in terms of reflocculent efficiency and rheological properties. The distinction was attributed to the different behavior of the same dispersant (NH4+ salt of poly(acrylic acid); PAA–NH4+) in ball milling and wet‐jet milling. Alumina particles after the wet‐jet milling retained the initial surface conditions, although ball‐milled alumina particles yielded more hydroxyl groups on the surface. Furthermore, degradation of dispersant on milling was investigated qualitatively. Infra‐red analysis and isoelectric point measurements suggested that degradation of the dispersant occurred during ball milling, indicating neutralization of the dispersant due to formation of monodentate COOX groups. On the other hand, in the case of wet‐jet milling, COO− groups of PAA–NH4+ were not degraded at all, indicating maintenance of the structures of dispersant with electrostatic repulsion. Change in the polymer size of the dispersant by different milling methods was confirmed using high performance liquid chromatography (HPLC) measurements. The HPLC results of the wet‐jet milled samples showed that a dispersant with a larger molecular size was generated. Force measurement on approach via the colloid probe method in the centrifuged supernatant of the milled slurries confirmed that the interaction distance between an α‐alumina colloid probe and c‐sapphire surface was about two times larger in the wet‐jet‐milled slurry supernatant compared with the ball milled one. Thus, it was found that wet‐jet milling process led to a stable slurry because of the maintenance of not only steric repulsion but also electrostatic repulsion.
Excimer Laser Crystallized (Pb,La)(Zr,Ti)O3 Thin Films
Authors: Bharadwaja S. S. N. , Dechakupt T. , Trolier‐McKinstry S. , Beratan H.
Published: February 2008

A KrF pulsed excimer laser (248 nm) was utilized to crystallize sputtered La‐modified Pb(Zr,Ti)O3 (3:30:70) (PLZT) films on LaNiO3‐coated silicon substrates. The film surface was irradiated with defocused laser pulses in an oxygen ambient at various substrate temperatures. Polycrystalline, phase pure perovskite PLZT thin films were produced for substrate temperatures of 250°C and higher. The dielectric constant and loss tangent values of laser‐assisted crystallized (10 min exposure at 10 Hz using a substrate temperature of 400°C) PLZT thin films at 10 kHz were 406 and 0.027; in comparison, rapid thermal annealed films (annealed at 700°C for 1 min) showed values of 400 and 0.021, respectively. Laser crystallized films exhibited a remanent polarization value of 14 μC/cm2 with a coercive field |(E+c+E−c)|/2 of 95 kV/cm.
Permeability of Laminated Green Ceramic Tapes as a Function of Binder Loading
Authors: Yun Jeong Woo , Lombardo Stephen J.
Published: February 2008

The gas permeability of laminated green ceramic tapes was determined versus organic loading for samples subjected to air oxidation. The dielectric in the tapes was barium titanate, and the binder consisted primarily of poly(vinyl butyral) and dioctyl phthalate. Both the normalized gas flux and the gas permeability were seen to approach constant values for five or more tapes laminated together. Because the characteristic pore size was 0.5–1 μm, Poiseuille flow was the dominant flow mechanism, and thus Darcy's law was valid. The permeability of five laminated tapes was a factor of five smaller than for unlaminated tapes. Values were also obtained for the permeability versus binder loading in terms of the microstructural features of specific surface, porosity, and a parameter to account for tortuosity and constrictions.
Interspecific competition between the ichneumonid Campoletis chlorideae and the braconid Microplitis mediator in their host Helicoverpa armigera
Authors: Tian Shen‐Peng , Zhang Ji‐Hong , Yan Yun‐Hua , Wang Chen‐Zhu
Published: February 2008

We investigated interspecific competition between Campoletis chlorideae Uchida (Hymenoptera: Ichneumonidae) and Microplitis mediator (Haliday) (Hymenoptera: Braconidae) in their host, the cotton bollworm, Helicoverpa armigera (Hübner) (Lepidoptera: Noctuidae) under laboratory conditions. Cotton bollworm larvae were allowed to be parasitized by both wasp species simultaneously or sequentially at different time intervals. When host larvae were parasitized simultaneously by both parasitoids, the majority of the cocoons produced were of M. mediator. When host larvae were parasitized initially by M. mediator followed by C. chlorideae at 12 or 24 h, parasitoids emerging from the multiparasitized hosts were mainly M. mediator. In contrast, when host larvae were parasitized initially by C. chlorideae, followed by M. mediator 12 or 24 h later, parasitoids emerging from the multiparasitized hosts were mainly C. chlorideae. Dissections of host larvae at various time intervals after parasitization by the two parasitoids showed that first instars of M. mediator could physically attack the larvae of C. chlorideae, but not the eggs of C. chlorideae. When a host was parasitized by both wasp species sequentially, more host larvae died and the number of wasp offspring was significantly reduced compared to a host parasitized by only one wasp. Conversely, in simultaneous multiparasitism, the host mortality and wasp offspring production were not significantly different from those parasitized by single wasp species.
Gene expression profiling demonstrates a novel role for foetal fibrocytes and the umbilical vessels in human fetoplacental development
Authors: Kim Jung‐Sun , Romero Roberto , Tarca Adi Laurentiu , LaJeunesse Christopher , Han Yu Mi , Kim Mi Jeong , Suh Yeon Lim , Draghici Sorin , Mittal Pooja , Gotsch Francesca , Kusanovic Juan Pedro , Hassan Sonia , Kim Chong Jai
Published: February 2008

There is a difference in the susceptibility to inflammation between the umbilical vein (UV) and the umbilical arteries (UAs). This led us to hypothesize that there is an intrinsic difference in the pro‐inflammatory response between UA and UV. Real‐time quantitative RT‐PCR and microarray analysis revealed higher expression of interleukin (IL)‐1β and IL‐8 mRNA in the UV and differential expression of 567 genes between the UA and UV associated with distinct biological processes, including the immune response. Differential expression of human leukocyte antigen (HLA)‐DRA mRNA between the UA and UV was due to unexpected HLA‐DR+ cells migrating via the umbilical vessels into Wharton's jelly, more frequently in the UV. A significant proportion of these cells co‐expressed CD45 and type I pro‐collagen, and acquired CD163 or α‐smooth muscle actin immunoreactivity in Wharton's jelly. Migrating cells were also found in the chorionic and stem villous vessels. Furthermore, the extent of migration increased with progression of gestation, but diminished in intrauterine growth restriction (IUGR). The observations herein strongly suggest that circulating foetal fibrocytes, routing via umbilical and placental vessels, are a reservoir for key cellular subsets in the placenta. This study reports fibrocytes in the human umbilical cord and placenta for the first time, and a novel role for both circulating foetal cells and the umbilical vessels in placental development, which is deranged in IUGR.
Pro‐atherogenic lung and oral pathogens induce an inflammatory response in human and mouse mast cells
Authors: Oksaharju Anna , Lappalainen Jani , Tuomainen Anita M. , Pussinen Pirkko J. , Puolakkainen Mirja , Kovanen Petri T. , Lindstedt Ken A.
Published: February 2008

A broad variety of microbes are present in atherosclerotic plaques and chronic bacterial infection increases the risk of atherosclerosis by mechanisms that have remained vague. One possible mechanism is that bacteria or bacterial products activate plaque mast cells that are known to participate in the pathogenesis of atherosclerosis. Here, we show by real‐time PCR analysis and ELISA that Chlamydia pneumoniae (Cpn) and a periodontal pathogen, Aggregatibacter actinomycetemcomitans (Aa), both induce a time and concentration‐dependent expression and secretion of interleukin 8 (IL‐8), tumour necrosis factor‐α (TNF‐α) and monocyte chemoattractant protein‐1 (MCP‐1) by cultured human peripheral blood‐derived mast cells, but not anti‐inflammatory molecules, such as IL‐10 or transforming growth factor β1 (TGF‐β1). The IL‐8 and MCP‐1 responses were immediate, whereas the onset of TNF‐α secretion was delayed. The Cpn‐mediated pro‐inflammatory effect was attenuated when the bacteria were inactivated by UV‐treatment. Human monocyte‐derived macrophages that were pre‐infected with Cpn also induced a significant pro‐inflammatory response in human mast cells, both in cocultures and when preconditioned media from Cpn‐infected macrophages were used. Intranasal and intravenous administration of live Cpn and Aa, respectively induced an accumulation of activated mast cells in the aortic sinus of apolipoprotein E‐deficient mice, however, with varying responses in the systemic levels of lipopolysaccharide (LPS) and TNF‐α. Pro‐atherogenic Cpn and Aa induce a pro‐inflammatory response in cultured human connective tissue‐type mast cells and activation of mouse aortic mast cells in vivo.
The glycosyltransferase activities of lysyl hydroxylase 3 (LH3) in the extracellular space are important for cell growth and viability
Authors: Wang Chunguang , Kovanen Vuokko , Raudasoja Päivi , Eskelinen Sinikka , Pospiech Helmut , Myllylä Raili
Published: February 2008

Lysyl hydroxylase (LH) isoform 3 is a post‐translational enzyme possessing LH, collagen galactosyltransferase (GT) and glucosyltransferase (GGT) activities. We have demonstrated that LH3 is found not only intracellularly, but also on the cell surface and in the extracellular space, suggesting additional functions for LH3. Here we show that the targeted disruption of LH3 by siRNA causes a marked reduction of both glycosyltransferase activities, and the overexpression of LH3 in HT‐1080 cells increases hydroxylation of lysyl residues and the subsequent galactosylation and glucosylation of hydroxylysyl residues. These data confirm the multi‐functionality of LH3 in cells. Furthermore, treatment of cells in culture medium with a LH3 N‐terminal fragment affects the cell behaviour, rapidly leading to arrest of growth and further to lethality if the fragment is glycosyltransferase‐deficient, and leading to stimulation of proliferation if the fragment contains LH3 glycosyltransferase activities. The effect is reversible, the cells recovering after removal of the glycosyltransferase‐deficient fragment. The findings were confirmed by overexpressing the full‐length LH3 in native or mutated forms in the cells. The data indicate that the increase in proliferation depends on the glycosyltransferase activity of LH3. The overexpression of a glycosyltransferase‐deficient mutant or targeted disruption of LH3 by siRNA in cells results in abnormal cell morphology followed by cell death. Our data clearly indicate that the deficiency of LH3 glycosyltransferase activities, especially in the extracellular space, causes growth arrest revealing the importance of the glycosyltransferase activities of LH3 for cell growth and viability, and identifying LH3 as a potential target for medical applications, such as cancer therapy.
Activation of Wnt signalling in stroma from pancreatic cancer identified by gene expression profiling
Authors: Pilarsky Christian , Ammerpohl Ole , Sipos Bence , Dahl Edgar , Hartmann Arndt , Wellmann Axel , Braunschweig Till , Löhr Matthias , Jesnowski Ralf , Friess Helmut , Wente Moritz Nicolas , Kristiansen Glen , Jahnke Beatrix , Denz Axel , Rückert Felix , Schackert Hans K. , Klöppel Günter , Kalthoff Holger , Saeger Hans Detlev , Grützmann Robert
Published: February 2008

Pancreatic ductal adenocarcinoma (PDAC) is characterized by an abundant desmoplastic stroma. Interactions between cancer and stromal cells play a critical role in tumour invasion, metastasis and chemoresistance. Therefore, we hypothesized that gene expression profile of the stromal components of pancreatic carcinoma is different from chronic pancreatitis and reflects the interaction with the tumour. We investigated the gene expression of eleven stromal tissues from PDAC, nine from chronic pancreatitis and cell lines of stromal origin using the Affymetrix U133 GeneChip set. The tissue samples were microdissected, the RNA was extracted, amplified and labelled using a repetitive in vitro transcription protocol. Differentially expressed genes were identified and validated using quantitative RT‐PCR and immuno‐histochemistry. We found 255 genes to be overexpressed and 61 genes to be underexpressed within the stroma of pancreatic carcinoma compared to the stroma of chronic pancreatitis. Analysis of the involved signal transduction pathways revealed a number of genes associated with the Wnt pathway of which the differential expression of SFRP1 and WNT5a was confirmed using immunohistochemistry. Moreover, we could demonstrate that WNT5a expression was induced in fibroblasts during cocultivation with a pancreatic carcinoma cell line. The identified differences in the expression profile of stroma cells derived from tumour compared to cells of inflammatory origin suggest a specific response of the tissue surrounding malignant cells. The overexpression of WNT5a, a gene involved in the non canonical Wnt signalling and chondrocyte development might contribute to the strong desmoplastic reaction seen in pancreatic cancer.
Localization of the low‐affinity nerve growth factor receptor p75 in human limbal epithelial cells
Authors: Girolamo Nick Di , Sarris Maria , Chui Jeanie , Cheema Haroon , Coroneo Minas T. , Wakefield Denis
Published: February 2008

Biological effects of nerve growth factor (NGF) are mediated through receptors known as nerve growth factor receptors (NGFR), which include p75 and TrkA. This study was initiated after identifying NGFR as an up‐regulated gene in the limbus by cDNA microarray analysis and we postulate that its expression may be indicative of a stem/progenitor cell phenotype. Immunohistochemistry was performed on normal human adult (n= 5) and foetal (n= 3) corneal tissue using antibodies directed against p75, TrkA, NGF, p63, ABCG2 and CK3/12. Limbal, conjunctival and pterygium tissue was obtained from patients (n= 10) undergoing pterygium resection and used for immunohistochemical assessment. Paraffin‐embedded archival human skin specimens (n= 4) were also evaluated. In vitro expression of NGFR was determined in limbal, conjunctival and pterygium‐derived epithelial cells. p75 was selectively expressed by basal epithelial cells in pterygia, conjunctiva and limbus, but was absent in the central cornea. These results were confirmed with two additional p75 specific antibodies. In contrast, TrkA was found in full‐thickness pterygium, conjunctival, limbal and corneal epithelium in both adult and foetal eyes. p75 expression was identified in a small percentage, while TrkA was found on the entire population of cultured conjunctival, limbal and pterygium‐derived epithelial cells. This receptor was also observed in selective regions of the human epidermis and hair follicle bulge. Our results illustrate the selective expression of p75 in basal pterygium, conjunctival and limbal epithelium, while staining was absent in adult and foetal central cornea. p75 may represent an additional ocular surface epithelial stem/progenitor cell signature gene.
Proteasome inhibitor‐induced apoptosis is mediated by positive feedback amplification of PKCδ proteolytic activation and mitochondrial translocation
Authors: Sun Faneng , Kanthasamy Arthi , Song Chunjuan , Yang Yongjie , Anantharam Vellareddy , Kanthasamy Anumantha G.
Published: February 2008

Emerging evidence implicates impaired protein degradation by the ubiquitin proteasome system (UPS) in Parkinson's disease; however cellular mechanisms underlying dopaminergic degeneration during proteasomal dysfunction are yet to be characterized. In the present study, we identified that the novel PKC isoform PKCδ plays a central role in mediating apoptotic cell death following UPS dysfunction in dopaminergic neuronal cells. Inhibition of proteasome function by MG‐132 in dopaminergic neuronal cell model (N27 cells) rapidly depolarized mitochondria independent of ROS generation to activate the apoptotic cascade involving cytochrome c release, and caspase‐9 and caspase‐3 activation. PKCδ was a key downstream effector of caspase‐3 because the kinase was proteolytically cleaved by caspase‐3 following exposure to proteasome inhibitors MG‐132 or lactacystin, resulting in a persistent increase in the kinase activity. Notably MG‐132 treatment resulted in translocation of proteolytically cleaved PKCδ fragments to mitochondria in a time‐dependent fashion, and the PKCδ inhibition effectively blocked the activation of caspase‐9 and caspase‐3, indicating that the accumulation of the PKCδ catalytic fragment in the mitochondrial fraction possibly amplifies mitochondria‐mediated apoptosis. Overexpression of the kinase active catalytic fragment of PKCδ (PKCδ‐CF) but not the regulatory fragment (RF), or mitochondria‐targeted expression of PKCδ‐CF triggers caspase‐3 activation and apoptosis. Furthermore, inhibition of PKCδ proteolytic cleavage by a caspase‐3 cleavage‐resistant mutant (PKCδ‐CRM) or suppression of PKCδ expression by siRNA significantly attenuated MG‐132‐induced caspase‐9 and ‐3 activation and DNA fragmentation. Collectively, these results demonstrate that proteolytically activated PKCδ has a significant feedback regulatory role in amplification of the mitochondria‐mediated apoptotic cascade during proteasome dysfunction in dopaminergic neuronal cells.
Depression and mortality in the visually‐impaired, community‐dwelling, elderly population of Quebec
Authors: Tournier Marie , Moride Yola , Ducruet Thierry , Moshyk Andriy , Rochon Sophie
Published: February 2008

Purpose:  To assess the effect of visual impairment (VI) on the risk of depression or death in the community‐dwelling elderly population.

Methods:  A population‐based, retrospective fixed cohort study was conducted in the community‐dwelling elderly (age ≥ 65 years) outpatient population of Quebec. The cohort was assembled through the Quebec medical services database and consisted of the 5063 patients aged ≥ 65 years who received a diagnosis of VI during the years 2000–2004. The reference cohort consisted of 16 932 elderly subjects who were randomly selected among members of the public drug programme. The outcome variables were depression and death. The main independent variable was VI and covariates included age, gender, chronic disease score, fracture and diabetes.

Results:  Controlling for covariates, VI was associated with an increased risk of depression although the effect was not modified by severity (hazard ratio [HR] = 1.35, 95% confidence interval [CI] 1.10–1.66 for severe VI; HR = 1.35, 95% CI 1.09–1.69 for moderate VI). Visual impairment was associated with an increased risk of mortality; patients with moderate vision loss had a higher risk of death (HR = 1.70, 95% CI 1.55–1.87) than those with severe vision loss (HR = 1.34, 95% CI 1.21–1.48).

Conclusions:  Given the ageing of the population, VI in elderly subjects is becoming a public health concern. These findings enhance the need to detect and treat VI in order to improve the quality of life and to prevent premature mortality in the elderly population.
Intracameral triamcinolone acetonide to control postoperative inflammation following cataract surgery with phacoemulsification
Authors: Karalezli Aylin , Borazan Mehmet , Akova Yonca A.
Published: February 2008

Purpose:  To explore the efficacy, safety and tolerability of 1 mg intracameral triamcinolone acetonide (TA) in controlling ocular inflammation in patients undergoing cataract surgery.

Methods:  Sixty eyes of 60 patients undergoing cataract extraction with phacoemulsification at the Department of Ophthalmology, Baskent University School of Medicine were randomized into two groups. After surgery, eyes in group A were injected with 1 mg/0.1 ml TA into the anterior chamber, but eyes in group B were not. Postoperatively; in group B, topical prednisolone acetate 1% eyedrops were administered six times per day for 7 days, then four times per day for 15 days, to control postoperative inflammation. In group A, topical corticosteroids were not used. To evaluate the efficacy of intracameral TA, anterior chamber cells, anterior chamber flare and conjunctival hyperaemia were measured on postoperative days 1, 7 and 30 by slit‐lamp biomicroscopy. The safety of intracameral TA was evaluated by visual acuity measurements, intraocular pressure values and fundus examination. Tolerance variables were assessed by the degree of burning, stinging and blurred vision.

Results:  Both treatments were equally effective in controlling postoperative inflammation following phacoemulsification. No statistically significant differences between groups were observed for the efficacy, safety and tolerance variables, and no serious adverse events were observed.

Conclusions:  Intracameral TA of 1 mg can effectively be used to control postoperative inflammation after uncomplicated cataract surgery with phacoemulsification. This makes it possible to decrease the dosage and duration of topical prednisolone acetate.
The F13 residue is critical for interaction among the coat protein subunits of papaya mosaic virus
Authors: Laliberté Gagné M. E. , Lecours K. , Gagné S. , Leclerc D.
Published: February 2008

Papaya mosaic virus (PapMV) coat protein (CP) in Escherichia coli was previously showed to self‐assemble in nucleocapsid‐like particles (NLPs) that were similar in shape and appearance to the native virus. We have also shown that a truncated CP missing the N‐terminal 26 amino acids is monomeric and loses its ability to bind RNA. It is likely that the N‐terminus of the CP is important for the interaction between the subunits in self‐assembly into NLPs. In this work, through deletion and mutation analysis, we have shown that the deletion of 13 amino acids is sufficient to generate the monomeric form of the CP. Furthermore, we have shown that residue F13 is critical for self‐assembly of the CP subunits into NLPs. The replacement of F13 with hydrophobic residues (L or Y) generated mutated forms of the CP that were able to self‐assemble into NLPs. However, the replacement of F13 by A, G, R, E or S was detrimental to the self‐assembly of the protein into NLPs. We concluded that a hydrophobic interaction at the N‐terminus is important to ensure self‐assembly of the protein into NLPs. We also discuss the importance of F13 for assembly of other members of the potexvirus family.
Discovery of GSK837149A, an inhibitor of human fatty acid synthase targeting the β‐ketoacyl reductase reaction
Authors: Vázquez María Jesús , Leavens William , Liu Ronggang , Rodríguez Beatriz , Read Martin , Richards Stephen , Winegar Deborah , Domínguez Juan Manuel
Published: February 2008

GSK837149A has been identified as a selective inhibitor of human fatty acid synthase (FAS). The compound was first isolated as a minor impurity in a sample found to be active against the enzyme in a high‐throughput screening campaign. The structure of this compound was confirmed by NMR and MS studies, and evaluation of the newly synthesized molecule confirmed its activity against FAS. The compound and other analogs synthesized, all being symmetrical structures containing a bisulfonamide urea, act by inhibiting the β‐ketoacyl reductase activity of the enzyme. GSK837149A inhibits FAS in a reversible mode, with a Ki value of ∼ 30 nm, and it possibly binds to the enzyme–ketoacyl‐ACP complex. Although initial results suggest that cell penetration for these compounds is impaired, they still can be regarded as useful tools with which to probe and explore the β‐ketoacyl reductase active site in FAS, helping in the design of new inhibitors.
Erectile Dysfunction in Men Receiving Methadone and Buprenorphine Maintenance Treatment
Authors: Hallinan Richard , Byrne Andrew , Agho Kingsley , McMahon Chris , Tynan Philip , Attia John
Published: February 2008

Introduction

Use of opiates/opioids is associated with hypoactive sexual desire, erectile and orgasmic dysfunction.

Aim

To determine prevalence and investigate etiology of sexual dysfunction in men on methadone or buprenorphine maintenance treatment (MMT, BMT).

Main Outcome Measures

International Index of Erectile Function (IIEF), hormone assays, Beck Depression Inventory.

Methods

A total of 103 men (mean age 37.6 ± 7.9) on MMT (N=84) or BMT (N=19) were evaluated using the IIEF, hormone assays, Beck Depression Inventory, body mass index (BMI), demographic, and other substance use measures.

Results

Mean total IIEF scores for partnered men were lower for MMT (50.4 ± 18.2; N=53) than reference groups (61.4 ± 16.8; N=415; P <0.0001) or BMT (61.4 ± 7.0; N=14; P =0.048). Among partnered men on MMT, 53% had erectile dysfunction (ED) compared with 24% of reference groups; 26% had moderate to severe ED, 12.1% in under 40s and 40.0% among those 40+ years. On multiple regression, depression, older age, and lower total testosterone were associated with lower IIEF and EF domain; on multivariate analysis, there were no significant associations between IIEF or EF and free testosterone, opioid dose, cannabis or other substance use, viral hepatitis, or BMI. Total testosterone accounted for 16% of IIEF and 15% of EF variance. Men without sexual partners had lower Desire and Erection Confidence scores and less recent sexual activity, suggesting potentially higher prevalence of sexual dysfunction in this group.

Conclusion

Men on MMT, but not BMT, have high prevalence of ED, related to hypogonadism and depression. Practitioners should screen for sexual dysfunction in men receiving opioid replacement treatment. Future studies of sexual dysfunction in opioid-treated men should examine the potential benefits of dose reduction, androgen replacement, treatment of depression, and choice of opioid.
History of the International Society of Sexual Medicine (ISSM)— The Beginnings
Authors: Lewis Ronald , Wagner Gorm
Published: February 2008

Introduction

This is the first article in a series of articles outlining the history of what became the International Society for Sexual Medicine (ISSM).

Aim

This first article deals with the beginning meetings of the group of world scientists who first met to discuss corpus cavernosal revascularization and other new ideas regarding the etiology and treatment for impotence (as it was known then) in New York City in 1978, and subsequently in Monaco in 1980.

Methods

Strict adherence to documented historical sources including books published from the meeting, published peer review literature where appropriate, programs from the actual meetings, detailed written notes by the authors taken at the time of the meetings, and letters of correspondence between key members of these meetings were used in preparing this historical review. The memories of the two authors, although still good in their opinion, did not serve as the source of the material that is presented.

Results

This first meeting was the impetus for the third meeting to be held 2 years later in Copenhagen, Denmark in 1982. This meeting and the subsequent meetings in 1984 and 1986 in Paris, France and Prague, Czechoslovakia, respectively, became the formative years for the budding society, which will serve as the time format for the authors' next article.

Conclusions

This article outlines the discussions that occurred at these two meetings and presents a history of this early society that would eventually become the ISSM.