bluuebunny/crossref_metadata_2025 huggingface dataset:
Remorse and the production of truth
Authors: Martel Joane
Published: October 2010

This article reflects on the confession as a traditional focal point of criminal law and penal theories. Specifically, it questions the privileged status traditionally conferred to the confession within the hierarchy of legal proof and punishment as a remnant of Christian influence which should be made visible. This reflection draws on the case of Robert Latimer, one of the few judicial cases historically to have polarized Canadian public opinion. After serving seven years in a federal penitentiary for the ‘mercy killing’ of his 12-year-old severally handicapped daughter, Saskatchewan farmer, Robert Latimer, was denied day parole by the National Parole Board of Canada on 5 December 2007. Despite in-prison psychological and parole reports confirming Latimer’s low risk to reoffend, parole board members denied his request on the apparent sole basis that he had not developed sufficient remorse. This case highlights how remorse, as a particular discursive transaction, is an obligatory passage point or an oral corroboration indispensable to complete the written demonstration (i.e. psychological and parole reports) of an offender’s successful integration of the ‘truth’ about her and her crime. Hence, remorse may constitute the only valuable way for offenders to re-take their place within the ritual of ‘Truth’ production.
The conditional effects of victim and offender ethnicity and victim gender on sentences for non-capital cases
Authors: Curry Theodore R
Published: October 2010

An extensive body of research shows that capital sentences tend to be more likely for Blacks who kill Whites, while more recent studies point to a higher likelihood of capital sentences for killers of White females. The present research broadens these areas of scholarship by including Hispanics and considering sentences for other types of violent crimes. Supporting theory are findings that longer sentences are meted out to offenders who victimize White females, and to Hispanic and African American offenders who victimize Whites. These findings, however, are confined to homicide cases and absent from sexual assault and robbery cases. Contradicting predictions are longer sentences for offenders who victimized Hispanic females, which is observed for robbery as well as homicide. Implications for theory and future research are discussed.
The costly consequences of populist posturing: ASBOs, victims, ‘rebalancing’ and diminution in support for civil liberties
Authors: Tonry Michael
Published: October 2010

In its effort to win electoral support by attacking the courts and other criminal justice agencies, loudly seeking to rebalance the criminal justice system in favour of the victim, and weakening civil liberties and protections against wrongful convictions, the Labour government of Tony Blair played dangerous games. There is ample evidence that tensions between the young and the old, and between the well-off and the dispossessed, were exacerbated. By repeatedly talking and acting as if crime had reached crisis proportions and required radical responses, at a time when crime rates were falling, the Government increased public anxieties and fears. By repeatedly insisting that the criminal justice system was not working satisfactorily, the Government undermined faith in legal institutions. By insisting that traditional procedural rights and protections are unimportant and can be cut back without loss of anything important, public understanding and support for fundamental ideas about liberty, fairness and justice were undermined. It is a pity and does not augur well for the future of civil liberties and rights in England and Wales.
Pilgrims: an ethnography of sacredness
Authors: Rose Mitch
Published: October 2010

The aim of this paper is to illustrate how subjectivity is constituted via exteriorities. Drawing upon the work of Levinas and others, it examines how voices irretrievably outside the subject call to us, on a pre-subjective level, welcoming us into various modalities of identity and belonging. In this sense, identity is conceived not as something we have but something we are given. Identity is a primordial response to various others, some of which are material and sensible and others wholly infinite and eternally beyond our perceptible horizons. The exploration of this call is conducted through an ethnography of sacredness focused around a ‘new age’ tourist group visiting Egypt in March 2007.This is not an ethnography of pilgrims or pilgrimage but on sacredness itself. By focusing on one modality through which the call announces itself (i.e. sacredness), I hope to help the reader hear how the call takes shape. Thus, the paper uses ethnography to create a space for listening. It illuminates a site (sacredness) where the various voices of the call can potentially be heard.
Extra-articular Mimickers of Lateral Meniscal Tears
Authors: Barker Joseph U. , Strauss Eric J. , Lodha Sameer , Bach Bernard R.
Published: October 2010

Context:

Lateral meniscus tears are a common entity seen in sports medicine. Although lateral-side knee pain is often the result of a meniscus injury, several extra-articular pathologies share signs and symptoms with a meniscus tear. It is critical for the clinician to be able to identify and understand extra-articular pathologies that can present similar to a lateral meniscus tear.

Evidence Acquisition:

Data were collected through a thorough review of the literature conducted through a MEDLINE search for all relevant articles between 1980 and February 2010.

Study Type:

Clinical review.

Results:

Common extra-articular pathologies that can mimic lateral meniscal tears include iliotibial band syndrome, proximal tibiofibular joint instability, snapping biceps femoris or popliteus tendons, and peroneal nerve compression syndrome or neuritis. The patient history, physical examination features, and radiographic findings can be used to separate these entities from the more common intra-articular knee pathologies.

Conclusions:

In treating patients who present with lateral-sided knee pain, clinicians should be able to recognize and treat extra-articular pathologies that can present in a similar fashion as lateral meniscus tears.
Friends (and Sometimes Enemies) With Cognitive Benefits
Authors: Ybarra Oscar , Winkielman Piotr , Yeh Irene , Burnstein Eugene , Kavanagh Liam
Published: October 2010

Recent findings indicate interventions can boost executive functions—mental processes that have long been thought to be static and not open to change. The authors examined whether and how short-term social interactions could create such cognitive benefits. Study 1 found that basic get-to-know-you interactions (with or without an explicit cooperative goal) boosted executive function relative to controls and as much as nonsocial intellective activities. In contrast, interactions involving a competitive goal resulted in no boosts. Studies 2 and 3 tested a proposed mechanism for the results—that people need to engage with others and take their perspective to realize cognitive boosts. The findings show that competitive interactions, if structured to allow for interpersonal engagement, can boost executive functions. The results highlight how social functioning can enhance core mental capacities.
Frequent Sex Protects Intimates From the Negative Implications of Their Neuroticism
Authors: Russell V. Michelle , McNulty James K.
Published: October 2010

A robust literature indicates that neuroticism has numerous negative implications for romantic relationships. But are there factors that can protect intimates from such implications? Given that negative affect accounts for part of the association between neuroticism and relationship distress, and given that the positive affect associated with sex may negate that negative affect, the authors predicted that sexual frequency would moderate the association between neuroticism and relationship satisfaction. A total of 72 newlywed couples reported their marital satisfaction and sexual frequency up to seven times over the first 4 years of marriage. Consistent with predictions, a lagged multilevel analysis revealed that although neuroticism was negatively associated with marital satisfaction on average, it was unrelated to marital satisfaction when couples had engaged in relatively frequent sex over the past 6 months. These findings join others in highlighting the importance of attending to the broader context of the relationship to developing a complete understanding of relationships.
CXCL12-CXCR4 chemokine signaling is essential for NK-cell development in adult mice
Authors: Noda Mamiko , Omatsu Yoshiki , Sugiyama Tatsuki , Oishi Shinya , Fujii Nobutaka , Nagasawa Takashi
Published: October 2010

Natural killer (NK) cells are granular lymphocytes that are generated from hematopoietic stem cells and play vital roles in the innate immune response against tumors and viral infection. Generation of NK cells is known to require several cytokines, including interleukin-15 (IL-15) and Fms-like tyrosine kinase 3 ligand, but not IL-2 or IL-7. Here we investigated the in vivo role of CXC chemokine ligand-12 (CXCL12) and its primary receptor CXCR4 in NK-cell development. The numbers of NK cells appeared normal in embryos lacking CXCL12 or CXCR4; however, the numbers of functional NK cells were severely reduced in the bone marrow, spleen, and peripheral blood from adult CXCR4 conditionally deficient mice compared with control animals, probably resulting from cell-intrinsic CXCR4 deficiency. In culture, CXCL12 enhanced the generation of NK cells from lymphoid-primed multipotent progenitors and immature NK cells. In the bone marrow, expression of IL-15 mRNA was considerably higher in CXCL12-abundant reticular (CAR) cells than in other marrow cells, and most NK cells were in contact with the processes of CAR cells. Thus, CXCL12-CXCR4 chemokine signaling is essential for NK-cell development in adults, and CAR cells might function as a niche for NK cells in bone marrow.
Thrombospondin-1 is not the major activator of TGF-β1 in thrombopoietin-induced myelofibrosis
Authors: Evrard Solène , Bluteau Olivier , Tulliez Micheline , Rameau Philippe , Gonin Patrick , Zetterberg Eva , Palmblad Jan , Bonnefoy Arnaud , Villeval Jean-Luc , Vainchenker William , Giraudier Stéphane , Wagner-Ballon Orianne
Published: October 2010

Transforming growth factor-β1 (TGF-β1) is the most important cytokine involved in the promotion of myelofibrosis. Mechanisms leading to its local activation in the bone marrow environment remain unclear. As a recent study has highlighted the role of thrombospondin-1 (TSP-1) in platelet-derived TGF-β1 activation, we investigated the role of TSP-1 in the TPOhigh murine model of myelofibrosis. Two groups of engrafted mice, WT TPOhigh and Tsp-1–null TPOhigh, were constituted. All mice developed a similar myeloproliferative syndrome and an increase in total TGF-β1 levels in the plasma and in extracellular fluids of marrow and spleen. Surprisingly, we were able to detect the active form of TGF-β1 in Tsp-1–null TPOhigh mice. Accordingly, these mice developed marrow and spleen fibrosis, with intriguingly a higher grade than in WT TPOhigh mice. Our results show that TSP-1 is not the major activator of TGF-β1 in TPO-induced myelofibrosis, suggesting the contribution of another mechanism in the megakaryocyte/platelet compartment.
An essential role for Ran GTPase in epithelial ovarian cancer cell survival
Authors: Barrès Véronique , Ouellet Véronique , Lafontaine Julie , Tonin Patricia N , Provencher Diane M , Mes-Masson Anne-Marie
Published: October 2010

Background

We previously identified that Ran protein, a member of the Ras GTPase family, is highly expressed in high grade and high stage serous epithelial ovarian cancers, and that its overexpression is associated with a poor prognosis. Ran is known to contribute to both nucleocytoplasmic transport and cell cycle progression, but its role in ovarian cancer is not well defined.

Results

Using a lentivirus-based tetracycline-inducible shRNA approach, we show that downregulation of Ran expression in aggressive ovarian cancer cell lines affects cellular proliferation by inducing a caspase-3 associated apoptosis. Using a xenograft tumor assay, we demonstrate that depletion of Ran results in decreased tumorigenesis, and eventual tumor formation is associated with tumor cells that express Ran protein.

Conclusion

Our results suggest a role for Ran in ovarian cancer cell survival and tumorigenicity and suggest that this critical GTPase may be suitable as a therapeutic target.
Psychosocial stress and strategies for managing adversity: measuring population resilience in New South Wales, Australia
Authors: Taylor Melanie , Barr Margo , Stevens Garry , Bryson-Taylor Donald , Agho Kingsley , Jacobs Jennifer , Raphael Beverley
Published: October 2010

Background

Populations around the world are facing an increasing number of adversities such as the global financial crisis, terrorism, conflict, and climate change. The aim of this paper was to investigate self-reported strategies and sources of support used to get through "tough times" in an Australian context and to identify patterns of response in the general population and differences in potentially vulnerable subgroups.

Methods

Data were collected through a cross-sectional survey of the New South Wales population in Australia. The final sample consisted of 3,995 New South Wales residents aged 16 years and above who responded to the question: "What are the things that get you through tough times?"

Results

Respondents provided brief comments that were coded into 14 main subject-area categories. The most frequently reported responses were family and self (52%); friends and neighbors (21%); use of positive emotional and philosophical strategies (17%), such as sense of humor, determination, and the belief that things would get better; and religious beliefs (11%). The responses of four population subgroups were compared, based on gender, household income, level of psychological distress, and whether a language other than English was spoken at home. Women reported greater use of friends and neighbors and religious or spiritual beliefs for support, whereas men reported greater use of drinking/smoking and financial supports. Those with lower incomes reported greater reliance on positive emotional and philosophical strategies and on religious or spiritual beliefs. Those with high levels of psychological distress reported greater use of leisure interests and hobbies, drinking/smoking, and less use of positive lifestyle strategies, such as adequate sleep, relaxation, or work/life balance. Those who spoke a language other than English at home were less likely to report relying on self or others (family/friends) or positive emotional and philosophical strategies to get through tough times.

Conclusions

Understanding strategies and sources of support used by the population to get through adversity is the first step toward identifying the best approaches to build and support strengths and reduce vulnerabilities. It is also possible to reflect on how large-scale threats such as pandemics, disasters, conflict, bereavement, and loss could impact individual and population resilience.
Adrenomedullin increases fibroblast-like synoviocyte adhesion to extracellular matrix proteins by upregulating integrin activation
Authors: Ah Kioon Marie-Dominique , Asensio Carine , Ea Hang-Korng , Uzan Benjamin , Cohen-Solal Martine , Lioté Frédéric
Published: October 2010

Introduction

Rheumatoid arthritis (RA) is characterized by bone and cartilage invasion by fibroblast-like synoviocytes (FLSs). Adrenomedullin, a peptide with anabolic and antiapoptotic properties, is secreted by rheumatoid FLSs. Adrenomedullin also increases the expression of adhesion molecules in endothelial cells and keratinocytes. Here, we investigated whether adrenomedullin mediated FLS adhesion to extracellular matrix (ECM) proteins.

Methods

FLSs were isolated from synovial tissues from RA and osteoarthritis (OA) patients. Plates were coated overnight with the ECM proteins vitronectin, fibronectin, and type I collagen (Coll.I). Adrenomedullin was used as a soluble FLS ligand before plating. We tested interactions with the adrenomedullin receptor antagonist (22-52)adrenomedullin and with the protein kinase A (PKA) inhibitor H-89, and inhibition of co-receptor RAMP-2 by siRNA. Cell adhesion was measured by using color densitometry. Activation of α2 and β1 integrins was evaluated by fluorescent microscopy; integrin inhibition, by RGD peptides; and the talin-integrin interaction, by immunoprecipitation (IP).

Results

Adrenomedullin specifically increased RA-FLS adhesion to vitronectin, fibronectin, and Coll.I; no such effect was found for OA-FLS adhesion. Basal or adrenomedullin-stimulated RA-FLS adhesion was inhibited by (22-52)adrenomedullin, H-89, and RAMP-2 siRNA. Adrenomedullin-stimulated adhesion was inhibited by RGD peptides, and associated with α2 and β1 integrin activation. This activation was shown with IP to be related to an integrin-talin interaction and was significantly decreased by (22-52)adrenomedullin.

Conclusions

Adrenomedullin-stimulated RA-FLS adhesion was specific for ECM proteins and mediated by α2 and β1 integrins. This effect of adrenomedullin was dependent on adrenomedullin receptors. These results support a new role for adrenomedullin in rheumatoid synovial fibroblast pathobiology.
Mechanical Loading-Related Bone Gain Is Enhanced by Tamoxifen but Unaffected by Fulvestrant in Female Mice
Authors: Sugiyama Toshihiro , Galea Gabriel L. , Lanyon Lance E. , Price Joanna S.
Published: October 2010

Accumulating evidence indicates that estrogen receptors (ERs) are involved in the mechano-adaptive mechanisms by which loading influences the mass and architecture of bones to establish and maintain their structural load-bearing competence. In the present study, we assessed the effects of the ER modulators tamoxifen and fulvestrant (ICI 182,780) on loading-related changes in the volume and structure of trabecular and cortical bone in the tibiae of female mice. Ten days after actual or sham ovariectomy, 17-wk-old female C57BL/6 mice were treated with vehicle (peanut oil), tamoxifen (0.02, 0.2, or 2 mg/kg · d), fulvestrant (4 mg/kg · d), or their combination and the right tibiae subjected to a short period of noninvasive axial loading (40 cycles/d) on 5 d during the subsequent 2 wk. In the left control tibiae, ovariectomy, tamoxifen, or fulvestrant did not have any significant effect on cortical bone volume, whereas trabecular bone volume was decreased by ovariectomy, increased by tamoxifen, and unaffected by fulvestrant. In the right tibiae, loading was associated with increases in both trabecular and cortical bone volume. Notably, the medium dose of tamoxifen synergistically enhanced loading-related gain in trabecular bone volume through an increase in trabecular thickness. Fulvestrant had no influence on the effects of loading but abrogated the enhancement of loading-related bone gain by tamoxifen. These data demonstrate that, at least in female mice, the adaptive response to mechanical loading of trabecular bone can be enhanced by ER modulators, in this case by tamoxifen.
Transgenerational Inheritance of Glucose Intolerance in a Mouse Model of Neonatal Overnutrition
Authors: Pentinat Thais , Ramon-Krauel Marta , Cebria Judith , Diaz Ruben , Jimenez-Chillaron Josep C.
Published: October 2010

Epidemiological and clinical data show that rapid weight gain early in life is strongly associated with several components of the metabolic syndrome. Strikingly, abnormal growth rates in early life can additionally influence diabetes risk in subsequent generations. Here we aim to study whether neonatal overgrowth induces diabetes in offspring and grand-offspring of affected individuals using a mouse model of neonatal overfeeding. We induced neonatal overgrowth (ON-F0) by culling offspring to four pups per dam during lactation. By age 4 months, ON-F0 mice developed many features of the metabolic syndrome, including obesity, insulin resistance, and glucose intolerance. We then studied whether male offspring (ON-F1) and grand-offspring (ON-F2) of ON-F0 male mice, which were not overfed during lactation, developed features of the metabolic syndrome with aging. ON-F1 mice developed fed and fasting hyperinsulimemia, hypertryglyceridemia, insulin resistance, and glucose intolerance, but not obesity, by age 4 months. In contrast, ON-F2 male mice showed a more moderate phenotype and only developed fasting hyperglycemia and glucose intolerance by age 4 months. Impaired glucose tolerance in ON-F1 and ON-F2 mice appeared to be accounted for primarily by peripheral insulin resistance, because beta-cell function remained normal or even increased in these cohorts. Nutritional challenges occurring during sensitive periods of development may have adverse metabolic consequences well beyond the lifespan of affected individuals and manifest in subsequent generations. Transgenerational progression of metabolic phenotypes through the male lineage supports a potential role for epigenetic mechanisms in mediating these effects.
Dax1 Up-Regulates Oct4 Expression in Mouse Embryonic Stem Cells via LRH-1 and SRA
Authors: Kelly Victoria R. , Xu Bin , Kuick Rork , Koenig Ronald J. , Hammer Gary D.
Published: October 2010

Dax1 (Nr0b1) is an atypical orphan nuclear receptor that has recently been shown to play a role in mouse embryonic stem (mES) cell pluripotency. Here we describe a mechanism by which Dax1 maintains pluripotency. In steroidogenic cells, Dax1 protein interacts with the NR5A nuclear receptor steroidogenic factor 1 (Nr5a1) to inhibit transcription of target genes. In mES cells, liver receptor homolog 1 (LRH-1, Nr5a2), the other NR5A family member, is expressed, and LRH-1 has been shown to interact with Dax1. We demonstrate by coimmunoprecipitation that Dax1 is, indeed, able to form a complex with LRH-1 in mES cells. Because Dax1 was historically characterized as an inhibitor of steroidogenic factor 1-mediated transcriptional activation, we hypothesized that Dax1 would inhibit LRH-1 action in mES cells. Therefore, we examined the effect of Dax1 on the LRH-1-mediated activation of the critical ES cell factor Oct4 (Pou5f1). Chromatin immunoprecipitation localized Dax1 to the Oct4 promoter at the LRH-1 binding site, and luciferase assays together with Dax1 overexpression and knockdown experiments revealed that, rather than repress, Dax1 accentuated LRH-1-mediated activation of the Oct4 gene. Similar to our previously published studies that defined the RNA coactivator steroid receptor RNA activator as the critical mediator of Dax1 coactivation function, Dax1 augmentation of LRH-1-mediated Oct4 activation is dependent upon steroid receptor RNA activator. Finally, utilizing published chromatin immunoprecipitation data of whole-genome binding sites of LRH-1 and Dax1, we show that LRH-1 and Dax1 commonly colocalize at 288 genes (43% of LRH-1 target genes), many of which are involved in mES cell pluripotency. Thus, our results indicate that Dax1 plays an important role in the maintenance of pluripotency in mES cells through interaction with LRH-1 and transcriptional activation of Oct4 and other genes.
Suppressive potencies of calcineurin inhibitors against the mitogen-induced blastogenesis of peripheral-blood mononuclear cells of myasthenia gravis patients
Authors: Tanaka Sachiko , Nakajima Kanako , Hirano Toshihiko , Oka Kitaro , Saito Toyokazu , Wakata Nobuo
Published: October 2010

The calcineurin inhibitors, tacrolimus and ciclosporin, are two useful immunosuppressive drugs for the treatment of myasthenia gravis (MG), for patients who have low responses to glucocorticoids. We have studied the suppressive potencies of tacrolimus and ciclosporin on concanavalin A-induced blastogenesis of peripheral-blood mononuclear cells (PBMCs) obtained from 38 MG patients and 26 healthy volunteers. Differences in the IC50 values of the two calcineurin inhibitors between the patients and the healthy subjects were evaluated. The median (range) IC50 values for tacrolimus and ciclosporin on the blastogenesis of PBMCs of MG patients were 0.06 (0.001–100) and 0.41 (0.09–83.0) ng mL−1, respectively. In contrast, the median (range) IC50 values of tacrolimus and ciclosporin on healthy PBMCs were 0.16 (0.001–0.33) and 5.59 (1.4–31.3), respectively, and thus ciclosporin potencies against PBMCs of MG patients were significantly higher than those against PBMCs of healthy subjects (P < 0.0001). The differences in tacrolimus IC50 values between the patients and healthy subjects were not significant. There was a correlation between ciclosporin IC50 values against the blastogenesis of PBMCs of MG patients and the duration of the disease (r = 0.35, P = 0.049). A significant correlation between the IC50 values of ciclosporin and those of prednisolone against the blastogenesis of PBMCs of MG patients was also observed (r = 0.56, P = 0.003). Furthermore, the ciclosporin IC50 values significantly correlated with the periods of glucocorticoid administration for MG treatment (r = 0.42, P = 0.038). Such correlations were not observed with the tacrolimus IC50 values. These results suggested that glucocorticoid administration had an influence on PBMC response to the suppressive efficacy of ciclosporin in MG.
Protective effects of total flavonoids of Bidens bipinnata L. against carbon tetrachloride-induced liver fibrosis in rats
Authors: Yuan Li-ping , Chen Fei-hu , Ling Lu , Bo Hu , Chen Zhi-wu , Li Fan , Zhong Ming-mei , Xia Li-juan
Published: October 2010

Bidens bipinnata L. is well known in China as a traditional Chinese medicine and has been used to treat hepatitis in clinics for many years. In a previous study we found that total flavonoids of Bidens bipinnata L. (TFB) had a protective effect against carbon tetrachloride (CCl4)-induced acute liver injury in mice. Now this study was designed to investigate its therapeutic effect against CCl4-induced liver fibrosis in rats and to determine, in part, its mechanism of action. The liver fibrosis model was established by subcutaneous injection of 50% CCl4 twice a week for 18 weeks. TFB (40, 80 and 160 mg kg−1) was administered by gastrogavage daily from the 9th week. The results showed that TFB (80 and 160 mg kg−1) treatment for 10 weeks significantly reduced the elevated liver index (liver weight/body weight) and spleen index (spleen weight/body weight), elevated levels of serum transaminases (alanine aminotransferase and aspartate aminotransferase), hyaluronic acid, type III procollagen and hepatic hydroxyproline. In addition, TFB markedly inhibited CCl4-induced lipid peroxidation and enhanced the activity of the antioxidant enzymes superoxide dismutase and glutathione peroxidase. Moreover, TFB (80 and 160 mg kg−1) treatment improved the morphologic changes of hepatic fibrosis induced by CCl4 and suppressed nuclear factor (NF)-kB, α-smooth muscle actin (SMA) protein expression and transforming growth factor (TGF)-β1 gene expression in the liver of liver fibrosis of rats. In conclusion, TFB was able to ameliorate liver injury and protect rats from CCl4-induced liver fibrosis by suppressing oxidative stress. This process may be related to inhibiting the induction of NF-kB on hepatic stellate cell activation and the expression of TGF-β1.
Effect of pH and water-soluble polymers on the aqueous solubility of nimesulide in the absence and presence of β-cyclodextrin derivatives
Authors: Alexanian Christina , Papademou Helen , Vertzoni Maria , Archontaki Helen , Valsami Georgia
Published: October 2010

The aqueous solubility of nimesulide in the absence and presence of β-cyclodextrin (β-CD) and its alkyl derivatives hydroxypropyl-β-CD and methyl-β-CD was studied. We also investigated the effect of water-soluble polymers, hydroxypropylmethyl-cellulose, sodium-carboxymethyl-cellulose, polyvinyl- pyrrolidone and polyethyleneglycol on the solubilization efficacy and complexation ability of cyclodextrins with nimesulide. The solubility of nimesulide in the absence and presence of cyclodextrins and polymers was studied using a phase solubility technique combined with a spectrophotometric method. The study was carried out at 25°C and pH values of 6.0 and 7.0. Conditions in terms of polymer concentration and polymer heating with and without sonication were optimized. Values of the solubility enhancement factor of nimesulide in the presence of each cyclodextrin and in the absence and presence of each polymer were determined and the formation constants, K, of the inclusion complexes formed calculated. β-CDs increased the aqueous solubility of nimesulide in the following order: methyl-β-CD > β-CD > hydroxypropyl-β-CD. Addition of hydroxypropylmethyl-cellulose at a concentration of 0.1% (w/v) had the greatest influence on complexation of all three β-CDs with nimesulide, while preheating of the polymer at 70°C under sonication resulted in an additional two-fold increase in the aqueous solubility of the drug. Sodium- carboxymethyl-cellulose, polyvinylpyrrolidone and polyethyleneglycol had minor effects on the aqueous solubility of nimesulide. Thus β-CD, hydroxypropyl-β-CD and methyl-β-CD are proposed as good solubilizing agents for nimesulide in the presence and absence of hydroxypropylmethyl- cellulose in order to enhance its oral bioavailability.
Cirsilineol inhibits proliferation of cancer cells by inducing apoptosis via mitochondrial pathway
Authors: Sheng Xia , Sun Yang , Yin Ye , Chen Ting , Xu Qiang
Published: October 2010

Cirsilineol (4′,5-dihydroxy-3′,6,7-trimethoxyflavone) is a compound isolated from the herb of Artemisia vestita Wall (Compositae). In this study, we aimed at examining the anti-proliferative activity of cirsilineol against multiple types of cancer cells and the underlying mechanisms. Cirsilineol significantly inhibited proliferation of Caov-3, Skov-3, PC3 and Hela cells in a concentration-dependent manner. The compound also dose-dependently induced apoptosis in Caov-3 cells, as determined by annexin V/propidium iodide staining. Besides, cirsilineol induced a remarkable change in mitochondrial membrane potential and caused release of cytochrome c to cytosol. Furthermore, the compound caused a marked activation of capase-3, caspase-9 and poly (ADP-ribose) polymerase (PARP). These results suggested that the induction of apoptosis via the mitochondrial pathway was involved in the anti-proliferative activity of cirsilineol against cancer cells.
Inhibitory mechanisms of dihydroginsenoside Rg3 in platelet aggregation: Critical roles of ERK2 and cAMP
Authors: Lee Whi Min , Kim Sung Dae , Park Myung Hwan , Cho Jae Youl , Park Hwa Jin , Seo Geon Sik , Rhee Man Hee
Published: October 2010

Ginsenoside Rg3, a single ginseng saponin, is known to be a major anti-platelet component of protopanaxadiol that is isolated from Korean red ginseng. In this study, we investigated whether dihydroginsenoside Rg3, a stable chemical derivative of ginsenoside Rg3, also demonstrated anti-platelet activity. Dihydroginsenoside Rg3 inhibited thrombin-induced platelet aggregation in a concentration-dependent manner with an IC50 (concentration producing 50% inhibition) of 18.8 ± 0.4 μM. Ginsenoside Rg3 inhibited platelet aggregation which was induced by thrombin (0.1 U mL−1) with an IC50 of 40.2 ± 0.9 μM. We next determined whether dihydroginsenoside Rg3 affected different types of ligand-induced platelet aggregation. We found that dihydroginsenoside Rg3 inhibited collagen-induced platelet aggregation with an IC50 of 20.0 ± 0.9 μM. To elucidate the inhibitory mechanism of dihydroginsenoside Rg3 on aggregation, we analysed its downstream signalling pathway. It was interesting to note that dihydroginsenoside Rg3 elevated cyclic AMP production in resting platelets, but did not affect cyclic GMP production. In addition, we found that dihydroginsenoside Rg3 potently suppressed phosphorylation of extracellular signal-regulated kinase 2 (ERK2), which was stimulated by collagen (2.5 μg mL−1), but not of p38 mitogen-activated protein kinase. Taken together, our results indicate that dihydroginsenoside Rg3 potently inhibited platelet aggregation via the modulation of downstream signalling components such as cAMP and ERK2.
Efficacy of anise oil, dwarf-pine oil and chamomile oil against thymidine-kinase-positive and thymidine-kinase-negative herpesviruses
Authors: Koch Christine , Reichling Jürgen , Kehm Roland , Sharaf Mona M , Zentgraf Hanswalter , Schneele Jürgen , Schnitzler Paul
Published: October 2010

The effect of anise oil, dwarf-pine oil and chamomile oil against different thymidine-kinase-positive (aciclovir-sensitive) and thymidine-kinase-negative (aciclovir-resistant) herpes simplex virus type 1 (HSV-1) strains was examined. Clinical HSV-1 isolates containing frameshift mutations in the thymidine kinase (TK) gene, an insertion or a deletion, yield a non-functional thymidine kinase enzyme resulting in phenotypical resistance against aciclovir. The inhibitory activity of three different essential oils against herpes simplex virus isolates was tested in-vitro using a plaque reduction assay. All essential oils exhibited high levels of antiviral activity against aciclovir-sensitive HSV strain KOS and aciclovir-resistant clinical HSV isolates as well as aciclovir-resistant strain Angelotti. At maximum noncytotoxic concentrations of the plant oils, plaque formation was significantly reduced by 96.6–99.9%, when herpesviruses were preincubated with drugs before attachment to host cells. No significant effect on viral infectivity could be achieved by adding these compounds during the replication phase. These results indicate that anise oil, dwarf-pine oil and chamomile oil affected the virus by interrupting adsorption of herpesviruses and in a different manner than aciclovir, which is effective after attachment inside the infected cells. Thus the investigated essential oils are capable of exerting a direct effect on HSV and might be useful in the treatment of drug-resistant viruses. Chamomile oil did not reveal any irritating potential on hen's egg chorioallantoic membrane, demonstrated the highest selectivity index among the oils tested and was highly active against clinically relevant aciclovir-resistant HSV-1 strains.
Staphylococcus epidermidis device-related infections: pathogenesis and clinical management
Authors: McCann Maureen T , Gilmore Brendan F , Gorman Sean P
Published: October 2010

Staphylococcus epidermidis, the most frequently isolated coagulase-negative staphylococcus, is the leading cause of infection related to implanted medical devices (IMDs). This is directly related to its capability to establish multilayered, highly structured biofilms on artificial surfaces. At present, conventional systemic therapies using standard antimicrobial agents represent the main strategy to treat and prevent medical device-associated infections. However, device-related infections are notoriously difficult to treat and bacteria within biofilm communities on the surface of IMDs frequently outlive treatment, and removal of the medical device is often required for successful therapy. Importantly, major advances in this research area have been made, leading to a greater understanding of the complexities of biofilm formation of S. epidermidis and resulting in significant developments in the treatment and prevention of infections related to this member of the coagulase-negative group of staphylococci. This review will examine the pathogenesis of the clinically significant S. epidermidis and provide an overview of the conventional and emerging antibiofilm approaches in the management of medical device-associated infections related to this important nosocomial pathogen.
Depressant-like effects of parthenolide in a rodent behavioural antidepressant test battery
Authors: Pandey Dilip Kumar , Rajkumar Ramamoorthy , Mahesh Radhakrishnan , Radha Raghuraman
Published: October 2010

The anti-serotonergic effects of parthenolide (PTL) demonstrated in platelets inspired the present psychopharmacological investigation, which employs a battery of rodent behavioural assays of depression. In mice, PTL (0.5-2 mg kg−1) exhibited dose-dependent depressant-like effects in a forced swim test and a tail suspension test, without affecting the baseline locomotor status. The doses (1 and 2 mg kg−1) that induced depressant-like effects were found to significantly reduce 5-hydroxytrypto-phan-induced head twitch response. Interaction studies revealed that the depressant-like effects of PTL (1 mg kg−1) were reversed more efficiently by serotonergic antidepressants (venlafaxine, escitalopram, citalopram, fluoxetine) than by others (desipramine, bupropion) tested. Chronic treatment of PTL (1 and 2 mg kg−1) augmented the hyper-emotionality of olfactory bulbectomized rats, when compared with sham rats, as observed in modified open field, elevated plus maze and social interaction paradigms. This study depicts the severe depressogenic potential of PTL (in its pure form) plausibly mediated by platelet/neuronal hypo-serotonergic effects.
Effects of isorhynchophylline on angiotensin II-induced proliferation in rat vascular smooth muscle cells
Authors: Zhang Feng , Sun An-Sheng , Yu Li-Mei , Wu Qin , Gong Qi-Hai
Published: October 2010

Proliferation of vascular smooth muscle cells (VSMCs) is a crucial event in cardiovascular diseases. Isorhynchophylline, an alkaloid from a traditional Chinese medicine Gambirplant, has been used to treat cardiovascular diseases. The aim of this study was to investigate the effects of isorhynchophylline on angiotensin II (Ang II)-induced proliferation of rat VSMCs. VSMCs were isolated from rat artery and cultured for 14 days before experimentation. The effect of isorhynchophylline on Ang II-induced proliferation was evaluated by cell number, MTT assay and flow cytometry, and nitric oxide (NO) content and activity of NO synthase (NOS) were measured. The expression of proto-oncogene c-fos, osteopontin (OPN) and proliferating cell nuclear antigen (PCNA) mRNAs was measured by real-time RT-PCR. VSMC cultures were verified by morphology and immunostaining with α-smooth muscle actin. Isorhynchophylline (0.1–10.0 μM) was not toxic to VSMCs, but markedly decreased Ang II (1.0 μm)-enhanced cell number and MTT intensity, and blocked cell transition from G0/G1 to S phase. Furthermore, isorhynchophylline increased the NO content and NOS activity, and suppressed Ang II-induced over-expression of c-fos, OPN and PCNA. Thus, isorhynchophylline was effective against Ang-II induced cell proliferation, an effect that appears to be due, at least in part, to increased NO production, regulation of the cell cycle, and depressed expression of c-fos, OPN and PCNA related to VMSC proliferation.
Metformin regulates osteoblast and adipocyte differentiation of rat mesenchymal stem cells
Authors: Gao Ying , Xue Jing , Li Xiaoyu , Jia Yongqian , Hu Jing
Published: October 2010

Metformin is widely used for the treatment of type 2 diabetes mellitus. In this study, we evaluated the effects of metformin on the osteoblast and adipocyte differentiation of rat marrow mesenchymal stem cells (MSCs) in culture. Treatment of MSCs in osteoblastic or adipogenic medium with 100 μM metformin for 21 days led to an increased mRNA expression of the osteoblast markers but a decreased mRNA expression of the adipocyte markers in the MSCs. Metformin markedly stimulated deposition of mineralized nodules and blocked the formation of cytoplasmic lipid droplets. In addition, alkaline phosphate activity and Western blot analysis for core binding factor a1 (Cbfa 1) and peroxisome proliferator-activated receptor gamma 2 (PPARγ2) proteins also confirmed that metformin inhibited adipocyte differentiation and promoted osteoblast differentiation. The reciprocal relationship between osteoblastic and adipogenic differentiation suggests that metformin may regulate osteoblastic and adipogenic differentiation through inhibition of PPARγ.
Ozone oxidative post-conditioning in acute renal failure
Authors: Calunga José Luis , Trujillo Yanelis , Menéndez Silvia , Zamora Zullyt , Alonso Yaima , Merino Nelson , Montero Teresa
Published: October 2010

Objectives

The ischaemia–reperfusion process is largely mediated by reactive oxygen species. Taking into account that a transient and controlled administration of ozone is able to upregulate cellular antioxidant enzymes, a morphological, biochemical and functional renal study was performed in rats undergoing warm renal ischaemia.

Methods

Rats were divided into four groups. All except the negative controls underwent 60 min' bilateral renal ischaemia followed by 10 days' reperfusion. The positive control group received no further treatment. The ozone group received an ozone/oxygen mixture (ozone dose 0.5 mg/kg) immediately after the ischaemia and daily for the 10 days' reperfusion; the oxygen group were given the same concentration of oxygen alone (13 mg/kg). Biochemical parameters fructosamine, phospholipase A2, catalase, superoxide dismutase and thiobarbituric acid reactive substances were measured, as well as renal plasma flow and glomerular filtration rate.

Key findings

Renal plasma flow and glomerular filtration rate decreased significantly in the positive controls and the oxygen group whereas values in the ozone group were similar to those in the negative control group. With respect to the biochemical parameters, ozone maintained a homeostasis redox, with significant increases in catalase and superoxide dismutase activities and similar values for phospholipase A2 and fructosamine compared with the negative control group. Fewer morphological alterations were seen in kidneys from the ozone group. No advantages were obtained in the positive control and oxygen groups.

Conclusions

The protective effect of ozone may be explained by upregulation of the antioxidant defence system and beneficial effects on blood circulation and in oxygen metabolism. Ozone treatment may represent a therapeutic approach for minimising renal damage after transplantation.
In-vitro respiratory drug absorption models possess nominal functional P-glycoprotein activity
Authors: Madlova Michaela , Bosquillon Cynthia , Asker Dan , Dolezal Pavel , Forbes Ben
Published: October 2010

Objectives

The P-glycoprotein (P-gp) efflux pump is known to be present within several major physiological barriers including the brain, kidney, intestine and placenta. However, the function of P-gp in the airways of the lung is unclear. The purpose of this study was to use the highly specific P-gp inhibitor GF120918A to investigate the activity of the P-gp transporter in the airways to determine whether P-gp could influence inhaled drug disposition.

Methods

P-gp activity was measured as a change in digoxin transport in the presence of GF120918A in normal human bronchial epithelial (NHBE) cells, Calu-3 cell layers and the ex-vivo rat lung.

Key findings

The efflux ratios (ERs) in NHBE and Calu-3 cells were between 0.5 and 2, in contrast to 10.7 in the Caco-2 cell control. These low levels of GF120918A-sensitive polarised digoxin transport were measured in the absorptive direction in NHBE cells (ER = 0.5) and in the secretory direction in Calu-3 cells (ER = 2), but only after 21 days in culture for both cell systems and only in Calu-3 cells at passage >50. The airspace to perfusate transfer kinetics of digoxin in the ex-vivo rat lung were unchanged in the presence of GF120918A.

Conclusions

These results demonstrated that although low levels of highly culture-dependent P-gp activity could be measured in cell-lines, these should not be interpreted to mean that P-gp is a major determinant of drug disposition in the airways of the lung.
Acute and chronic diuretic effect of ethanolic extract of leaves ofCocculus hirsutus(L.) Diles in normal rats
Authors: Badole Sachin L , Bodhankar Subhash L , Patel Naimesh M , Bhardwaj Subodh
Published: October 2010

Objectives

The objective of this study was to evaluate the acute and chronic diuretic effect of the ethanolic extract of the leaves of Cocculus hirsutus (L.) Diles.

Methods

The ethanolic extract was administered (100, 200 and 400 mg/kg, p.o.) in Wistar rats. In the acute study, rats received drugs orally and urine was collected after 1, 2, 3, 4, 5 and 6 h. The chronic study involved repeated administration of ethanolic extract for 28 days and urine was collected on day 1, 7, 14, 21 and 28. The parameters were total urine volume, concentration of Na+, K+ and Cl- ions, creatinine in urine and serum. Urine output, electrolytes (Na+, K+ and Cl- ions) and creatinine were determined on day 7, 14, 21 and 28.

Key findings

The highest dose (400 mg/kg) of the ethanolic extract significantly (P < 0.01) enhanced urine output. Excretion of cations (Na+ and K+ ions) and anions (Cl- ions) increased significantly with respect to the control (gum acacia 2% dissolved in saline, 10 ml/kg) group. The increase of cations in the urine after treatment with ethanolic extract was dose dependent. The ethanolic extract of the leaves of C. hirsutus (100, 200 and 400 mg/kg) and furosemide (10 mg/kg) did not significantly change the concentration of Na+, K+ and Cl- ions in serum. The ethanolic extract of the leaves of C. hirsutus (100, 200 and 400 mg/kg) and furosemide (10 mg/kg) increased the excretion of creatinine in urine but with a corresponding decrease in serum.

Conclusions

It was concluded that the ethanolic extract of the leaves of C. hirsutus (400 mg/kg) had significant diuretic effect in rats.
Effect of rutin on warfarin anticoagulation and pharmacokinetics of warfarin enantiomers in rats
Authors: Chan Associate Professor Eli , Hegde Akhil , Chen Xin
Published: October 2010

Objectives

The effects of the flavonoid rutin on the anticoagulant activity of oral warfarin and the protein binding and pharmacokinetics of its enantiomers were investigated in rats.

Methods

A single dose of racemic warfarin, 1.5 mg/kg, was administered orally to rats either alone or on day 5 of an 8-day oral regimen of rutin, 1 g/kg daily.

Results

Rutin reduced the anticoagulant effect of racemic warfarin, evident as a 31% reduction in the area under the prothrombin complex activty–time curve (P < 0.05).

Key findings

Rutin had no apparent effect on pre-treatment baseline blood coagulation. It enhanced the in-vitro serum protein binding of S- and R-warfarin (reflected by 40% and 26% reductions in unbound fraction, respectively), and thus restricted distribution by 33 and 21%, respectively. Treatment with rutin significantly decreased the elimination half-life of S-warfarin by 37% as a result of the 69% increase in unbound clearance of the S-enantiomer. This effect was attributed to a significant 77% increase in the unbound formation clearance of the overall oxidative and reductive metabolites, and an increase in the unbound renal clearance of the more potent S-enantiomer of warfarin.

Conclusions

Concurrent rutin administration is likely to reduce the anticoagulant effect of racemic warfarin, reflecting a significant decrease in the elimination half-life of the more potent S-enantiomer.