bluuebunny/crossref_metadata_2025 huggingface dataset:
Parks or people? National parks and the case of Del Este, Dominican Republic
Authors: Macleod Donald V.L.
Published: August 2007

Beginning with a brief overview of the USA national park model, this paper outlines significant changes in attitudes towards resident peoples worldwide. It reviews relevant literature dealing with parks in various countries, and argues that the traditional division between people and parks, part of the intellectual context, should be challenged. It also reports that the involvement of resident peoples in management decisions is increasing. Nevertheless, at grass-roots level, as anthropological research and a case study of Del Este in the Dominican Republic show, the struggle for resources continues, with international economic power and local culture remaining dominant factors in environmental conservation.
Children’s and young people’s participation in development in the South and in urban regeneration in the North
Authors: Mayo Marjorie
Published: August 2007

This paper summarizes the varying reasons why children’s participation has emerged on development/regeneration agendas in both Northern and Southern contexts. Nongovernmental organizations and campaigning groups have played significant roles, championing the case for children’s involvement and transferring learning from experiences in the South to the North as well as vice versa. Despite these developing initiatives to enable children’s voices to be heard, there are still too many examples of tokenism, however, with major gaps between rhetoric and reality. The paper concludes by raising questions about possible ways forward, including questions about the need for wider institutional change.
Histone deacetylase–mediated transcriptional activation reduces proviral loads in HTLV-1–associated myelopathy/tropical spastic paraparesis patients
Authors: Lezin Agnès , Gillet Nicolas , Olindo Stéphane , Signaté Aïssatou , Grandvaux Nathalie , Verlaeten Olivier , Belrose Gildas , de Carvalho Bittencourt Marcelo , Hiscott John , Asquith Becca , Burny Arsène , Smadja Didier , Césaire Raymond , Willems Luc
Published: August 2007

Epigenetic modifications of chromatin may play a role in maintaining viral latency and thus persistence of the human T-lymphotropic virus type 1 (HTLV-1), which is responsible for HTLV-associated myelopathy/tropical spastic paraparesis (HAM/TSP). A major determinant of disease progression is increased peripheral blood proviral load (PVL), possibly via the accumulation of infected cells in the central nervous system (CNS) creating a damaging inflammatory response. Current therapeutic approaches that focus on reducing either cell proliferation, viral replication, or tissue invasion are still unsatisfactory. Contrasting with these inhibitory strategies, we evaluated the efficacy of a novel approach aimed, paradoxically, at activating viral gene expression to expose virus-positive cells to the host immune response. We used valproate (VPA), a histone deacetylase inhibitor that has been used for decades as a chronic, safe treatment for epileptic disorders. Based on in vitro and in vivo data, we provide evidence that transient activation of the latent viral reservoir causes its collapse, a process that may alleviate the condition of HAM/TSP. This represents the first such approach to treating HAM/TSP, using gene activation therapy to tilt the host-pathogen balance in favor of an existing antiviral response. This trial is registered at http://clinicaltrials.gov/as no. NCT00519181.
Deletions within the HSV-tk transgene in long-lasting circulating gene-modified T cells infused with a hematopoietic graft
Authors: Deschamps Marina , Mercier-Lethondal Patricia , Certoux Jean Marie , Henry Carole , Lioure Bruno , Pagneux Céline , Cahn Jean Yves , Deconinck Eric , Robinet Eric , Tiberghien Pierre , Ferrand Christophe
Published: August 2007

In our previous phase 1/2 study aimed at controlling graft-versus-host disease, 12 patients received Herpes simplex virus thymidine kinase (HSV-tk+)/neomycin phosphotransferase (NeoR+)–expressing donor gene-modified T cells (GMCs) and underwent an HLA-identical sibling T-cell–depleted bone marrow transplantation (BMT). This study's objective was to follow up, to quantify, and to characterize persistently circulating GMCs more than 10 years after BMT. Circulating GMCs remain detectable in all 4 evaluable patients. However, NeoR- and HSV-tk–polymerase chain reaction (PCR) differently quantified in vivo counts, suggesting deletions within the HSV-tk gene. Further experiments, including a novel “transgene walking” PCR method, confirmed the presence of deletions. The deletions were unique, patient-specific, present in most circulating GMCs expressing NeoR, and shown to occur at time of GMC production. Unique patient-specific retroviral insertion sites (ISs) were found in all GMCs capable of in vitro expansion/cloning as well. These findings suggest a rare initial gene deletion event and an in vivo survival advantage of rare GMC clones resulting from an anti–HSV-tk immune response and/or ganciclovir treatment. In conclusion, we show that donor mature T cells infused with a T-cell–depleted graft persist in vivo for more than a decade. These cells, containing transgene deletions and subjected to significant in vivo selection, represent a small fraction of T cells infused at transplantation.
PARE: A tool for comparing protein abundance and mRNA expression data
Authors: Yu Eric Z , Burba Anne E Counterman , Gerstein Mark
Published: August 2007

Background

Techniques for measuring protein abundance are rapidly advancing and we are now in a situation where we anticipate many protein abundance data sets will be available in the near future. Since proteins are translated from mRNAs, their expression is expected to be related to their abundance, to some degree.

Results

We have developed a web tool, called PARE (Protein Abundance and mRNA Expression; http://proteomics.gersteinlab.org), to correlate these two quantities. In addition to globally comparing the quantities of protein and mRNA, PARE allows users to select subsets of proteins for focused study (based on functional categories and complexes). Furthermore, it highlights correlation outliers, which are potentially worth further examination.

Conclusion

We anticipate PARE will facilitate comparative studies on mRNA and protein abundance by the proteomics community.
Comparison of quenching and extraction methodologies for metabolome analysis of Lactobacillus plantarum
Authors: Faijes Magda , Mars Astrid E , Smid Eddy J
Published: August 2007

Background

A reliable quenching and metabolite extraction method has been developed for Lactobacillus plantarum. The energy charge value was used as a critical indicator for fixation of metabolism.

Results

Four different aqueous quenching solutions, all containing 60% of methanol, were compared for their efficiency. Only the solutions containing either 70 mM HEPES or 0.85% (w/v) ammonium carbonate (pH 5.5) caused less than 10% cell leakage and the energy charge of the quenched cells was high, indicating rapid inactivation of the metabolism.

The efficiency of extraction of intracellular metabolites from cell cultures depends on the extraction methods, and is expected to vary between micro-organisms. For L. plantarum, we have compared five different extraction methodologies based on (i) cold methanol, (ii) perchloric acid, (iii) boiling ethanol, (iv) chloroform/methanol (1:1) and (v) chloroform/water (1:1). Quantification of representative intracellular metabolites showed that the best extraction efficiencies were achieved with cold methanol, boiling ethanol and perchloric acid.

Conclusion

The ammonium carbonate solution was selected as the most suitable quenching buffer for metabolomics studies in L. plantarum because (i) leakage is minimal, (ii) the energy charge indicates good fixation of metabolism, and (iii) all components are easily removed during freeze-drying. A modified procedure based on cold methanol extraction combined good extractability with mild extraction conditions and high enzymatic inactivation. These features make the combination of these quenching and extraction protocols very suitable for metabolomics studies with L. plantarum.
Molecular portrait of cisplatin induced response in human testis cancer cell lines based on gene expression profiles
Authors: Duale Nur , Lindeman Birgitte , Komada Mitsuko , Olsen Ann-Karin , Andreassen Ashild , Soderlund Erik J , Brunborg Gunnar
Published: August 2007

Background

Testicular germ cell tumors (TGCTs) respond well to cisplatin-based chemotherapy and show a low incidence of acquired resistance compared to most somatic tumors. The reasons for these specific characteristics are not known in detail but seem to be multifactorial. We have studied gene expression profiles of testicular and colon cancer derived cell lines treated with cisplatin. The main goal of this study was to identify novel gene expression profiles with their functional categories and the biochemical pathways that are associated with TGCT cells' response to cisplatin.

Results

Genes that were differentially expressed between the TGCT cell lines vs the (somatic) HCT116 cell line, after cisplatin treatment, were identified using the significance analysis of microarrays (SAM) method. The response of TGCT cells was strikingly different from that of HCT116, and we identified 1794 genes that were differentially expressed. Functional classification of these genes showed that they participate in a variety of different and widely distributed functional categories and biochemical pathways. Database mining showed significant association of genes (n = 41) induced by cisplatin in our study, and genes previously reported to by expressed in differentiated TGCT cells. We identified 37 p53-responsive genes that were altered after cisplatin exposure. We also identified 40 target genes for two microRNAs, hsa-mir-372 and 373 that may interfere with p53 signaling in TGCTs. The tumor suppressor genes NEO1 and LATS2, and the estrogen receptor gene ESR1, all have binding sites for p53 and hsa-mir-372/373. NEO1 and LATS2 were down-regulated in TGCT cells following cisplatin exposure, while ESR1 was up-regulated in TGCT cells. Cisplatin-induced genes associated with terminal growth arrest through senescence were identified, indicating associations which were not previously described for TGCT cells.

Conclusion

By linking our gene expression data to publicly available databases and literature, we provide a global pattern of cisplatin induced cellular response that is specific for testicular cancer cell lines. We have identified cisplatin-responsive functional classes and pathways, such as the angiogenesis, Wnt, integrin, and cadherin signaling pathways. The identification of differentially expressed genes in this study may contribute to a better understanding of the unusual sensitivity of TGCT to some DNA-damaging agents.
The impact of operative approach on outcome of surgery for gastro-oesophageal tumours
Authors: Suttie Stuart A , Li Alan GK , Quinn Martha , Park Kenneth GM
Published: August 2007

Background

The choice of operation for tumours at or around the gastro-oesophageal junction remains controversial with little evidence to support one technique over another. This study examines the prevalence of margin involvement and nodal disease and their impact on outcome following three surgical approaches (Ivor Lewis, transhiatal and left thoraco-laparotomy) for these tumours.

Methods

A retrospective analysis was conducted of patients undergoing surgery for distal oesophageal and gastro-oesophageal junction tumours by a single surgeon over ten years. Comparisons were undertaken in terms of tumour clearance, nodal yield, postoperative morbidity, mortality, and median survival. All patients were followed up until death or the end of the data collection (mean follow up 33.2 months).

Results

A total of 104 patients were operated on of which 102 underwent resection (98%). Median age was 64.1 yrs (range 32.1–79.4) with 77 males and 25 females. Procedures included 29 Ivor Lewis, 31 transhiatal and 42 left-thoraco-laparotomies. Postoperative mortality was 2.9% and median survival 23 months. Margin involvement was 24.1% (two distal, one proximal and 17 circumferential margins). Operative approach had no significant effect on nodal clearance, margin involvement, postoperative mortality or morbidity and survival. Lymph node positive disease had a significantly worse median survival of 15.8 months compared to 39.7 months for node negative (p = 0.007), irrespective of approach.

Conclusion

Surgical approach had no effect on postoperative mortality, circumferential tumour, nodal clearance or survival. This suggests that the choice of operative approach for tumours at the gastro-oesophageal junction may be based on the individual patient and tumour location rather than surgical dogma.
Genomic and proteomic profiling II: Comparative assessment of gene expression profiles in leiomyomas, keloids, and surgically-induced scars
Authors: Luo Xiaoping , Pan Qun , Liu Li , Chegini Nasser
Published: August 2007

Background

Leiomyoma have often been compared to keloids because of their fibrotic characteristic and higher rate of occurrence among African Americans as compared to other ethnic groups. To evaluate such a correlation at molecular level this study comparatively analyzed leiomyomas with keloids, surgical scars and peritoneal adhesions to identify genes that are either commonly and/or individually distinguish these fibrotic disorders despite differences in the nature of their development and growth.

Methods

Microarray gene expression profiling and realtime PCR.

Results

The analysis identified 3 to 12% of the genes on the arrays as differentially expressed among these tissues based on P ranking at greater than or equal to 0.005 followed by 2-fold cutoff change selection. Of these genes about 400 genes were identified as differentially expressed in leiomyomas as compared to keloids/incisional scars, and 85 genes as compared to peritoneal adhesions (greater than or equal to 0.01). Functional analysis indicated that the majority of these genes serve as regulators of cell growth (cell cycle/apoptosis), tissue turnover, transcription factors and signal transduction. Of these genes the expression of E2F1, RUNX3, EGR3, TBPIP, ECM-2, ESM1, THBS1, GAS1, ADAM17, CST6, FBLN5, and COL18A was confirmed in these tissues using quantitative realtime PCR based on low-density arrays.

Conclusion

the results indicated that the molecular feature of leiomyomas is comparable but may be under different tissue-specific regulatory control to those of keloids and differ at the levels rather than tissue-specific expression of selected number of genes functionally regulating cell growth and apoptosis, inflammation, angiogenesis and tissue turnover.
Initial community perspectives on the Health Service Extension Programme in Welkait, Ethiopia
Authors: Negusse Haile , McAuliffe Eilish , MacLachlan Malcolm
Published: August 2007

Background

The Health Service Extension Programme (HSEP) is an innovative approach to addressing the shortfall in health human resources in Ethiopia. It has developed a new cadre of Health Extension Workers (HEWs), who are charged with providing the health and hygiene promotion and some treatment services, which together constitute the bedrock of Ethiopia's community health system.

Methods

This study seeks to explore the experience of the HSEP from the perspective of the community who received the service. A random sample of 60 female heads-of-household in a remote area of Tigray participated in a structured interview survey.

Results

Although Health Extension Workers (HEWs) had visited them less frequently than planned, participants generally found the programme to be helpful. Despite this, their basic health knowledge was still quite poor regarding the major communicable diseases and their vectors. Participants felt the new HESP represented an improvement on previous health provision. HEWs were preferred over Traditional Birth Attendants for assistance with labour

Conclusion

While the introduction of HEWs has been a positive experience for women living at the study site, the frequency of visits, extent of effectively imparted health knowledge and affects of HEWs on other health providers needs to be further explored.
An AICD-based functional screen to identify APP metabolism regulators
Authors: Zhang Can , Khandelwal Preeti J , Chakraborty Ranjita , Cuellar Trinna L , Sarangi Srikant , Patel Shyam A , Cosentino Christopher P , O'Connor Michael , Lee Jeremy C , Tanzi Rudolph E , Saunders Aleister J
Published: August 2007

Background

A central event in Alzheimer's disease (AD) is the regulated intramembraneous proteolysis of the β-amyloid precursor protein (APP), to generate the β-amyloid (Aβ) peptide and the APP intracellular domain (AICD). Aβ is the major component of amyloid plaques and AICD displays transcriptional activation properties. We have taken advantage of AICD transactivation properties to develop a genetic screen to identify regulators of APP metabolism. This screen relies on an APP-Gal4 fusion protein, which upon normal proteolysis, produces AICD-Gal4. Production of AICD-Gal4 induces Gal4-UAS driven luciferase expression. Therefore, when regulators of APP metabolism are modulated, luciferase expression is altered.

Results

To validate this experimental approach we modulated α-, β-, and γ-secretase levels and activities. Changes in AICD-Gal4 levels as measured by Western blot analysis were strongly and significantly correlated to the observed changes in AICD-Gal4 mediated luciferase activity. To determine if a known regulator of APP trafficking/maturation and Presenilin1 endoproteolysis could be detected using the AICD-Gal4 mediated luciferase assay, we knocked-down Ubiquilin 1 and observed decreased luciferase activity. We confirmed that Ubiquilin 1 modulated AICD-Gal4 levels by Western blot analysis and also observed that Ubiquilin 1 modulated total APP levels, the ratio of mature to immature APP, as well as PS1 endoproteolysis.

Conclusion

Taken together, we have shown that this screen can identify known APP metabolism regulators that control proteolysis, intracellular trafficking, maturation and levels of APP and its proteolytic products. We demonstrate for the first time that Ubiquilin 1 regulates APP metabolism in the human neuroblastoma cell line, SH-SY5Y.
A Central Role for Neuronal Adenosine 5′-Monophosphate-Activated Protein Kinase in Cancer-Induced Anorexia
Authors: Ropelle Eduardo R. , Pauli José R. , Zecchin Karina G. , Ueno Mirian , de Souza Cláudio T. , Morari Joseane , Faria Marcel C. , Velloso Lício A. , Saad Mario J. A. , Carvalheira José B. C.
Published: August 2007

The pathogenesis of cancer anorexia is multifactorial and associated with disturbances of the central physiological mechanisms controlling food intake. However, the neurochemical mechanisms responsible for cancer-induced anorexia are unclear. Here we show that chronic infusion of 5-amino-4imidazolecarboxamide-riboside into the third cerebral ventricle and a chronic peripheral injection of 2 deoxy-d-glucose promotes hypothalamic AMP-activated protein kinase (AMPK) activation, increases food intake, and prolongs the survival of anorexic tumor-bearing (TB) rats. In parallel, the pharmacological activation of hypothalamic AMPK in TB animals markedly reduced the hypothalamic production of inducible nitric oxide synthase, IL-1β, and TNF-α and modulated the expression of proopiomelanocortin, a hypothalamic neuropeptide that is involved in the control of energy homeostasis. Furthermore, the daily oral and intracerebroventricular treatment with biguanide antidiabetic drug metformin also induced AMPK phosphorylation in the central nervous system and increased food intake and life span in anorexic TB rats. Collectively, the findings of this study suggest that hypothalamic AMPK activation reverses cancer anorexia by inhibiting the production of proinflammatory molecules and controlling the neuropeptide expression in the hypothalamus, reflecting in a prolonged life span in TB rats. Thus, our data indicate that hypothalamic AMPK activation presents an attractive opportunity for the treatment of cancer-induced anorexia.
Pax4 Paired Domain Mediates Direct Protein Transduction into Mammalian Cells
Authors: Lu Jun , Li Ge , Lan Michael S. , Zhang Shuyu , Fan Weiwei , Wang Hongwei , Lu Daru
Published: August 2007

Pax4, a paired-box transcription factor, is a key regulator of pancreatic islet cell growth and differentiation. Here, we report for the first time that the Pax4 protein can permeate into various cell types including pancreatic islets. The paired domain of Pax4 serves as a novel protein transduction domain (PTD). The Pax4 protein can transduce in a dose- and time-dependent manner. The cellular uptake of Pax4 PTD can be completely blocked by heparin, whereas cytochalasin D and amiloride were partially effective in blocking the Pax4 protein entry. Transduced intact Pax4 protein functions similarly to the endogenous Pax4. It inhibits the Pax6 mediated transactivation and protects Min6 cells against TNFα-induced apoptosis. These data suggest that Pax4 protein transduction could be a safe and valuable strategy for protecting islet cell growth in culture from apoptosis and promoting islet cell differentiation.
Solid lipid nanoparticles (SLN) as carriers for the topical delivery of econazole nitrate: in-vitro characterization, ex-vivo and in-vivo studies
Authors: Sanna Vanna , Gavini Elisabetta , Cossu Massimo , Rassu Giovanna , Giunchedi Paolo
Published: August 2007

Solid lipid nanoparticles (SLN) designed for topical administration of econazole nitrate (ECN), were prepared by o/w high-shear homogenization method using different ratios of lipid and drug (5:1 and 10:1). SLN were characterized in terms of particle size, morphology, encapsulation efficiency and crystalline structure. After incorporation of SLN into hydrogels, rheological measurements were performed, and ex-vivo drug permeation tests were carried out using porcine stratum corneum (SC). In-vivo study of percutaneous absorption of ECN as a function of application time and composition of gels was carried out by tape-stripping technique. Penetration tests of the drug from a conventional gel were performed as comparison. High-shear homogenization method resulted in a good technique for preparation of ECN-loaded SLN. Particles had a mean diameter of about 150 nm and a regular shape and smooth surface. The encapsulation efficiency values were about 100%. Ex-vivo tests showed that SLN were able to control the drug release through the SC; the release rate depended upon the lipid content on the nanoparticles. In-vivo studies demonstrated that SLN promoted a rapid penetration of ECN through the SC after 1 h and improved the diffusion of the drug in the deeper skin layers after 3 h of application compared with the reference gel.
Novel, cell-penetrating molecular transporters with flexible backbones and permanently charged side-chains
Authors: Bodor N , Tóth-Sarudy É , Holm T , Pallagi I , Vass E , Buchwald P , Langel Ü
Published: August 2007

Various cell-penetrating peptides have been discovered recently that can translocate across plasma membranes and can even carry large cargo molecules into the cells. Because under physiological conditions most of these peptides carry considerable positive charges due to the presence of basic amino acids such as arginine, we decided to investigate whether molecular transporters composed of permanently charged side-chains also possess such cell penetrating ability. Arginine-rich oligomers that have a backbone with increased flexibility due to incorporation of non-α-amino acids (ε-aminocaproic acid) have been found to be effective molecular transporters. Here, we report the preparation of analogue structures by replacing the arginine residues with the quaternary form of a novel redox amino acid (Nys+) that contain a trigonelline moiety; it has already been shown possible to replace the original basic amino acid side-chain of neuropeptides without significant activity-loss due to the sufficiently close steric and electronic analogy between the new Nys+ and the original side-chains (in their protonated form, e.g., Arg+, Lys+). A nonamer analogue showed transporter activity resulting in increased cellular uptake in human carcinoma (HeLa) cells.
Central nervous system distribution kinetics of indinavir in rats
Authors: Hamidi Mehrdad
Published: August 2007

The central nervous system (CNS) distribution kinetics of indinavir were extensively evaluated using a combinational in-vivo model comprising the integration plot method (a single-passage approach) and neuropharmacokinetic method (a multiple-passage approach). A 5 mg kg−1 dose of indinavir was administered intravenously to rats. Blood and cerebrospinal fluid (CSF) samples and whole brain were collected from the animals at specified time points and the drug concentration in each sample was determined using a high-performance liquid chromatography method. For the neuropharmacokinetic study, the simultaneous plasma, CSF and brain concentrations were fitted to an integrated model, which resulted in the estimation of the influx (Kin) and efflux (Kout) rate constants of the drug to/from CSF and brain parenchyma. The integration plot method involved plotting the brainplasma or CSF-plasma concentration ratios (Kp,app) against AUC0r̊t/Cp(t), and estimating the uptake clearance of the drug by brain/CSF from the slope of the initial linear portion of the plot. The Kin and Kout values of the drug to/from CSF were estimated to be 2.42 times 10−2 and 13.26 times 10−2min−1, respectively, and the corresponding values for brain parenchyma were 1.02 times 10−2 and 1.32 times 10−2 min−1, respectively. The uptake clearances of indinavir by CSF and brain parenchyma were 8.89 and 8.38 μLmin−1 g−1, respectively. The permeability surface area products of the drug for the blood-brain barrier and blood-CSF barrier were estimated as 1.05 times 10−2 and 2.45 times 10−2 mL min−1 g−1, respectively. The estimated kinetic parameters indicated limited CNS entry of the drug because of the limited blood-brain barrier permeability and the efficient drug efflux from CNS, particularly from CSF.
The influence of improved glycaemic control with chlorpropamide on microvascular reactivity and nitric oxide synthase activity in diabetic rats
Authors: Sartoretto J L , Santos R A , Scavone C , Tostes R C , Nigro D , Carvalho M H C , Cuman R K N , Fortes Z B
Published: August 2007

Hyperglycaemia is a primary cause of vascular complications in diabetes. A hallmark of these vascular complications is endothelial cell dysfunction, which is partly due to reduced production of nitric oxide. The aim of this study was to verify the influence of improved glycaemic control with chlorpropamide on microvascular reactivity, endothelial nitric oxide synthase (e-NOS) expression, and NOS activity in neonatal streptozotocin-induced diabetic rats (n-STZ). Diabetes was induced by STZ injection into neonates Wistar rats. n-STZ diabetic rats were treated with chlorpropamide (200 mg kg−1, 15 days, by gavage). The changes in mesenteric arteriolar and venular diameters were determined in anaesthetized control and n-STZ diabetic rats, before and after topical application of acetylcholine, bradykinin and sodium nitroprusside (SNP). We also assessed e-NOS expression (using polymerase chain reaction after reverse transcription of mRNAs into cDNAs) and NOS activity (conversion of L-arginine to citrulline) in the mesenteric vascular bed of chlorpropamide-treated n-STZ, vehicle-treated n-STZ, and control rats. In n-STZ, chlorpropamide treatment reduced high glycaemic levels, improved glucose tolerance and homoeostatic model assessment (HOMA-beta), and restored NOS activity. Impaired vasodilator responses of arterioles and venules to acetylcholine, bradykinin and SNP were partially corrected by chlorpropamide treatment in n-STZ. We concluded that improved metabolic control and restored NOS activity might be collaborating with improved microvascular reactivity found in chlorpropamide-treated n-STZ.
Scavenging properties of metronidazole on free oxygen radicals in a skin lipid model system
Authors: Narayanan Sabrina , Hùnerbein Andreas , Getie Melkamu , Jäckel Andreas , Neubert Reinhard H H
Published: August 2007

Reactive oxygen species (ROS) play a vital role in the pathophysiology of the skin disease rosacea, a chronic, genetically-determined and UV-triggered disease, leading to facial redness and blemishes and exhibiting a deep impact on a patient's self-esteem and quality of life. ROS can cause oxidative damage to nucleic acids, sugars, proteins and lipids, thereby contributing to adverse effects on the skin. Metronidazole has been the first-line topical agent therapy for many years; nevertheless the mechanism of action is still not well understood. The therapeutic efficacy of metronidazole has been attributed to its antioxidant effects, which can involve two pathways: decreased generation of ROS within tissues or scavenging and inactivation of existing ROS. Previous investigations have shown that metronidazole reduces ROS by decreasing ROS production in cellular in-vitro systems. The aim of the following study was to demonstrate that metronidazole additionally exhibits anti-oxidative properties in a cell-free system, by acting as an antioxidant scavenger. A simple skin lipid model (oxidative) system and a complex skin adapted lipid system in conjunction with thiobarbituric acid (TBA) test, a quantitative assay for the detection of malondialdehyde (MDA) and therefore lipid peroxidation, were used to determine the antioxidative properties of metronidazole after UV irradiation. Results clearly show that metronidazole has antioxidative properties in a cell-free environment, acting as a free radical scavenger. Simple skin lipid model: in the presence of 10, 100 and 500 μg mL−1 metronidazole the MDA concentration was reduced by 25, 36 and 49%, respectively. Complex skin lipid system: in the presence of 100 and 500 μg mL−1 metronidazole the MDA concentration was reduced by 19 and 34%, respectively. The results obtained in this study and from previous publications strongly suggest that metronidazole exhibits antioxidative effects via two mechanisms: decrease in ROS production through modulation of neutrophil activity and decrease in ROS concentration by exhibiting ROS scavenging properties. The remarkable clinical efficacy of metronidazole in the treatment of rosacea is probably due to its ability to decrease ROS via different mechanisms, thereby protecting skin components from induced damage.
Theogallin and L-theanine as active ingredients in decaffeinated green tea extract: I. electrophysiological characterization in the rat hippocampus in-vitro
Authors: Dimpfel Wilfried , Kler Adolf , Kriesl Erwin , Lehnfeld Romanus
Published: August 2007

The in-vitro hippocampus slice preparation was used to mimic a physiological situation where nervous tissue is exposed directly to the water soluble extract of green tea and some of its constituents. This investigation provides evidence that L-theanine- and theogallin-enriched decaffeinated green tea extract is able to change the physiological pattern of electrical hippocampus activity in a concentration dependent manner (EC50 3 mg L−1). Of the seven fractions or single components tested (fraction containing all amino acids without L-theanine, fractions containing all amino acids plus L-theanine, glutamic acid, theogallin, its metabolites quinic acid and gallic acid, and L-theanine alone), glutamic acid produced the strongest changes in terms of increased population spike amplitude after single stimuli and increased long-term potentiation, commonly taken as representative for enhancement of spatial and time dependent memory. The presence of theogallin alone shifted the activity in the same direction. Similar results as with theogallin were obtained in the presence of quinic acid. No effect was seen with gallic acid. Opposite changes (decrease of population spike amplitude and attenuated long-term potentiation) were observed in the presence of L-theanine alone. No effects were detected during the addition of the amino acid mixture unless L-theanine was added, leading to a decrease of the responses as observed for the action of L-theanine alone. The results provide evidence for the involvement of several active principles in the action of enriched green tea extract on electrical brain activity. The overall enhancement of hippocampal pyramidal cell responses as observed for the crude extract seems to be due to the combined action of glutamic acid and theogallin (or its presumable metabolite quinic acid), whereas L-theanine seems to have an opposite effect. However, this action was not strong enough to antagonize the effects of glutamic acid and theogallin. The results are in line with the observation that the tested green tea extract improves cognition at concomitant mental relaxation in man.
Combined effect of total alkaloids from Feculae Bombycis and natural flavonoids on diabetes
Authors: Geng Peng , Yang Yang , Gao Zhihui , Yu Yangsheng , Shi Qian , Bai Gang
Published: August 2007

Both total alkaloids from Feculae Bombycis (TAFB) and natural flavonoids can inhibit α-glucosidase activity to depress the glucose level in blood. To investigate the cooperative effect of TAFB and flavonoids on blood glucose, we have studied their combined function compared with individual ingredients on enzymology, in-vitro and in-vivo. In the enzymological assay, the combination of TAFB and flavonoids showed more effective inhibition, compared with either TAFB or flavonoids alone, to α-glucosidase activity. In the everted intestine model in-vitro, the combined inhibition of starch hydrolysation and glucose transference to blood was much stronger than with separate components. In short-term studies with normal and experimentally-induced diabetic mice in-vivo, the combination of TAFB and flavonoids also had a stronger suppressive effect on the postprandial elevation in blood glucose after oral administration. In long-term treatment to diabetic mice in-vivo, the compound prescription could depress not only the fasting blood glucose, but also the fasting blood total cholesterol. These results demonstrated that TAFB and flavonoids could inhibit α-glucosidase activity cooperatively, which would successfully depress blood glucose level in the therapy of diabetes.
Anti-inflammatory and analgesic activities of the ethanolic extracts fromZanthoxylum riedelianum(Rutaceae) leaves and stem bark
Authors: Lima Leonardo Mandalho , Perazzo Fábio Ferreira , Carvalho José Carlos Tavares , Bastos Jairo Kenupp
Published: August 2007

We have evaluated the anti-inflammatory and analgesic properties of the leaves (LCE) and stem bark (BCE) crude extracts of Zanthoxylum riedelianum (Rutaceae). Different fractions of the stem bark extract (hexane, BCEH; dichloromethane, BCED; ethyl acetate, BCEE; and lyophilized aqueous residual, BCEW) were also investigated. We studied the effects of the extracts and fractions using the rat paw oedema test induced by carrageenan, dextran, histamine or nystatin; the mouse abdominal constriction test; the mouse hot-plate test (only for LCE and BCE); and the mouse formalin test. Both extracts and all BCE fractions displayed anti-inflammatory activity in the carrageenan-induced oedema model, but not for dextran, histamine or nystatin. Considering the analgesic models, both extracts showed antinociceptive activity, but BCE was more active than LCE in models of central pain. All BCE fractions showed significant inhibition in the abdominal constriction test and in both phases of the formalin test. When BCED was submitted to phytochemical procedures it led to the isolation of six lignans (sesamin, methylpluviatolide, dimethylmatairesinol, piperitol-4′-O-γ,γ-dimethylallyl ether, kaerophyllin and hinokinin), and a triterpene (lupeol). Inhibition of cyclooxygenase and its metabolites may have been involved in the mechanism of action of this plant, considering previous studies reporting the anti-inflammatory and analgesic activity for the identified lignans, as well as anti-inflammatory activity for lupeol.
Salutary effects of Corydalis yanhusuo extract on cardiac hypertrophy due to pressure overload in rats
Authors: Wen Chengping , Wu Limao , Ling Haiyun , Li Lianda
Published: August 2007

We have evaluated the effects of an alcohol extract from the rhizome of Corydalis yanhusuo W.T. (CY), a well-known traditional Chinese medicinal herb, on pressure-overloaded cardiac hypertrophy induced by transverse abdominal aorta constriction (TAAC) in rats. Rats were given vehicle or CY extract (200 or 50 mg kg−1 per day) from the second week after induction of pressure overload, for a period of 7 weeks. Haemodynamic parameters, relative heart weight and myocyte cross-sectional area were measured in each group. We also estimated left ventricular (LV) collagen volume fraction (CVF) using Masson trichrome staining, and type I collagen expression by Western blot assay. Chronic TAAC caused notable cardiac hypertrophy and heart dysfunction. Significant collagen deposition and greater type I collagen expression were found in model control rats. These changes were not significantly reversed after treatment with 50 mgkg−1 CY, whereas 200 mgkg−1 significantly improved heart function and prevented cardiac hypertrophy, with parallel reductions in myocardial fibrosis, as evidenced by reduced LV CVF and reduced levels of type I collagen. In conclusion, chronic treatment of rats with CY extract attenuated development of cardiac hypertrophy.
Gu Ling Pian, a traditional Chinese medicine, regulates function and OPG/RANKL synthesis of osteoblasts via the p38 MAPK pathway
Authors: Zhao Yi , Li Juan , Liu Yi , Yu Ke-qiang , Zhang Juan , Chen Xiao-guang
Published: August 2007

Osteoporosis is a common disease that makes bones prone to fracture and can affect both men and women. Many traditional Chinese medicine formulations have the potential effect of preventing osteoporosis. Gu Ling Pian (GLP), a traditional Chinese medicine formulation, comprised of tonifying kidney herbal medicines, has been demonstrated to prevent osteoporosis by increasing bone mineral density, however the exact mechanism has not yet been elucidated. Osteoprotegerin (OPG), a receptor activator of NF-κB (RANK), and RANK ligand (RANKL) play critical roles in bone remodelling by regulating the function of osteoclasts. In this study, we investigated the effect of GLP on osteoblasts, namely MG-63 cells. The cell proliferation and differentiation, synthesis of OPG/RANKL and p38 expression were tested on MG-63 cells exposed to serum from rats fed with GLP or not. The results showed that GLP significantly promoted MG-63 cell proliferation and differentiation. Upregulation of OPG and down-regulation of RANKL at the protein and mRNA level were observed in GLP serum treated MG-63 cells using an enzyme-linked immunosorbent assay and real-time polymerase chain reaction. Further, treatment with GLP serum increased the level of p38 phosphorylation but did not affect the total p38 expression. These effects can be blocked by the p38 specific inhibitor SB203580. The results indicate that GLP can effectively promote the proliferation and differentiation of osteoblasts and regulate their OPG/RANKL expression, while the effects may be mediated via the p38 MAPK pathway. The findings suggest that GLP induces bone formation and may be beneficial for patients with osteoporosis.
Separation and purification of saponins from Semen Ziziphus jujuba and their sedative and hypnotic effects
Authors: Jiang Jian-Guo , Huang Xiao-Juan , Chen Jian
Published: August 2007

Semen Ziziphus jujuba (SZJ) has long been used in Chinese traditional medicine for the treatment of anxiety and insomnia because of its effect of decreasing monoaminergic system activity; saponins are thought to be the main bioactive factors. To investigate the sedative and hypnotic effects of saponins from SZJ, silica gel column chromatography and thin-layer chromatography were used to purify the crude extract of total saponins from SZJ. High-performance liquid chromatography showed that saponins from SZJ comprised two components, compounds I and II. Animal tests were conducted using these two compounds to compare their sedative and hypnotic effects. Results showed that both compounds had a significant effect (P < 0.05, P < 0.01) on walking time compared with that of the control group. Compound I had a significant effect on coordinated movement (P < 0.05). Both compounds prolonged the suprathreshold barbiturate induced sleeping time (P < 0.05). The number of sleeping animals increased by 30% and 20% for compounds I and II, respectively, under the sub-threshold dose of sodium barbital.
Vascular remodeling of the mouse yolk sac requires hemodynamic force
Authors: Lucitti Jennifer L. , Jones Elizabeth A. V. , Huang Chengqun , Chen Ju , Fraser Scott E. , Dickinson Mary E.
Published: August 2007

The embryonic heart and vessels are dynamic and form and remodel while functional. Much has been learned about the genetic mechanisms underlying the development of the cardiovascular system, but we are just beginning to understand how changes in heart and vessel structure are influenced by hemodynamic forces such as shear stress. Recent work has shown that vessel remodeling in the mouse yolk sac is secondarily effected when cardiac function is reduced or absent. These findings indicate that proper circulation is required for vessel remodeling, but have not defined whether the role of circulation is to provide mechanical cues, to deliver oxygen or to circulate signaling molecules. Here, we used time-lapse confocal microscopy to determine the role of fluid-derived forces in vessel remodeling in the developing murine yolk sac. Novel methods were used to characterize flows in normal embryos and in embryos with impaired contractility (Mlc2a-/-). We found abnormal plasma and erythroblast circulation in these embryos, which led us to hypothesize that the entry of erythroblasts into circulation is a key event in triggering vessel remodeling. We tested this by sequestering erythroblasts in the blood islands, thereby lowering the hematocrit and reducing shear stress, and found that vessel remodeling and the expression of eNOS (Nos3) depends on erythroblast flow. Further, we rescued remodeling defects and eNOS expression in low-hematocrit embryos by restoring the viscosity of the blood. These data show that hemodynamic force is necessary and sufficient to induce vessel remodeling in the mammalian yolk sac.
Fallowfield's Sexual Activity Questionnaire in women with without and at risk of cancer
Authors: Atkins Louise , Fallowfield Lesley J
Published: August 2007

Objectives. To determine the effect of cancer, cancer risk, menopausal status and psychological factors on sexual activity as measured by Fallowfield's Sexual Activity Questionnaire (FSAQ).

Study design and main outcome measures. Five groups of women completed the FSAQ: 1451 healthy women who were participating in an ovarian cancer screening trial; 488 healthy women at increased risk of breast cancer who were participating in a chemoprevention trial; 154 healthy women at increased risk of breast cancer who had been offered risk-reducing surgery; 117 women with advanced ovarian cancer; and a healthy non-study sample of 162 women.

Results. There were significant between-group differences regarding age ( F=1373.79, P<0.01) and the proportion of women who were sexually active (χ2(4)=212.62, P<0.01) (more younger women reported being sexually active). The most commonly cited reason for sexual inactivity was the absence of a partner. In relation to their sexual activity, women with ovarian cancer reported less pleasure ( F=18.27, P<0.01), more discomfort ( F=21.33, P<0.01) and less frequency ( F=200.01, P<0.01) than the other groups. Premenopausal women reported more pleasure ( t=4.41, P<0.01), less discomfort ( t=11.79, P<0.01) and greater frequency of sexual activity ( t=8.58, P<0.01) than postmenopausal women. Psychological morbidity was associated with decreased pleasure in sexual activity among the women with an elevated risk of cancer – that is, those participating in the chemoprevention trial ( t=4.20, P<0.01) and those offered risk-reducing surgery ( t=3.32, P<0.01).

Conclusions: The FSAQ is a useful tool for measuring sexual activity in women with cancer and women at a normal or increased risk of developing cancer. Age, cancer, psychological distress and menopausal status affect sexual activity in these groups of women and should be considered in future investigations.
Hysteroscopy in the diagnosis of postmenopausal bleeding
Authors: Guruwadayarhalli Bramara , Jones Siân E , Srinivasan Vyjayanthi
Published: August 2007

Postmenopausal bleeding (PMB) accounts for 5% of gynaecology referrals. Investigations should exclude malignancy and pre-malignancy, and diagnose the benign conditions that need treatment. The three modalities that are most commonly used are transvaginal ultrasound scan (TVS), endometrial biopsy (EB) and hysteroscopy. Most authors agree that the first-line investigation should be TVS, followed by endometrial assessment (EB or hysteroscopy) if the endometrial thickness is >4 mm. When scanning demonstrates the possibility of pathology, outpatient hysteroscopy and biopsy are the gold standard for investigating the endometrial cavity. Focal pathology can be removed during the hysteroscopy, thereby reducing hospital admissions and costs.
Efficacy and tolerability of continuous combined hormone replacement therapy in early postmenopausal women
Authors: Mattsson L A , Skouby S , Rees M , Heikkinen J , Kudela M , Stadnicki-Kolendo A , Mattila L , Salminen K , Vuorela A , Mustonen M ,   The Indivina 321 Study Group
Published: August 2007

Objective. Continuous combined hormone replacement therapy (ccHRT) based on estradiol valerate (E2V) and medroxyprogesterone acetate (MPA) is effective for relief of menopausal symptoms three years or more after the menopause. This study was undertaken to examine the efficacy and tolerability of ccHRT in early postmenopausal women (last menstrual period 1.3 years before study entry).

Study design. This was a 52-week, randomized, double-blind, multinational study of ccHRT comprising three different dose combinations of E2V/MPA in 459 early postmenopausal non-hysterectomized women experiencing 30 or more moderate to severe hot flushes a week and/or vasomotor symptoms requiring treatment.

Main outcomes measures. The primary endpoint was change in frequency and severity of moderate to severe hot flushes at 12 weeks. Secondary outcome measures included number of bleeding days and evaluation of tolerability.

Results. The frequency of hot flushes was reduced by ≥70% after one month ( P<0.001 for all doses at week 2 onwards), with little evidence of statistically different dose effects. Severity of flushing was also attenuated by ccHRT. Mean number of bleeding days fell to <1 per 28-day cycle at 52 weeks. Rates of amenorrhoea approached 80–90% at the end of the study, but were significantly lower at several time points with the highest-dose regimen (2 mg E2V + 5 mg MPA) than with the lower-dose options (1 mg E2V + 2.5 mg MPA and 1 mg E2V + 5 mg MPA; P<0.05). Adverse events declined in frequency over time with all regimens but throughout the study were more numerous with the highest-dose regimen than with lower doses ( P= 0.0002).

Conclusions. Continuous combined HRT was effective for the relief of climacteric symptoms in early postmenopausal women and was well tolerated.
Ethical publishing: the innocent author's guide to avoiding misconduct
Authors: Wager Elizabeth
Published: August 2007

Publication misconduct includes a range of unethical behaviours, such as plagiarism, breach of confidence and in appropriate authorship. The most egregious cases are easy to recognize and widely condemned, but the gradient between normal and unethical behaviour is often a gradual one. Clinicians and researchers should be aware of the full spectrum of publication misconduct and understand that some widely accepted practices may be unethical. This paper describes the various types of publication misconduct and offers guidance to authors, reviewers and journal editors about ways to detect and prevent them.