bluuebunny/crossref_metadata_2025 huggingface dataset:
Intermittent pneumatic compression for prevention of pulmonary thromboembolism after gynecologic surgery
Authors: Suzuki Nao , Kataoka Fumio , Higashiguchi Atsushi , Hirao Takeshi , Ezawa Sachiko , Nomura Hiroyuki , Tomita Akiyo , Susumu Nobuyuki , Aoki Daisuke
Published: November 2005

Background

To investigate the incidence of pulmonary embolism and risk factors for this condition after obstetric and gynecologic surgery, as well as the efficacy of intermittent pneumatic compression.

Methods

A total of 6,218 patients operated at Keio University Hospital excluding obstetric or infertility-related surgery and uterine cervical conization were evaluated retrospectively to determine the preventive effect of intermittent pneumatic compression on postoperative pulmonary embolism.

Results

Pulmonary embolism occurred in 42 patients (0.68%). Multivariate analysis showed that malignancy, blood transfusion, and a body mass index ≥25 kg/m2 or ≥28 kg/m2 were independent risk factors for postoperative pulmonary embolism. A significantly lower incidence of pulmonary embolism occurred in patients receiving pneumatic compression postoperatively versus those without it. Among gynecologic malignancies, endometrial cancer was a significant risk factor for pulmonary embolism.

Conclusion

Preventive measures, including intermittent pneumatic compression, should be taken to avoid postoperative pulmonary thromboembolism in the gynecology field.
Activation of nuclear factor kappa B (NF-κB) by connective tissue growth factor (CCN2) is involved in sustaining the survival of primary rat hepatic stellate cells
Authors: Gao Runping , Brigstock David R
Published: November 2005

Background/Aims

Connective tissue growth factor (CCN2) is a matricellular protein that plays a role in hepatic stellate cell (HSC)-mediated fibrogenesis. The aim of this study was to investigate the regulation by CCN2 of cell survival pathways in primary HSC.

Methods

Primary HSC were obtained by in situ enzymatic perfusion of rat liver. NF-κB activation was assessed by immunoblotting for IκBα phosphorylation and degradation and by NF-κB p50 or p65 nuclear accumulation. NF-κB DNA-binding activity was determined by gel mobility shift assay while NF-κB response gene expression was evaluated using a luciferase reporter. Cell viability was assessed by Trypan blue staining or ATP luminescent assay while apoptosis was evaluated by caspase-3 activity.

Results

CCN2 induced IκBα phosphorylation and degradation as well as nuclear accumulation of NF-κB. Activated NF-κB comprised three dimers, p65/p65, p65/p50 and p50/p50, that individually bound to DNA-binding sites and subsequently triggered transcriptional activity. This was confirmed by showing that CCN2 promoted activity of a NF-κB luciferase reporter. CCN2 promoted survival of serum-starved HSC and protected the cells from death induced by blocking the NF-κB signaling pathway using Bay-11-7082, a specific inhibitor of IκBα phosphorylation.

Conclusion

CCN2 contributes to the survival of primary HSC through the NF-κB pathway.
Feed-Forward Inhibition: A Novel Cellular Mechanism for the Analgesic Effect of Substance P
Authors: Wu Long-Jun , Xu Hui , Ko Shanelle W , Yoshimura Megumu , Zhuo Min
Published: November 2005

Substance P (SP) is a neuropeptide well known for its contribution to pain transmission in the spinal cord, however, less is known about the possible modulatory effects of SP. A new study by Gu and colleagues, published in Molecular Pain (2005, 1:20), describes its potential role in feed-forward inhibition in lamina V of the dorsal horn of the spinal cord. This inhibition seems to function through a direct excitation of GABAergic interneurons by substance P released from primary afferent fibers and has a distinct temporal phase of action from the well-described glutamate-dependent feed-forward inhibition. It is believed that through this inhibition, substance P can balance nociceptive output from the spinal cord.
A comparison of three- and four-option English tests for university entrance selection purposes in Japan
Authors: Shizuka Tetsuhito , Takeuchi Osamu , Yashima Tomoko , Yoshizawa Kiyomi
Published: November 2005

The present study investigated the effects of reducing the number of options per item on psychometric characteristics of a Japanese EFL university entrance examination. A four-option multiple-choice reading test used for entrance screening at a university in Japan was later converted to a three-option version by eliminating the least frequently endorsed option in each item, and was given to a separate group. Responses to the two tests indicated that using three options instead of four did not significantly change the mean item facility or the mean item discrimination. Distractor analyses revealed that whether four or three options were provided, the actual test-takers’ responses spread, on the average, over about 2.6 options per item, that the mean number of functioning distractors was much lower than 2, and that reducing the least popular option had only a minimal effect on the performance of the remaining options. These results suggested that three-option items performed nearly as well as their four-option counterparts.
The Yes/No test as a measure of receptive vocabulary knowledge
Authors: Mochida kira , Harrington Michael
Published: November 2005

Performance on the Yes/No test (Huibregtse et al., 2002) was assessed as a predictor of scores on the Vocabulary Levels Test (VLT), a standard test of receptive second language (L2) vocabulary knowledge (Nation, 1990). The use of identical items on both tests allowed a direct comparison of test performance, with alternative methods for scoring the Yes/No test also examined (Huibregtse et al., 2002). Overall, performance on both tests by English L2 university students ( n - 36) was similar. Mean test accuracy on the various Yes/No methods ranged from 76-82%, comparable to VLT performance at 83%. However, paired t-tests showed the scoring methods used to correct raw hit performance increased the difference between the Yes/No test and criterion VLT scores to some degree. All Yes/No scores were strong predictors of VLT performance, regardless of method used, r = .8. Raw hit rate was the best predictor of VLT performance, due in part to the >5% false alarm rate. The low false alarm rate may be due to the participants, drawn primarily from non-Latin alphabet first languages (L1s), and the nature of the instructions. The results indicate the Yes/No test is a valid measure of the type of L2 vocabulary knowledge assessed by the VLT, with implications for classroom application.
Language for special academic purposes (LSAP) testing: the effect of background knowledge revisited
Authors: Krekeler Christian
Published: November 2005

This study investigates the effect of background knowledge in languages for specific academic purposes (LSAP) tests. Following the observation of previous studies that the effect of background knowledge varies according to the level of language proficiency, the study applied the theory of linguistic thresholds to LSAP reading tests. The research question was whether students would be able to draw on their background knowledge only at certain levels of second language (L2) proficiency. International students in Germany took part in a study based on two LSAP reading tests from different subject areas. The texts were subject specific but did not assume previous knowledge. Language proficiency was assessed by C-tests; background knowledge by three different variables. The effect of background knowledge on reading test performance was strong. Whilst the effect of background knowledge did vary somewhat according to the level of language proficiency, the findings were inconclusive in relation to possible thresholds. In the case of the employed LSAP tests, which were not highly specific, they were fuzzy or non-existent and the concept seems inappropriate in relation to language tests for academic purposes.
Constructing a Morality of Caring: Codes and values in Australian Carer Discourse
Authors: Winch Sarah
Published: November 2005

In this analysis I apply a Foucauldian approach to ethics to examine the politically prescribed moral and ethical character required of carers of aged persons at home in Australia and the role of nurses in shaping these behaviours. The work that spousal carers provide, although often founded on love and/or obligation, has been formalized through a variety of policy initiatives and technologies that serve to construct the moral approach they must adopt. This shaping of conduct at the most personal level takes place through the application of codes of behaviour policed largely by nurses. These codes redefine the mode of coexistence between an aged husband and wife and propose a new form of relationship that is derived from and supports policies of the deinstitutionalization of care services for elderly persons. In this way modern carer policy has drawn on knowledge and governance of the self to produce a morality of caring that is both authoritative and scientific.
The Caring Relationship in Hospice Care: An analysis based on the ethics of the caring conversation
Authors: Olthuis Gert , Dekkers Wim , Leget Carlo , Vogelaar Paul
Published: November 2005

Good nursing is more than exercising a specific set of skills. It involves the personal identity of the nurse. The aim of this article is to answer two questions: (1) what kind of person should the hospice nurse be? and (2) how should the hospice nurse engage in caring conversations? To answer these questions we analyse a nurse’s story that is intended to be a profile of an exemplary hospice nurse. This story was constructed from an analysis of five semistructured interviews with hospice nurses, based on the ‘ethics of the caring conversation’, which is inspired by the ethical perspective of Paul Ricoeur. The research questions concentrate on the norms of respect, responsibility and reciprocity, which are integral parts of the ‘ethics of the caring conversation’.
Nurses as Moral Practitioners Encountering Parents in Neonatal Intensive Care Units
Authors: Fegran Liv , Helseth Sølvi , Slettebø Åshild
Published: November 2005

Historically, the care of hospitalized children has evolved from being performed in isolation from parents to a situation where the parents and the child are regarded as a unit, and parents and nurses as equal partners in the child’s care. Parents are totally dependent on professionals’ knowledge and expertise, while nurses are dependent on the children’s emotional connection with their parents in order to provide optimal care. Even when interdependency exists, nurses as professionals hold the power to decide whether and to what extent parents should be involved in their child’s care. This article focuses on nurses’ responsibility to act ethically and reflectively in a collaborative partnership with parents. To illuminate the issue of nurses as moral practitioners, we present an observation of contemporary child care, and discuss it from the perspective of the Danish moral philosopher KE Løgstrup and his book The ethical demand.
Finnish Nurses’ Interpretations of Patient Autonomy in the Context of End-of-Life Decision Making
Authors: Hildén Hanna-Mari , Honkasalo Marja-Liisa
Published: November 2005

Our aim was to study how nurses interpret patient autonomy in end-of-life decision making. This study built on our previous quantitative study, which evaluated the experiences of and views on end-of-life decision making of a representative sample of Finnish nurses taken from the whole country. We performed qualitative interviews with 17 nurses and analysed these using discourse analysis. In their talk, the nurses demonstrated three different discourses, namely, the ‘supporter’, the ‘analyst’ and the ‘practical’ discourses, each of which outlined a certain position for patients and relatives, and a certain identity for the nurses in end-of-life decision making. The nurses’ talk showed notable differences when compared with that of physicians, highlighting the differences that take place in respect of the image of a person’s work, professional culture, professional identification and responsibilities. An important finding was that the nurses often described their participation in end-of-life decision making in terms of indirect influence.
Pharmacological actions of Cordyceps, a prized folk medicine
Authors: Ng T B , Wang H X
Published: November 2005

Cordyceps species, including C. sinensis, C. militaris, C. pruinosa and C. ophioglossoides, are prized traditional medicinal materials. The aim of this article is to review the chemical constituents and pharmacological actions of Cordyceps species. The chemical constituents include cordycepin (3′-deoxyadenosine) and its derivatives, ergosterol, polysaccharides, a glycoprotein and peptides containing α-aminoisobutyric acid. They include anti-tumour, anti-metastatic, immunomodulatory, antioxidant, anti-inflammatory, insecticidal, antimicrobial, hypolipidaemic, hypoglycaemic, anti-ageing, neuroprotective and renoprotective effects. Polysaccharide accounts for the anti-inflammatory, antioxidant, anti-tumour, anti-metastatic, immunomodulatory, hypoglycaemic, steroidogenic and hypolipidaemic effects. Cordycepin contributes to the anti-tumour, insecticidal and antibacterial activity. Ergosterol exhibits anti-tumour and immunomodulatory activity. A DNase has been characterized.
Controlled release tamsulosin hydrochloride from alginate beads with waxy materials
Authors: Kim Min-Soo , Park Gyeong-Deuk , Jun Seoung-Wook , Lee Sibeum , Park Jeong-Sook , Hwang Sung-Joo
Published: November 2005

The objective of this study was to develop oral controlled release delivery systems for tamsulosin hydrochloride (TSH) using alginate beads with various waxy materials, such as Compritol 888 ATO, Precirol ATO 5 and Gelucires. The beads were prepared from sodium alginate—waxy material—TSH slurry dropped onto calcium chloride to form spherical beads. The effects of the addition of various waxy materials to alginate beads on the drug encapsulation efficiency, bead size and morphology were investigated. The drug encapsulation efficiency significantly increased with the addition of waxy materials. The TSH-loaded alginate beads with and without waxy materials were almost spherical particles with an average diameter of 1.44 and 1.22mm, respectively. In dissolution study, the TSH-loaded alginate beads with waxy materials exhibited controlled release behaviour over a 6-h period, while beads without waxy materials showed release of 100% TSH within 2h. These results may be attributed to the formation of a more rigid alginate matrix structure due to incorporated waxy materials. From the Dunnett's t-test and the f2 factor, the release of TSH from alginate beads, a similar dissolution pattern to that of the marketed product (Harunal capsules) could be achieved by adding Gelucire 50/13 into TSH-loaded alginate beads. From these results, oral controlled release of TSH could be achieved with loading in alginate beads with waxy materials, such as Compritol 888 ATO, Precirol ATO 5 and Gelucires.
Cefuroxime axetil solid dispersions prepared using solution enhanced dispersion by supercritical fluids
Authors: Jun Seoung Wook , Kim Min-Soo , Jo Guk Hyun , Lee Sibeum , Woo Jong Soo , Park Jeong-Sook , Hwang Sung-Joo
Published: November 2005

Cefuroxime axetil (CA) solid dispersions with HPMC 2910/PVP K-30 were prepared using solution enhanced dispersion by supercritical fluids (SEDS) in an effort to increase the dissolution rate of poorly water-soluble drugs. Their physicochemical properties in solid state were characterized by differential scanning calorimeter (DSC), powder X-ray diffraction (PXRD), Fourier transform infrared spectrometry (FT-IR) and scanning electron microscopy. No endothermic and characteristic diffraction peaks corresponding to CA were observed for the solid dispersions in DSC and PXRD. FTIR analysis demonstrated the presence of intermolecular hydrogen bonds between CA and HPMC 2910/PVP K-30 in solid dispersions, resulting in the formation of amorphous or non-crystalline CA. Dissolution studies indicated that the dissolution rates were remarkably increased in solid dispersions compared with those in the physical mixture and drug alone. In conclusion, an amorphous or non-crystalline CA solid dispersion prepared using SEDS could be very useful for the formulation of solid dosage forms.
Clinical pharmacokinetics of the cyclooxygenase inhibiting nitric oxide donator (CINOD) AZD3582
Authors: Fagerholm Urban , Björnsson Marcus A
Published: November 2005

The clinical pharmacokinetics of the COX-inhibiting nitric oxide donator (CINOD) AZD3582 and its metabolites, including naproxen, nitric oxide and nitrate, are summarized. AZD3582 has low aqueous solubility, moderate and passive intestinal permeability and is degraded by intestinal esterases. Its oral bioavailability (F) appears to be maximally a few per cent, and increases by several-fold after food intake. Ninety-four per cent or more of an AZD3582 dose is absorbed, of which at least 9–20% appears to be taken up as intact substance. AZD3582 has a predicted plasma protein binding degree of ∼ 0.1%, a half-life (t½) of 3 to 10 h and does not accumulate after repeated once- and twice-daily dosing. In patients AZD3582 does not provide a significantly better gastrointestinal (GI) side-effect profile than the highly permeable and locally irritating naproxen. Possible reasons for this include considerable GI uptake as naproxen, limited duration and extent of nitric oxide donation in the GI mucosa and the circulation, tolerance development (involving auto-inhibition of nitric oxide catalysing enzymes) and mucosal damage caused by nitric oxide. Blood pressure data suggest that nitric oxide is mainly donated within 3h. The uptake of naproxen is slightly slower and lower (≥ 94% relative GI uptake and 80–85% relative F) after AZD3582 administration compared with naproxen dosing. The naproxen t½ and trough steady-state concentrations after AZD3582 and naproxen dosing are similar. The average systemic nitrate exposure is approximately doubled after dosing of 375 to 750 mg AZD3582 twice daily.
Size-dependent disposition of nanoparticles and microparticles following subconjunctival administration
Authors: Amrite Aniruddha C , Kompella Uday B
Published: November 2005

The purpose of this study was to determine the retention and ocular distribution of subconjunctivally administered nanoparticles and microparticles. Fluorescent polystyrene particles (carboxylate modified, negatively charged) of various sizes (20 nm, 200 nm and 2 μm; Fluospheres, dose 400 μg) were administered to male Sprague-Dawley rats by subconjunctival injection under anaesthesia. The disposition of the particles in the periocular and ocular tissues was studied for up to 60 days by quantifying the particle amounts using liquid extraction followed by spectrofluorimetric analysis. The effect of dose on the particle disposition was investigated with a 40-μg dose of the particles. The effect of an increase in surface hydrophobicity was evaluated for the 20 and 200 nm particles at 1 day post administration. Following periocular administration, penetration into the ocular tissues was negligible for the carboxylate-modified microparticles as well as nanoparticles. Almost the entire dose of the 200 nm and 2 μm particles was retained in the periocular tissue at 60 days post-administration. The 20 nm particles disappeared rapidly from the periocular tissue with 15 and 8% of administered dose remaining after 1 and 7 days, respectively. The 20 nm particles could not be detected in the periocular tissue at 60-days post-administration. An increase in the surface hydrophobicity did not affect the periocular retention of 200 nm particles but elevated that of the 20 nm particles, at the end of day 1. It was concluded that subconjunctivally administered 200 nm and larger particles can be almost completely retained at the site of administration for at least two months. Periocular administration of particulate systems of this size would likely be useful as sustained drug delivery systems.
Sulfasalazine transport in in-vitro, ex-vivo and in-vivo absorption models: contribution of efflux carriers and their modulation by co-administration of synthetic nature-identical fruit extracts
Authors: Mols Raf , Deferme Sven , Augustijns Patrick
Published: November 2005

Sulfasalazine is characterised by low oral bioavailability. In this study, its intestinal transport characteristics were studied in an in-vitro, ex-vivo and in-situ system. The absorptive transport of sulfasalazine across Caco-2 monolayers appeared to be lower than the secretory transport (Papp-abs = 0.21 ± 0.02 times 10−6 cm s−1 and Papp-secr = 2.97 ± 0.30 times 10−6 cm s−1, respectively). This polarity in transport of sulfasalazine was not mediated by P-glycoprotein (P-gp), as inclusion of verapamil (100 μm) did not have any effect on the transport polarity of sulfasalazine. However, inclusion of the multidrug resistance-associated protein (MRP) inhibitors benzbromarone (50 μm) and sulfinpyrazone (1 mm), and the glutathione-depleting agent chlorodinitrobenzene (100 μm), resulted in an increased absorptive transport of sulfasalazine in the Caco-2 system (Papp-abs = 0.64 ± 0.02, 0.51 ± 0.04 and 0.60 ± 0.03 times 10−6 cm s−1, respectively). The interference of carriers implies that, during absorption, interactions with food components may occur at the level of this carrier. Therefore, the effect of food extracts was studied in a parallel set of experiments. For two standardized nature-identical fruit extracts (pineapple and apricot extract) a concentration-dependent absorption-enhancing effect could be observed in the Caco-2 system. The functional expression of similar carriers was also demonstrated in rat ileum in the Ussing chamber system. Interaction studies with fruit extracts in the Ussing chamber system, as well as in the in-situ intestinal perfusion study, revealed a 2- to 4-fold increase in the absorptive transport of sulfasalazine. These results indicate that food components in the intestinal lumen can have a significant impact on the intestinal absorption characteristics of sulfasalazine by modulating the biochemical barrier function of the intestinal mucosa.
Antidiabetic effect of a new peptide from Squalus mitsukurii liver (S-8300) in streptozocin-induced diabetic mice
Authors: Huang Fengjie , Wu Wutong
Published: November 2005

We have evaluated the antidiabetic effect of S-8300 (a peptide extracted from shark liver (Squalus mitsukurii)) in streptozocin (streptozotocin)-diabetic mice. Diabetes was induced by a single intravenous injection of streptozocin (150 mg kg−1). The effects of S-8300 (3 or 10 mg kg−1) on diabetic mice were investigated by observing the changes in the levels of fasting plasma glucose, glycosylated haemoglobin, hepatic glycogen, triglycerides, cholesterol, free fatty acid, superoxide dismutase, and malondialdehyde. Body weight, kidney weight and the degree of injured β-cells in pancreatic islets were recorded also. Diabetic mice treated with S-8300 showed a significant decrease in the levels of fasting plasma glucose, glycosylated haemoglobin, triglycerides, cholesterol, free fatty acid in plasma and malondialdehyde in tissues. The animals showed a significant increase in the content of hepatic glycogen and the activity of superoxide dismutase. Treatment with S-8300 attenuated the degree of injured β-cells in the pancreatic islets. The effect of S-8300 was similar to that of glibenclamide (5 mg kg−1).
Cytoprotective mechanism of baicalin against endothelial cell damage by peroxynitrite
Authors: Kim Dae Hyun , Chung Hae Young , Cho Ki Ho , Moon Sang Kwan , Kim Young Suk , Kim Dong Hyun , Choi Jae Sue
Published: November 2005

To evaluate the mechanism responsible for the cytoprotective effects of baicalin, an antioxidant flavonoid isolated from Scutellaria baicalensis, we investigated its effects against peroxynitrite (ONOO−)-induced endothelial cell (EC) damage. Baicalin showed efficient antioxidative actions by its ability to scavenge ONOO− and inhibit ONOO−-mediated nitrotyrosine formation in vitro. Using an EC (YPEN-1) culture system, baicalin exhibited cytoprotective effects against cell death by ONOO− that was induced exogenously with tert-butyl hydroperoxide (t-BHP) in the YPEN-1 model. Baicalin was also found to reduce the intracellular precursors of ONOO−, NO˙ and O2− in the t-BHP-treated ECs. Evidence from Western blotting further revealed down-regulated expressions of iNOS and COX-2, endogenous sources of NO˙ and O2− by baicalin treatment. In addition, pre-incubation of baicalin with EC suppressed t-BHP-induced nuclear factor kappa-B binding activity as determined by the transfection assay and Western blot analysis, further indicating baicalin's inhibition of iNOS and COX-2 expression. Based on the present data, we propose that baicalin scavenges ONOO− and protects cells against injury. Based on these data, it was concluded that baicalin is potentially a useful antioxidant against ONOO− and NO˙ and an inhibitor of iNOS and COX-2.
Apoptotic potential of sesquiterpene lactone ergolide through the inhibition of NF-κB signaling pathway
Authors: Song Yong Jin , Lee Dae Young , Kang Dong-Won , Kim Yong Kee , Kim Su-Nam , Lee Kang Ro , Lee Hyang Woo , Han Jeung-Whan , Lee Hoi Young
Published: November 2005

Treatment with ergolide, a sesquiterpene lactone from Inula britannica var chinensis, caused the induction of apoptosis in Jurkat T cells, which was confirmed by DNA fragmentation, caspase-3 activation and cleavage of poly(ADP-ribose) polymerase in response to ergolide. Furthermore, mitochondrial dysfunction appeared to be associated with ergolide-induced apoptosis, because Bax translocation and cytochrome c release were stimulated by ergolide. In parallel, the nuclear factor-κB (NF-κB) signaling pathway was significantly inhibited by ergolide, which was accompanied by down-regulation of cell survival molecules, such as X-chromosome-linked inhibitor of apoptosis and Bcl-2. In addition, the JNK signaling pathway was involved in ergolide-induced apoptosis. Collectively, our results identified a new mechanism for the anti-cancer property of ergolide, attributable to the induction of apoptosis through down-regulation of cell survival signal molecules resulting from inhibition of the NF-κB signaling pathway.
The role of endothelin receptor antagonism in collar-induced intimal thickening and vascular reactivity changes in rabbits
Authors: Reel Buket , Sozer Gonen Ozsarlak , Turkseven Saadet , Kerry Zeliha , Ozkal Sermin , Ozer Erdener , Islekel Huray , Oktay Gulgun , Tanriverdi Serpil
Published: November 2005

Intimal thickening, due to smooth muscle cell migration and proliferation, is considered to be one of the major components of vascular proliferative disorders such as atherosclerosis and restenosis. One experimental model, resulting in intimal thickening in the rabbit, involves placing a silicon collar around the carotid artery, and is used in this study. Endothelin is known to act as a strong mitogen and to stimulate smooth muscle cell proliferation and migration. We investigated the contribution of endothelin to the development of collar-induced intimal thickening and the effects of TAK-044, (5mg kg−1 daily, s.c.), a non-selective ETA/ETB receptor antagonist, on intimal thickening and vascular reactivity changes in the collared rabbit carotid artery. Endothelin levels and the intimal cross-sectional area, as well as the ratio of intimal area to media (index), increased significantly in collared arteries as compared with those in sham-operated arteries. TAK-044 significantly inhibited intimal thickening and also decreased the index without affecting increased endothelin levels in collared arteries. Vascular reactivity changes in response to collaring produced predictable effects, such as decreased contractile responses to vasoconstrictor agents and increased sensitivity to serotonin (5-hydroxytrypt-amine, 5-HT). In terms of contractile responses in this model, TAK-044, in particular, did not affect collar-induced vascular reactivity changes. These results suggest that endothelin may be involved in the pathogenesis of collar-induced intimal thickening. As an endothelin receptor antagonist, TAK-044 may potentially be beneficial in the treatment of atherosclerosis.
The phosphodiesterase 4 inhibitor AWD 12–281 is active in a new guinea-pig model of allergic skin inflammation predictive of human skin penetration and suppresses both Th1 and Th2 cytokines in mice
Authors: Hoppmann Joachim , Galetzka Christin , Höfgen Norbert , Rundfeldt Chris , Bämer Wolfgang , Kietzmann Manfred
Published: November 2005

The selective phosphodiesterase 4 (PDE4) inhibitor AWD 12–281 is structurally optimized for topical administration. It has potent effects in models of lung inflammation if administered as a dry powder inhalation. It has also demonstrated its anti-inflammatory property in a mouse model of cutaneous inflammation after topical administration. The aim of this study was to evaluate whether AWD 12–281 may be capable of penetrating human skin. Therefore a new guinea-pig model of allergic skin inflammation had to be developed. In ovalbumin-sensitized guinea-pigs, intracutaneous administration of ovalbumin results in a rapid development of allergic skin wheals. Topically administered AWD 12–281 was capable of reducing the development of wheals, indicating that this compound can penetrate the stratum corneum of guinea-pig skin as a predictor of human skin penetration. A secondary aim was the evaluation of a T cell subtype preference of AWD 12–281 since PDE4 inhibitors are said to preferentially inhibit Th2-type cytokines. Therefore, the effects of AWD 12–281 on a broad spectrum of Th1- and Th2-type cytokines were studied in tissue homogenates after allergen challenge in sensitized mice and in supernatants of anti CD3/anti-CD28-stimulated peripheral blood mononuclear cells (PBMCs). In both models, AWD 12–281 suppressed both T cell subtype cytokines indicating a broad spectrum activity of AWD 12–281. A further issue was to determine the duration of action and the concentration-response relationship of the topical activity of AWD 12–281 using a model of acute local inflammation — the arachidonic-acid-induced mouse ear oedema. The compound exhibited a dose-dependent effect with a minimally effective concentration of 0.3%; after repeated administration the minimally effective concentration was found to be 0.03%. A single administration of a 3% solution resulted in significant suppression of inflammation even 48 h after treatment. In conclusion, our results indicate that AWD 12–281 is a very promising drug candidate not only for the treatment of lung inflammation using inhalative administration but also for the treatment of atopic dermatitis.
Preparation and stereochemical integrity of certain thioesters of 2-arylpropionic acids and related compounds
Authors: Hanrahan Patrick E , Moynihan Humphrey A
Published: November 2005

2-Arylpropionate thioesters 5, 6a/6b and 7a/7b, 2-aryloxypropionate thioesters 8a/8b and 2-alkoxy-2-arylacetate thioesters 9a/9b were prepared from thiol 4 and the corresponding carboxylic acids. Thioesters 6a/6b, 7a/7b, 8a/8b and 9a/9b were monitored for evidence of inter-conversion between epimers in acetonitrile solvent at 40°C, by optical activity in the cases of 6a/6b and 7a/7b, and by 1H NMR spectroscopy in the cases of 8a/8b and 9a/9b. Only in the case of thioesters 9a/9b was significant inter-conversion between epimers observed.
Gastroprotection and effect of the simultaneous administration of Cuachalalate (Amphipterygium adstringens) on the pharmacokinetics and anti-inflammatory activity of diclofenac in rats
Authors: Navarrete Andrés , Sánchez-Mendoza María Elena , Arrieta Jesús , Cruz-Antonio Leticia , Oliva Iván , Castañeda-Hernández Gilberto
Published: November 2005

This work aimed to study the effect of Cuachalalate methanol extract (CME) on the anti-inflammatory activity and pharmacokinetics of diclofenac sodium, a frequently prescribed non-steroidal antiinflammatory drug (NSAID). The gastroprotective effect of CME on the gastric injury induced by diclofenac was studied in rats. CME showed a gastroprotective effect of 15.7% at 1 mg kg−1 and 72.5% at dose of 300 mg kg−1. Omeprazole, used as anti-ulcer reference drug, showed gastroprotective effects of 50–89.7% at doses tested (1–30 mg kg−1). The value of the 50% effective dose for the anti-inflammatory effect of diclofenac sodium (ED50 = 1.14 ± 0.23 mg kg−1) using carrageenaninduced rat paw oedema model, was not modified by the concomitant administration of 30 or 100 mg kg−1 of CME. The effect of CME (30, 100 and 300 mg kg−1, p.o.) on the pharmacokinetics of diclofenac sodium was studied. It was observed that the simultaneous administration of diclofenac sodium and 300 mg kg−1 of CME decreased significantly the values of Cmax (7.08 ± 1.42 μg mL−1) and AUC (12.67 ± 2.97 μg h mL−1), but not the value of tmax (0.13 (0.1–0.25) h) obtained with the administration of diclofenac alone. The simultaneous administration of 30 or 100 mg kg−1 of CME did not modify the pharmacokinetic parameters of diclofenac. The experimental findings in rats suggest that CME at doses lower than 100 mg kg−1 protects the gastric mucosa from the damage induced by diclofenac sodium without altering either the anti-inflammatory activity or the pharmacokinetics of this NSAID.
Protective effect of Hachimi-jio-gan against renal failure in a subtotal nephrectomy rat model
Authors: Yamabe Noriko , Yokozawa Takako , Kim Hyun Young , Cho Eun Ju
Published: November 2005

The protective effect of Hachimi-jio-gan extract against chronic renal failure in a subtotal nephrectomy rat model was investigated. The level of serum urea nitrogen by nephrectomy was increased over 15 weeks, but the administration of Hachimi-jio-gan at 50 and 200 mg led to the decrease. In addition, the levels of creatinine (Cr), urinary methylguanidine (MG) and MG/Cr were increased, whereas Cr clearance dramatically decreased in nephrectomized rats. However, oral administration of Hachimi-jio-gan extract prevented the elevation of these uremic toxins in serum and urine, and the production of hydroxyl radical. Moreover, nephrectomy led to a significant decline in superoxide dismutase (SOD) and catalase activities, but increased glutathione peroxidase activity compared with normal levels, indicating an abnormal antioxidative system. The increased activity of both SOD and catalase by the oral administration of Hachimi-jio-gan suggested that these enzymes are associated with the protective role of Hachimi-jio-gan extract against oxidative stress by nephrectomy. Moreover, the decrease in serum albumin in nephrectomized control rats was increased and proteinuria was ameliorated by the administration of Hachimi-jio-gan with improved glomerular hyalinosis, interstitial fibrosis and inflammation, suggesting the beneficial effect of Hachimi-jio-gan to prevent glomerular sclerosis and progressive renal fibrosis. This study suggests that Hachimi-jio-gan plays a protective role in the progression of chronic renal failure through the decline in uremic toxins, elevation of antioxidative enzyme activity such as SOD and catalase, and amelioration of histopathological lesions in the kidney.
Quantitative analysis of the major constituents of St John's wort with HPLC-ESI-MS
Authors: Chandrasekera Dhammitha H , Heinrich Michael , Ashton David , Welham Kevin J , Middleton Richard
Published: November 2005

A method was developed to profile the major constituents of St John's wort extracts using highperformance liquid chromatography-electrospray mass spectrometry (HPLC-ESI-MS). The objective was to simultaneously separate, identify and quantify hyperforin, hypericin, pseudohypericin, rutin, hyperoside, isoquercetrin, quercitrin and chlorogenic acid using HPLC-MS. Quantification was performed using an external standardisation method with reference standards. The method consisted of two protocols: one for the analysis of flavonoids and glycosides and the other for the analysis of the more lipophilic hypericins and hyperforin. Both protocols used a reverse phase Luna phenyl hexyl column. The separation of the flavonoids and glycosides was achieved within 35 min and that of the hypericins and hyperforin within 9 min. The linear response range in ESI-MS was established for each compound and all had linear regression coefficient values greater than 0.97. Both protocols proved to be very specific for the constituents analysed. MS analysis showed no other signals within the analyte peaks. The method was robust and applicable to alcoholic tinctures, tablet/capsule extracts in various solvents and herb extracts. The method was applied to evaluate the phytopharmaceutical quality of St John's wort preparations available in the UK in order to test the method and investigate if they contain at least the main constituents and at what concentrations.
Inhibition by licochalcone A, a novel flavonoid isolated from liquorice root, of IL-1β-induced PGE2 production in human skin fibroblasts
Authors: Furuhashi Ikue , Iwata Susumu , Sato Toshitsugu , Inoue Hideo , Shibata Shoji
Published: November 2005

Licochalcone A, a novel flavonoid isolated from the root of Glycyrrhiza inflata, has been reported to exhibit anti-inflammatory activity in animal models. In this study, we examined the effect of licochalcone A on the production of chemical mediators such as prostaglandin (PG)E2 and cytokines by interleukin (IL)-1β in human skin fibroblasts. Licochalcone A (IC50 15.0 nm) inhibited PGE2 production, but not IL-6 and IL-8 production, in response to IL-1β. NS-398 (IC50 1.6 nm), a COX-2 selective inhibitor, also suppressed the PGE2 production. Furthermore, licochalcone A and NS-398 suppressed PGF2α production by IL-1β. However, licochalcone A (1 μm) had no effect on increased levels of cyclooxygenase (COX)-2 mRNA and protein in cells. Dexamethasone (100 nm) not only inhibited PGE2, PGF2α, IL-6 and IL-8 production but also strongly suppressed the expression of COX-2 mRNA and protein. Licochalcone A had no effect on COX-1-dependent PGE2 production, whereas indometacin (100 nm), a dual inhibitor of COX-1 and COX-2, was very effective. These results suggest that licochalcone A induces an anti-inflammatory effect through the inhibition of COX-2-dependent PGE2 production. Furthermore, it appears that the inhibitory effect of licochalcone A on PGE2 production in response to IL-1β is quite different from that of the steroid.
CysLT1 receptor is a target for extracellular nucleotide-induced heterologous desensitization: a possible feedback mechanism in inflammation
Authors: Capra Valérie , Ravasi Saula , Accomazzo Maria Rosa , Citro Simona , Grimoldi Monica , Abbracchio Maria P. , Rovati G. Enrico
Published: November 2005

Both cysteinyl-leukotrienes and extracellular nucleotides mediate inflammatory responses via specific G-protein-coupled receptors, the CysLT and the P2Y receptors, respectively. Since these mediators accumulate at sites of inflammation, and inflammatory cells express both classes of receptors, their responses are likely to be crossregulated. We investigated the molecular basis of desensitization and trafficking of the CysLT1 receptor constitutively and transiently expressed in the human monocyte/macrophage-like U937 or COS-7 cells in response to LTD4 or nucleotides. Exposure to agonist induced a rapid homologous desensitization of the CysLT1 receptor [as measured by the reduction in the maximal agonist-induced intracellular cytosolic Ca2+ ([Ca2+]i) transient], followed by receptor internalization (as assessed by equilibrium binding and confocal microscopy). Activation of P2Y receptors with ATP or UDP induced heterologous desensitization of the CysLT1 receptor. Conversely, LTD4-induced CysLT1 receptor activation had no effect on P2Y receptor responses, which suggests that the latter have a hierarchy in producing desensitizing signals. Furthermore, ATP/UDP-induced CysLT1 receptor desensitization was unable to cause receptor internalization, induced a faster recovery of CysLT1 functionality and was dependent upon protein kinase C. By contrast, homologous desensitization, which is probably dependent upon G-protein-receptor kinase 2 activation, induced a fast receptor downregulation and, accordingly, a slower recovery of CysLT1 functionality. Hence, CysLT1 receptor desensitization and trafficking are differentially regulated by the CysLT1 cognate ligand or by extracellular nucleotides. This crosstalk may have a profound physiological implication in the regulation of responses at sites of inflammation, and may represent just an example of a feedback mechanism used by cells to fine-tune their responses.
14-3-3 cooperates with LKB1 to regulate the activity and localization of QSK and SIK
Authors: Al-Hakim Abdallah K. , Göransson Olga , Deak Maria , Toth Rachel , Campbell David G. , Morrice Nick A. , Prescott Alan R. , Alessi Dario R.
Published: November 2005

The LKB1 tumour suppressor kinase phosphorylates and activates a number of protein kinases belonging to the AMP-activated protein kinase (AMPK) subfamily. We have used a modified tandem affinity purification strategy to identify proteins that interact with AMPKα, as well as the twelve AMPK-related kinases that are activated by LKB1. The AMPKβ and AMPKγ regulatory subunits were associated with AMPKα, but not with any of the AMPK-related kinases, explaining why AMP does not influence the activity of these enzymes. In addition, we identified novel binding partners that interacted with one or more of the AMPK subfamily enzymes, including fat facets/ubiquitin specific protease-9 (USP9), AAA-ATPase-p97, adenine nucleotide translocase, protein phosphatase 2A holoenzyme and isoforms of the phospho-protein binding adaptor 14-3-3. Interestingly, the 14-3-3 isoforms bound directly to the T-loop Thr residue of QSK and SIK, after these were phosphorylated by LKB1. Consistent with this, the 14-3-3 isoforms failed to interact with non-phosphorylated QSK and SIK, in LKB1 knockout muscle or in HeLa cells in which LKB1 is not expressed. Moreover, mutation of the T-loop Thr phosphorylated by LKB1, prevented QSK and SIK from interacting with 14-3-3 in vitro. Binding of 14-3-3 to QSK and SIK, enhanced catalytic activity towards the TORC2 protein and the AMARA peptide, and was required for the cytoplasmic localization of SIK and for localization of QSK to punctate structures within the cytoplasm. To our knowledge, this study provides the first example of 14-3-3 binding directly to the T-loop of a protein kinase and influencing its catalytic activity and cellular localization.
Re-defining the Golgi complex inPlasmodium falciparumusing the novel Golgi markerPfGRASP
Authors: Struck Nicole S. , de Souza Dias Suzana , Langer Christine , Marti Matthias , Pearce J. Andrew , Cowman Alan F. , Gilberger Tim W.
Published: November 2005

Plasmodium falciparum, the causative agent of malaria, relies on a sophisticated protein secretion system for host cell invasion and transformation. Although the parasite displays a secretory pathway similar to those of all eukaryotic organisms, a classical Golgi apparatus has never been described. We identified and characterised the putative Golgi matrix protein PfGRASP, a homologue of the Golgi re-assembly stacking protein (GRASP) family. We show that PfGRASP is expressed as a 70 kDa protein throughout the asexual life cycle of the parasite. We generated PfGRASP-GFP-expressing transgenic parasites and showed that this protein is localised to a single, juxtanuclear compartment in ring-stage parasites. The PfGRASP compartment is distinct from the ER, restricted within the boundaries of the parasite and colocalises with the cis-Golgi marker ERD2. Correct subcellular localisation of this Golgi matrix protein depends on a cross-species conserved functional myristoylation motif and is insensitive to Brefeldin A. Taken together our results define the Golgi apparatus in Plasmodium and depict the morphological organisation of the organelle throughout the asexual life cycle of the parasite.
TheCaenorhabditis elegansGATA factorelt-1is essential for differentiation and maintenance of hypodermal seam cells and for normal locomotion
Authors: Smith Judith A. , McGarr Pamela , Gilleard John S.
Published: November 2005

The Caenorhabditis elegans GATA transcription factor elt-1 has previously been shown to have a central role in the specification of hypodermal (epidermal) cell fates and acts several cell divisions before the birth of hypodermal cells. Here we report that elt-1 also has essential functions during subsequent development. Reporter gene studies show that elt-1 expression is maintained in lateral seam cells throughout development and elt-1 RNA interference experiments support an essential role for elt-1 in the differentiation of lateral seam cells in the embryo. The maintenance of seam-cell fates in all larval stages including L2d and dauer also requires elt-1. The elt-1 RNAi phenotype shows that seam cells are essential for the structural integrity of adult hermaphrodites in the vulval region and for diametric shrinkage during dauer larval formation. By contrast, severe seam-cell loss in the larval stages has little effect on moulting, indicating that the presence of these cells is not essential for this process. The elt-1 reporter gene is also expressed in neurones of the locomotory circuit. Loss of elt-1 function during postembryonic development results in a hypermotility phenotype whereas overexpression of elt-1 leads to a reciprocal phenotype of reduced motility and paralysis. These results suggest that elt-1 is a key regulator of neuronal function in larvae and adult worms.
Involvement of aquaporin-4 in astroglial cell migration and glial scar formation
Authors: Saadoun Samira , Papadopoulos Marios C. , Watanabe Hiroyuki , Yan Donghong , Manley Geoffrey T. , Verkman A. S.
Published: November 2005

Aquaporin-4, the major water-selective channel in astroglia throughout the central nervous system, facilitates water movement into and out of the brain. Here, we identify a novel role for aquaporin-4 in astroglial cell migration, as occurs during glial scar formation. Astroglia cultured from the neocortex of aquaporin-4-null mice had similar morphology, proliferation and adhesion, but markedly impaired migration determined by Transwell migration efficiency (18±2 vs 58±4% of cells migrated towards 10% serum in 8 hours; P<0.001) and wound healing rate (4.6 vs 7.0 μm/hour speed of wound edge; P<0.001) compared with wild-type mice. Transwell migration was similarly impaired (25±4% migrated cells) in wild-type astroglia after ∼90% reduction in aquaporin-4 protein expression by RNA inhibition. Aquaporin-4 was polarized to the leading edge of the plasma membrane in migrating wild-type astroglia, where rapid shape changes were seen by video microscopy. Astroglial cell migration was enhanced by a small extracellular osmotic gradient, suggesting that aquaporin-4 facilitates water influx across the leading edge of a migrating cell. In an in vivo model of reactive gliosis and astroglial cell migration produced by cortical stab injury, glial scar formation was remarkably impaired in aquaporin-4-null mice, with reduced migration of reactive astroglia towards the site of injury. Our findings provide evidence for the involvement of aquaporin-4 in astroglial cell migration, which occurs during glial scar formation in brain injury, stroke, tumor and focal abscess.