bluuebunny/crossref_metadata_2025 huggingface dataset:
Degradation of Myosin Light Chain in Isolated Rat Hearts Subjected to Ischemia-Reperfusion Injury
Authors: Sawicki Grzegorz , Leon Hernando , Sawicka Jolanta , Sariahmetoglu Meltem , Schulze Costas J. , Scott Paul G. , Szczesna-Cordary Danuta , Schulz Richard
Published: July 2005

Background—

Matrix metalloproteinase-2 (MMP-2) contributes to cardiac dysfunction resulting from ischemia-reperfusion (I/R) injury. MMP-2 not only remodels the extracellular matrix but also acts intracellularly in I/R by degrading troponin I. Whether other intracellular targets exist for MMP-2 during I/R is unknown.

Methods and Results—

Isolated rat hearts were subjected to 20 minutes of ischemia and 30 minutes of reperfusion. The impaired recovery of mechanical function of the heart was attenuated by the MMP inhibitors o-phenanthroline or doxycycline. Quantitative 2D electrophoresis of homogenates of aerobically perfused hearts (control) or those subjected to I/R injury (in the presence or absence of MMP inhibitors) showed 3 low-molecular-weight proteins with levels that were significantly increased upon I/R injury and normalized to control levels by MMP inhibitors. Mass spectrometry analysis identified all 3 proteins as fragments of myosin light chain 1, which possesses theoretical cleavage recognition sequences for MMP-2 and is rapidly degraded by it in vitro. The association of MMP-2 with the thick myofilament in fractions prepared from I/R hearts was observed with immunogold electron microscopy, gelatin zymography for MMP-2 activity, and immunoprecipitation. MMP-2 was found to cleave myosin light chain 1 between tyrosine 189 and glutamine 190 at the C terminus.

Conclusions—

Our results demonstrate that myosin light chain 1 is another novel substrate for MMP-2 in the cardiomyocyte and that its degradation may contribute to contractile dysfunction resulting from I/R injury to the heart.
Tritrophic Effects in Bt Cotton
Authors: Gutierrez Andrew Paul
Published: July 2005

Transgenic insecticidal Bt crops are being increasingly used worldwide, and concern is increasing about resistance and their effects on nontarget organisms. The toxin acts as a weak pesticide and, hence, the effects are subtler than those of chemical biocides. However, the toxin is ever present, but concentrations vary with age of plant and plant subunit, causing varying lethal and sublethal effects on pest survival, developmental time, and fecundity. Refuges for susceptibility to Bt occur spatially in non-Bt hosts and temporally within the crop because of time-varying toxicity and pest tolerance. Natural enemies feeding on Bt-intoxicated prey may have reduced longevity and, likely, fecundity that reduces their efficacy in controlling pest populations, and pest resurgence and secondary pest outbreaks may occur that may require insecticide use. System modeling is proposed as an efficient tool for examining the use of extant and future biotechnologies in pest control.
Brazilian Soybean Production: Emergy Analysis With an Expanded Scope
Authors: Ortega Enrique , Cavalett Otávio , Bonifácio Robert , Watanabe Marcos
Published: July 2005

This article offers the results of emergy analysis used to evaluate four different soybean production systems in Brazil that were divided into two main categories: biological models (organic and ecological farms) and industrial models (green-revolution chemical farms and herbicide with no-tillage farms). The biological models show better environmental, economical, and social performance indicators; however, at the national level, discussion of transgenic soybean seed release considers only industrial models without any mention of biological models. Classic emergy analysis shows biological options are the better alternatives but does not explain why decisions taken by farmers and government in Brazil were in opposition to these options. New research is proposed to identify and quantify the external forces that strongly interfere in the definition of public policy for soybean production. New parameters are proposed to enrich emergy methodology: Renewability of each input was considered in emergy calculations and negative externalities were included as additional services.
Spike, sex and subtext
Authors: Williamson Milly
Published: July 2005

The vampire Spike of Buffy the Vampire Slayer is the latest in a long line of a mbiguous but sympathetic vampires which have caught the public imagination, stretching back to Polidori’s Byronesque vampire, Lord Ruthven. This article argues that the vampire image that circulates across contemporary vampire fan cultures is one that exceeds any individual depiction of the vampire; the sympathetic vampire operates as a metatext for vampire fans who draw on textual cues to interpret vampires sympathetically, even when the text itself does not. In the case of Buffy the Vampire Slayer, the text overtly encourages a sympathetic subtextual reading of Spike by linking his glamour, sex appeal and rebellion to a hinted-at unseen suffering, which is easily recognized by fans. Fans read Spike’s bad-boy pose as symbolic of hidden pathos. Indeed, the text adopts conventions associated with fan fiction in order to encourage and sustain a surrounding fan culture.
Queering the bitch
Authors: Amy-Chinn Dee
Published: July 2005

According to Eve Kosofsky Sedgwick, queer exists when the constituent elements of anyone’s gender or sexuality are not made (or cannot be made) to signify monolithically. By this definition Spike is the queerest character in the ‘Buffyverse’: both his gender and sexuality are fluid - neither is secure and both are based around excess. His gender switches from male to female and his sexuality from ‘vanilla’ to more varied and non-traditional forms of eroticism. The article argues that the character of Spike opens up opportunities for the resignification of what it means to be male or female, man or monster, dominant or submissive, ‘vanilla’ or an exponent of erotic variation - opportunities we need to seize if we are to challenge the all-pervasive binaries which govern our understanding of sex, gender and sexuality, and the interrelationship between these terms.
From madman in the basement to self-sacrificing champion
Authors: Abbott Stacey
Published: July 2005

Towards the end of Season 6 of Buffy the Vampire Slayer, Spike undergoes an identity crisis and leaves Sunnydale in search of a solution. ‘Neither a monster nor a man’, Spike yearns for reconciliation of his divided self. The answer comes in the form of the return of his soul. This article explores how the return of Spike’s soul does not deliver a reconciled Spike but rather one which has been exponentially fragmented. In a show that prides itself on complex character development, Spike undergoes the most dramatic character arc of anyone on the series, taking place in one season in an almost schizophrenic fashion. Through close analysis of mise-en-scène and narrative structure this article demonstrates how each of these personas is presented as distinct and explores how identity in this season is not defined by growth and evolution but rather the recognition that we are each made up of a multitude of selves.
‘It’s all my interpretation’
Authors: Hills Matt , Williams Rebecca
Published: July 2005

This article considers how fans of Buffy the Vampire Slayer and Angel interpret the character of Spike through meanings attached to actor James Marsters as a ‘subcultural celebrity’. Work on TV’s celebrity actors has stressed how character and actor can become semiotically blurred. Rather than approaching this blurring of textual and extra-textual connotations as an essential property of television celebrity, we analyse how Marsters displays situated agency by discursively constructing ‘himself’ in publicity materials as ‘like Spike’. We then consider Marsters as a reader of Buffy. As a subcultural celebrity, we argue that Marsters is positioned between media producers and media fans, and therefore is able to offer up privileged interpretations of ‘his’ character, Spike, while simultaneously observing the symbolic power of producers’ preferred readings. Marsters supports certain fan readings of Spike, acting as a textual poacher who nevertheless is ‘inside’ the texts of Buffy the Vampire Slayer and Angel.
Moments of inspiration
Authors: Turnbull Sue
Published: July 2005

This article explores the way in which the actor, James Marsters, performs the character of Spike. Beginning with the Greek term ekphrasis (the verbal representation of visual representation) this article is an endeavour to describe and recover in language the effect which a particular performance, moment or TV series may have on us. The specific moment of performance that the article addresses is that of Spike’s first appearance on Buffy the Vampire Slayer in the episode ‘School Hard’ (2:3) - a point at which something magical occurs. We breathe in Marsters’ performance and establish an emotional connection with the character. It is this connection, based on Marsters’ embodied performance, which inspires fan investment in the character and influences subsequent conceptions of what the character should or should not do, resulting in a tension between scriptwriters and the fans who know better.
Who cares?
Authors: Forbat Liz , Service Kathryn Pekala
Published: July 2005

The complexity of the relationship between intellectual disability (ID) and dementia is increasingly acknowledged. In order to operationalize a route towards person-centred care, we introduce the hierarchy model (Pearce, 1999) as a tool to focus the attention of policy and practice on all aspects of caregiving. This tool, which is taken from the family therapy literature, enables practitioners to examine the broad systems that impact on the delivery and receipt of care. In this article, we focus on its utility in scrutinizing end-of-life and later stages of dementia by illustrating its use with three key areas in dementia care. These three areas provide some of the most challenging situations at the end stages, because of the possible treatment options, they are: nutrition, medical interventions, and the location of care provision. This model enables a focused approach to understanding how meaning is created within social interaction. The article draws out implications for practice and policy and has applications for practice internationally.
Diversities in approach to end-of-life: A view from Britain of the qualitative literature
Authors: Jones Kip
Published: July 2005

Objective: To systematically investigate qualitative literature on end-of-life issues and ethnicity/race/diversity, employing qualitative methods and philosophical concepts.

Design: A database of 119 references was compiled using a range of techniques, including information foraging theory. Qualitative principles, such as ‘citation snowballing’ and ‘data saturation’, were utilised to gather and consolidate the literature. A model of ‘signal and noise’ was employed to balance methodological rigour against the strength of the message itself in the literature included in the final review.

Results: Existing reviews of qualitative literature on palliative care are minimal, with little mention of ethnicity/race/diversity; palliative care generally pays little attention to qualitative methods. Concepts of ethnicity/race/diversity are socially constructed and these extend to the literature on end-of-life. Changing terminology of palliative care reflects emerging and competing ways to talk about the care provided to dying patients.

Conclusions: The ‘cookbook’ approach to diversity creates new myths or stereotypes, compounding this with inaccuracies or misunderstandings. Aspects other than formal religious beliefs are overlooked and not all members of an ethnic group will routinely follow the beliefs of a specific faith. Healthcare providers must recognise that the basic values, principles and assumptions of Western medicine and bioethics are themselves historically situated and culturally determined. The rights of families to medical knowledge and their roles in decision-making are just as valid, inalienable and crucial to the cultural belief systems of many ethic minority communities as patient autonomy models are to Western medicine.

A common theme emerging through the studies reviewed is a need for sensitivity to the varying expectations and mix of involvement of patients, practioners and families in end-of-life care and the need for information-sharing and decision-making amongst them, along a continuum of health and social care constructed by synthesis and integration of models emerging through this review.
Novel urine hepcidin assay by mass spectrometry
Authors: Kemna Erwin , Tjalsma Harold , Laarakkers Coby , Nemeth Elizabeta , Willems Hans , Swinkels Dorine
Published: July 2005

The hepatic peptide hormone hepcidin is the central regulator of iron metabolism and mediator of anemia of inflammation. To date, only one specific immuno-dot assay to measure hepcidin in urine had been documented. Here we report an alternative approach for quantification of hepcidin in urine by surface-enhanced laser desorption/ionization time-of-flight mass spectrometry (SELDI-TOF-MS). Peptide peaks were detected corresponding to the 3 forms of hepcidin normally found in urine. The identity of the peptide peak equivalent to hepcidin-25 was confirmed using synthetic human hepcidin-25. Validation of our MS data on samples with various hepcidin levels showed a strong correlation with previous immuno-dot assay results (Spearman R = 0.9275, P < .001). Most importantly, this hepcidin assay clearly discriminates between relevant clinical iron disorders. In conclusion, this novel MS urine hepcidin assay is easy to perform and available to a wide audience. This enables the implementation of hepcidin measurements in large clinical studies.
Preliminary Data Release for Randomized Clinical Trials of Noninferiority: A New Proposal
Authors: Korn Edward L. , Hunsberger Sally , Freidlin Boris , Smith Malcolm A. , Abrams Jeffrey S.
Published: July 2005

Noninferiority trials often require a long follow-up period for the data to reach the maturity needed for definitive analysis. A proposal is presented that allows for early release of outcome data from a carefully specified subset of noninferiority trials. This subset is defined so that the early release of the data will be potentially useful to patients who face a treatment decision but will not compromise the integrity of the trial or interfere with the completion of the trial to its definitive analysis. In particular, the release of the data will only occur after the last participant has been randomly assigned and is off treatment-arm–specific therapy and only if it is unlikely that subsequent treatment and/or follow-up practices will change based on the knowledge of released data. In contrast to standard interim monitoring, (1) the release of the data would be automatic and independent of the observed data, and (2) the trial would continue on to its planned final analysis and not be stopped. Examples are given demonstrating how the proposal would work, along with a discussion of possible objections to the proposal.
Phase I Trial of the Oral Antiangiogenesis Agent AG-013736 in Patients With Advanced Solid Tumors: Pharmacokinetic and Clinical Results
Authors: Rugo Hope S. , Herbst Roy S. , Liu Glenn , Park John W. , Kies Merrill S. , Steinfeldt Heidi M. , Pithavala Yazdi K. , Reich Steven D. , Freddo James L. , Wilding George
Published: July 2005

Purpose

We studied the safety, clinical activity, and pharmacokinetics (PK) of AG-013736, an oral receptor tyrosine kinase inhibitor of vascular endothelial cell growth factor, platelet-derived growth factor, and c-Kit, in patients with advanced cancer.

Patients and Methods

Patients received fixed doses of AG-013736 orally in 28-day cycles. In the first cohort, patients initially received two single test doses of AG-013736 (10 and 30 mg); subsequent dosing was determined by individual PK parameters. Doses in subsequent cohorts were assigned by using a traditional dose-escalation/de-escalation rule based on observed toxicities in the current and previous cohorts. PK analysis included evaluation of the effect of food and antacid.

Results

Thirty-six patients received AG-013736 at doses ranging from 5 to 30 mg by mouth twice daily. The dose-limiting toxicities observed included hypertension, hemoptysis, and stomatitis and were seen primarily at the higher dose levels. The observed hypertension was manageable with medication. Stomatitis was generally tolerable and managed by dose reduction or drug holidays. AG-013736 was absorbed rapidly, with peak plasma concentrations observed within 2 to 6 hours after dosing. The maximum-tolerated dose and recommended phase II dose of AG-013736 is 5 mg, twice daily, administered in the fasted state. No significant drug interaction with antacid was seen. There were three confirmed partial responses and other evidence of clinical activity.

Conclusion

In this study, we have demonstrated clinical activity and safety of AG-013736 in patients with advanced solid tumors and identified the dose for phase II testing. The unique phase I study design allowed early identification of important absorption and metabolic issues critical to phase II testing of this agent.
Echinacea species (Echinacea angustifolia (DC.) Hell., Echinacea pallida (Nutt.) Nutt., Echinacea purpurea (L.) Moench): a review of their chemistry, pharmacology and clinical properties
Authors: Barnes Joanne , Anderson Linda A , Gibbons Simon , Phillipson J David
Published: July 2005

This paper reviews the chemistry, pharmacology and clinical properties of Echinacea species used medicinally. The Echinacea species Echinacea angustifolia, Echinacea pallida and Echinacea purpurea have a long history of medicinal use for a variety of conditions, particularly infections, and today echinacea products are among the best-selling herbal preparations in several developed countries. Modern interest in echinacea is focused on its immunomodulatory effects, particularly in the prevention and treatment of upper respiratory tract infections. The chemistry of Echinacea species is well documented, and several groups of constituents, including alkamides and caffeic acid derivatives, are considered important for activity. There are, however, differences in the constituent profile of the three species. Commercial echinacea samples and marketed echinacea products may contain one or more of the three species, and analysis of samples of raw material and products has shown that some do not meet recognized standards for pharmaceutical quality. Evidence from preclinical studies supports some of the traditional and modern uses for echinacea, particularly the reputed immunostimulant (or immunomodulatory) properties. Several, but not all, clinical trials of echinacea preparations have reported effects superior to those of placebo in the prevention and treatment of upper respiratory tract infections. However, evidence of efficacy is not definitive as studies have included different patient groups and tested various different preparations and dosage regimens of echinacea. On the basis of the available limited safety data, echinacea appears to be well tolerated. However, further investigation and surveillance are required to establish the safety profiles of different echinacea preparations. Safety issues include the possibility of allergic reactions, the use of echinacea by patients with autoimmune diseases and the potential for echinacea preparations to interact with conventional medicines.
Disposition of morphine in plasma and cerebrospinal fluid varies during neonatal development in pigs
Authors: Rai Aarati , Bhalla Shaifali , Rebello Sam S , Kastrissios Helen , Gulati Anil
Published: July 2005

The pharmacological effects of morphine are mediated via the central nervous system (CNS) but its clearance from the CNS in neonates has not been investigated. We have proposed that neonatal development of the blood-brain barrier affected CNS clearance mechanisms and CNS exposure to morphine. Male piglets (n=5) aged one, three and six weeks were given morphine sulfate (0.5 mg kg−1, i.v.). Serial blood and cerebrospinal fluid (CSF) samples were withdrawn over 360 min after morphine administration. Morphine concentration was measured by radioimmunoassay. A three-compartment model was fitted to individual data. Estimated parameters were reported as median and range. The peak morphine concentrations in plasma were not significantly different in the one-, three- or six-week-old piglets. Plasma clearance at one week (4.5, 3.8-8.6 mL min−1 kg−1) was significantly lower than at three weeks (30.0, 19.1- 39.0 mL min−1 kg−1) and six weeks (37.0, 29.7–82.8 mL min−1 kg−1). The peak morphine concentration in CSF at one week (59.84, 31–67 ng mL−1) was higher than at three weeks (18.8, 17.7–25 ng mL−1) and six weeks (24.51, 16.5–84 ng mL−1), while CSF clearance was lower at one week (1.0, 0.18-9 mL min−1 kg−1) compared with three weeks (6.2, 2.3–9.3 mL min−1 kg−1) and six weeks (3.95, 1.3–85.7 mL min−1 kg−1). Apparent plasma: CSF transfer ratio at one week was greater than at three and six weeks. The reduced plasma and CSF morphine clearance in early infancy resulted in elevated systemic and central morphine exposure in neonatal pigs.
Flavonoid glycosides inhibit oral cancer cell proliferation — role of cellular uptake and hydrolysis to the aglycones
Authors: Browning Alyson M , Walle U Kristina , Walle Thomas
Published: July 2005

Epidemiologic evidence supports the view that dietary flavonoids exert protective effects in oral diseases, including cancer. However, the dietary forms of flavonoids, the flavonoid glycosides, are thought to be inactive, thus they must first be hydrolysed to their active aglycones. This may occur in the saliva in the oral cavity. We have examined if the flavonoid glycosides directly could affect cell proliferation, using the human oral squamous carcinoma SCC-9 cells. The cellular uptake and hydrolysis of the glycosides were assessed also. The four flavonoid glycosides tested each behaved differently. Genistin, the 7-glucoside of genistein, showed clear and consistent inhibition of cell proliferation, which appeared to be the result of rapid cellular uptake of the glucoside and hydrolysis to genistein. Spiraeoside, the 4′-glucoside of quercetin, showed a similar inhibition of cell proliferation, which also appeared to be associated with its hydrolysis to quercetin. Diosmin, the 7-rutinoside of diosmetin, surprisingly, was more potent and effective than diosmetin. In contrast, quercitrin, the 3-rhamnoside of quercetin, showed no effect and only minimal cellular uptake and no hydrolysis. In summary, dietary flavonoid glycosides may exert cellular effects in the oral cavity, but this varies greatly with the nature of the glycoside.
Amelioration of doxorubicin-induced myocardial oxidative stress and immunosuppression by grape seed proanthocyanidins in tumour-bearing mice
Authors: Zhang Xiao-Yu , Li Wen-Guang , Wu Yong-Jie , Gao Ming-Tang
Published: July 2005

We have investigated the protective effects of grape seed proanthocyanidins on doxorubicin-induced toxicity in tumour-bearing mice. The intraperitoneal administration of doxorubicin (2 mg kg−1 every other day, cumulative dosage for 18 mg kg−1) significantly inhibited the growth of sarcoma 180, and induced myocardial oxidative stress with decreased superoxide dismutase and glutathione peroxidase activity while increasing malondialdehyde formation in the heart or serum. Doxorubicin-induced myocardial oxidative stress also reduced lactate dehydrogenase and creatine kinase activity in the heart and elevated their levels in the serum. Doxorubicin also affected immune functions of tumour-bearing mice with significantly decreased interleukin-2 (IL-2) and interferon-γ (INF-γ) production, and slightly decreased natural killer (NK) cell cytotoxicity, lymphocyte proliferation and CD4+/CD8+ ratio. It markedly increased the percentages of cytotoxic T cells (CD3+CD8+), helper T cells (CD3+CD4+), IL-2R+CD4+, and IL-2R+ cells as compared with untreated tumour-bearing mice. The intragastric administration of proanthocyanidin (200 mg kg−1 daily) significantly inhibited tumour growth, and increased NK cell cytotoxicity, lymphocyte proliferation, CD4+/CD8+ ratio, IL-2 and INF-γ production. Moreover, proanthocyanidin strongly enhanced the anti-tumour effect of doxorubicin and the above immune responses, and completely eliminated myocardial oxidative stress induced by doxorubicin. In conclusion, intragastric administration of proanthocyanidin could enhance the anti-tumour activity of doxorubicin and ameliorate doxorubicin-induced myocardial oxidative stress and immunosuppression in tumour-bearing mice.
Pharmacological comparison of the vasorelaxant action displayed by kaurenoic acid and pimaradienoic acid
Authors: Tirapelli Carlos R , Ambrosio Sergio R , Coutinho Silvia T , de Oliveira Dionéia C R , da Costa Fernando B , de Oliveira Ana M
Published: July 2005

The vascular effects of two natural occurring diterpenes from the kaurane and pimarane classes were compared. The diterpenes ent-kaur-16-en-19-oic acid (kaurenoic acid; KA) and ent-pimara-8(14), 15-dien-19-oic acid (pimaradienoic acid; PA) were tested for their antispasmodic activity on isolated rat aorta. Vascular reactivity experiments, using standard muscle bath procedures, showed that KA and PA (both at 50 and 100 μm) inhibited phenylephrine and KCl-induced contraction in both endothelium-intact and endothelium-denuded rat aortic rings, with PA being more effective than KA. These compounds also reduced CaCl2-induced contraction in Ca2+-free solution containing KCl (30 mm). Again, PA produced a greater reduction in CaCl2-induced contraction than KA. PA (1–300 μm) and KA (1–450 μm) concentration dependently relaxed endothelium-denuded aortic rings pre-contracted with KCl (maximum relaxation 102.31 ± 6.94% and 82.71 ± 1.40%, respectively). Similarly, the relaxation induced by KA on aortic rings pre-contracted with phenylephrine (73.06 ± 3.68%) was less pronounced than that found for PA (102.21 ± 3.64%). Incubation of endothelium-denuded rings for different periods showed that at 50 μm, KA and PA achieved maximum inhibitory activity on KCl-induced contraction after incubation for 60 (53.48 ± 5.83%) and 30 min (83.89 ± 2.12%), respectively. At 100 μm, KA and PA inhibited KCl-induced contraction, with a maximum after incubation for 30 min (73.58 ± 5.30% and 92.07 ± 1.20%, respectively). The maximum inhibition induced by PA at both concentrations tested was greater than that induced by KA. The results provide evidence that structural differences between diterpenes, independent of the C-19 carboxylic acid site, influence selectivity for voltage-operated Ca2+ channels and rate of equilibrium with the target site for their vasorelaxant action in rat aortic rings.
Treatment of vascular smooth muscle cells with estradiol and beta-adrenergic agonists has an additive effect on cAMP levels, but no additive effect on inhibition of collagen synthesis
Authors: Dimopoulos George J , Langner Ronald O
Published: July 2005

Several studies have suggested that increased cell levels of cAMP result in decreased rates of collagen synthesis. Oestrogen treatment of vascular smooth muscle cells (VSMCs) has been shown to cause increased levels of cAMP and decreased rates of collagen synthesis. Beta-adrenergic agonists are also known to increase cellular levels of cAMP in VSMCs, although the effect of beta-adrenergic agonists on collagen synthetic rates in VSMCs is unknown. Since beta-agonists and oestrogens are commonly used clinical agents these studies were conducted to determine the potential of these agents to have an additive effect on cell cAMP levels and inhibition of collagen synthetic rates. When VSMCs were treated with both oestrogen and isoproterenol there was an additive effect on cellular cAMP levels although the observed decrease in collagen synthetic rates was the same as observed in cells treated with just oestrogen. Treatment of VSMCs with propranolol inhibited isoproterenol-induced changes in cAMP but had no effect on either oestrogen-induced increases in cAMP levels or inhibition of collagen synthesis. The cellular location of cAMP following beta-adrenergic agonist treatment was different from the distribution of cAMP in control or oestrogen-treated VSMCs. This difference in cellular distribution of cAMP may partially explain the absence of collagen synthesis inhibition following beta-adrenergic agonist treatment of VSMCs.
The effect of chloral hydrate on the in-vitro T3 binding to adult rat cerebral nuclei
Authors: Bolaris Stamatis , Constantinou Caterina , Valcana Theony , Margarity Marigoula
Published: July 2005

Chloral hydrate is a widely used hypnotic drug for children and animals but the possible interactions of its sedative action and thyroid hormones has not been investigated. In this study the effect of chloral hydrate on the in-vitro binding of triiodothyronine (T3) to cerebral nuclei of adult rats and on the thyroid hormones' synaptosomal and plasma availability were examined. Our results show that during deep anaesthesia caused by a single intraperitoneal administration of chloral hydrate (100 mg kg−1), the maximal number of nuclear thyroid hormone receptors (Bmax) and the equilibrium dissociation constant (Kd) were decreased. These changes returned to normal values when rats woke up (2 1/2 h after chloral hydrate administration). Plasma or synaptosomal levels of thyroid hormones were unaffected during chloral hydrate treatment. Our study demonstrates that the nuclear T3 binding in adult rat brain is affected by the sedative action of chloral hydrate.
Bronchodilatory effects of the aqueous extract of Gynostemma pentaphyllum and gypenosides III and VIII in anaesthetized guinea-pigs
Authors: Circosta Clara , de Pasquale Rita , Palumbo Dora R , Occhiuto Francesco
Published: July 2005

The bronchodilatory activity of the aqueous extract of Gynostemma pentaphyllum Makino leaves was investigated in anaesthetized guinea-pigs and compared with two of its isolated gypenosides (III and VIII). The results showed that the intravenous administration of the decoction of G. pentaphyllum (2.5, 5 or 10 mg kg−1) decreased bronchial resistance in basal conditions and significantly (P<0.01) reduced (68% inhibition) the bronchoconstrictor action of histamine. Furthermore, the extract antagonized (80% inhibition) the bronchoconstrictor response induced by the antigen in sensitized guinea-pigs. Gypenosides III (0.7 mg kg−1, i.v.) and VIII (0.3 mg kg−1, i.v.) caused a similar protective effect in both experimental models used; however, the duration and the intensity of the action was less than that of the extract containing corresponding quantities of gypenosides III and VIII. This study confirmed the validity of the traditional use of this plant in the treatment of asthma and other respiratory disorders.
Protective effects of baicalin on oxygen/glucose deprivation- and NMDA-induced injuries in rat hippocampal slices
Authors: Liu Lu-Ying , Wei Er-Qing , Zhao Yan-Min , Chen Fang-Xue , Wang Meng-Ling , Zhang Wei-Ping , Chen Zhong
Published: July 2005

Baicalin is a flavonoid derivative from Scutellaria baicalensis Georgi with various pharmacological effects. Recently, the neuroprotective effect of baicalin was reported. To confirm this effect and explore the possible mechanism, we have investigated the protective effect of baicalin on ischaemiclike or excitotoxic injury and the activation of protein kinase Cα (PKCα) in rat hippocampal slices. In-vitro ischaemic-like injury was induced by oxygen/glucose deprivation (OGD) and the excitotoxic injury by N-methyl-d-aspartate (NMDA). The viability and swelling of the slices were detected by triphenyltetrazolium chloride (TTC) staining and image analysis of light transmittance (LT), respectively. The translocation of PKCα was measured by immunoblotting. Baicalin was added during both injuries. Baicalin (0.1, 1, and 10 μmolL−1) concentration-dependently inhibited OGD-induced viability reduction and acute neuron swelling, and inhibited the increased portion of PKCα present in the membrane fraction over the total PKCα. Baicalin ameliorated NMDA-induced viability reduction (not LT elevation) and inhibited the NMDA-increased membrane portion of PKCα at 1 μmolL−1. We concluded that baicalin had a protective effect on ischaemic-like or excitotoxic injury in rat hippocampal slices, which might have been partly related to inhibition of PKCα translocation.
Determination of intraluminal theophylline concentrations after oral intake of an immediate-and a slow-release dosage form
Authors: Brouwers Joachim , Ingels Françoise , Tack Jan , Augustijns Patrick
Published: July 2005

The purpose of this study was to evaluate a protocol which enables determining luminal drug concentrations after oral drug administration in man. Human intestinal fluids were aspirated from two sampling sites (duodenum and jejunum) at different time points after oral intake of theophylline; an immediate- and a slow-release dosage form were used to demonstrate the feasibility of discriminating between different formulations. Osmolarity and pH of the aspirates were measured and theophylline concentrations were determined by HPLC-UV. After intake of the immediate-release formulation of theophylline, duodenal maximum concentrations up to 3 mm were reached within 30 min. Theophylline appeared to be almost completely absorbed before it reached the second sampling site in the jejunum, as observed jejunal concentrations were lower than 10% of the maximal duodenal concentrations. These results are in agreement with fast dissolution and fast absorption through the intestinal mucosa, which could be expected as theophylline belongs to class I of the Biopharmaceutical Classification System. In contrast to the immediate-release formulation, administering the slow-release dosage form resulted in a gradual appearance of theophylline, reaching maximal intestinal concentrations below 300 μm. The proposed methodology can be used to assess luminal drug concentrations and to monitor the time- and site-dependent composition of intestinal fluids after intake of an oral dosage form. This approach may contribute to a better understanding of the behaviour of oral drug formulations in the gastrointestinal tract and may be exploited to further unravel the complexity of the gastrointestinal absorption process. In addition, knowledge of luminal drug concentrations may assist in the selection of drug concentrations applied in in-vitro permeability assays.
Suppressive activity of epinastine hydrochloride on TARC production from human peripheral blood CD4+ T cells in-vitro
Authors: Kanai Ken-ichi , Asano Kazuhito , Hisamitsu Tadashi , Suzaki Harumi
Published: July 2005

Thymus- and activation-regulated chemokine (TARC) is an important molecule in the development and maintenance of allergic diseases. However, there is little information about the influence of anti-allergic agents on TARC production. The aim of this study is to examine the influence of epinastine hydrochloride, an H1-receptor antagonist, on TARC production from human peripheral blood CD4+ T cells using an in-vitro cell culture technique. CD4+ T cells prepared from healthy subjects were cultured in wells coated with a combination of OKT3 and anti-CD28 monoclonal antibody in the presence or absence of epinastine HCl for 24 h. The cells were also stimulated with interleukin (IL)-4 in a similar manner. Levels of TARC and IL-4 in culture supernatants were examined by ELISA. The addition of epinastine HCl exerted a dose-dependent suppressive effect on the production of both TARC and IL-4 from CD4+ T cells under co-stimulatory molecule stimulation. The minimum concentration of the agent showing a significant suppressive effect on TARC and IL-4 production was 5.0 μm and 2.5 μm, respectively. Epinastine HCl also suppressed the ability of cells to produce TARC in response to IL-4 stimulation, when the agent was added to cell cultures at more than 2.5 μm. It was concluded that this inhibitory action of epinastine HCl may be partially responsible for epinastine's attenuating effect on allergic diseases.
Gastroprotective effect of Astragaloside IV: role of prostaglandins, sulfhydryls and nitric oxide
Authors: Navarrete Andrés , Arrieta Jesús , Terrones Liliana , Abou-Gazar Hassan , Calis Ihsan
Published: July 2005

This investigation evaluated the gastroprotective activity of Astragaloside IV, a cycloartane-type triterpene glycoside isolated from Astragalus zahlbruckneri. Gastric mucosal damage was induced in rats by intragastric ethanol (1 mL/rat). Rats treated orally with Astragaloside IV suspended in Tween 80 at 3, 10 and 30 mg kg−1, showed 15, 37 and 52% gastroprotection, respectively. The gastroprotection observed at 30 mg kg−1 for this compound was attenuated in rats pretreated with NG-nitro-l-arginine methyl ester (70 mg kg−1, i.p), a nitric oxide (NO)-synthase inhibitor, suggesting that the gastroprotective mechanism of this glycoside involves, at least in part, the participation of NO. The gastroprotective effect of Astragaloside IV was not affected by the inhibition of prostaglandin synthesis with indometacin (10 mg kg−1, s.c.) nor by the block of endogenous sulfhydryls with N-ethylmaleimide (NEM, 10 mg kg−1, s.c.). Carbenoxolone was used as a gastroprotective model drug and showed a dose-dependent gastroprotective effect (25, 43 and 88% of gastroprotection, at 3, 10 and 30 mg kg−1, respectively). The partial participation of prostaglandins, sulfhydryls and NO was observed in the gastroprotective mechanism of carbenoxolone.
Modification of gamma radiation induced response of peritoneal macrophages and splenocytes by Hippophae rhamnoides (RH-3) in mice
Authors: Prakash H , Bala Madhu , Ali A , Goel H C
Published: July 2005

Alcoholic extract of Hippophae rhamnoides, RH-3, reported to render >80% survival against lethal whole body Co-60-gamma irradiation (10 Gy) in mice, was investigated for its immunostimulatory effects. In comparison with un-irradiated control, whole body irradiation did not reduce peritoneal macrophage counts at 24 h post-irradiation. RH-3 treatment (30 mg kg−1 body weight) alone or 30 min before whole-body irradiation enhanced viable counts of macrophages significantly (P≤0.05) compared with both un-irradiated control and irradiated groups. Whole-body irradiation reduced the number of viable splenocytes significantly (P≤0.05) compared with un-irradiated control at 24 h post-irradiation. RH-3 treatment alone or before whole-body irradiation appreciably countered radiation-induced decrease in splenocyte count. 3H-thymidine uptake method revealed that whole-body irradiation reduced splenocyte proliferation significantly (159 ± 45 counts min−1/106 cells; P±0.05) in comparison with control (607 ± 142 counts min−1) at 24 h after irradiation but RH-3 treatment before irradiation reduced the steep decrease and maintained it as 444 ± 153 counts-min−1. After whole-body irradiation, the ratio of spleen weight/mouse weight decreased to 1.5 ± 04 compared with 2.9 ± 0.32 in un-irradiated control at 24 h post-irradiation. Similarly, total protein content in splenocytes also decreased to 48 ± 6 μg/106 cells in comparison with 368 ± 16 μg/106 cells of un-irradiated control. RH-3 treatment before irradiation countered radiation-induced decrease in both spleen weight/mouse weight ratio (4.0 ± 0.35) and total protein content (360 ± 13 μg/106 splenocytes). In the supernatant of peritoneal macrophage cultures exposed to 2 Gy Co-60-gamma radiation ex-vivo, the total nitrite content was enhanced significantly (P<0.05) to 5.72 ± 0.09 μm in comparison with un-irradiated control (1.64 ± 0.09 μm). RH-3 treatment (30 μg mL−1) before irradiation reduced total nitrite significantly (0.93 ± 0.3; P≤0.05) in comparison with irradiated control group. At 24 h after whole body irradiation, the CD4+/CD8+ ratio reduced to 1.5 in comparison with un-irradiated control (1.9) but RH-3 treatment before irradiation restored the ratio to 2.1. These findings explicitly reveal the immunostimulatory activity of RH-3, which may play an important role in the manifestation of its radioprotective efficacy.
Absorption characteristics of model compounds from the small intestinal serosal surface and a comparison with other organ surfaces
Authors: Nishida Koyo , Kuma Akiko , Fumoto Shintaro , Nakashima Mikiro , Sasaki Hitoshi , Nakamura Junzo
Published: July 2005

We examined the absorption of phenolsulfonphthalein (PSP) and fluorescein isothiocyanate dextrans (FD-4, MW 4400; FD-10, MW 9500; FD-40, MW 40500) as model compounds through the small intestinal serosal surface. After application to the rat small intestinal serosal surface using a cylindrical diffusion cell, each compound was absorbed at different rates. The absorption ratios in 6 h after PSP, FD-4, FD-10 and FD-40 application were calculated to be 89.2, 34.6, 14.9 and 2.1% of dose, respectively. Elimination profiles of PSP, FD-4 and FD-10 from the small intestinal serosal surface obeyed first-order kinetics. Moreover, we calculated the apparent permeability coefficient Papp for comparison to other organ surfaces. The kidney had the highest absorption efficiency, as shown by having more than 1.5 times significantly higher Papp values of PSP, FD-4 and FD-10. Similar to the other organ surfaces, a correlation was observed between the Papp of the small intestine and the molecular weight of these hydrophilic compounds. In addition, the small intestine is likely to contribute largely to hydrophilic compound absorption from the peritoneal cavity, judging from absorption clearance, CLa, calculated using the peritoneal organ surface area.
Further investigations on the role of ascorbic acid in stratum corneum lipid models after UV exposure
Authors: Trommer Hagen , Böttcher Rolf , Huschka Christoph , Wohlrab Wolfgang , Neubert Reinhard H H
Published: July 2005

This study is the continuation of our research into vitamin C and its possible effects on human skin after topical administration. The effects of ascorbic acid, iron ions and UV irradiation on stratum corneum lipid models were investigated. The lipid models used were: a simple system (linolenic acid dispersion), a complex system (liposomes consisting of dipalmitoylphosphatidylcholine, cholesterol and linolenic acid) and complex systems with additionally incorporated ceramides (types III and IV). The lipid peroxidation was quantified by the thiobarbituric acid assay. A human adult low-calcium high-temperature (HaCaT) keratinocytes cell culture was used as a second in-vitro model. The amount of intracellular peroxides was determined by measuring the fluorescence intensity using the dihydrorhodamine 123 assay. Electron paramagnetic resonance spectroscopy was used to study the influence of ascorbic acid and iron ions on the signal intensity of 5-doxylstearic acid during UV exposure. Ascorbic acid showed prooxidative properties in the thiobarbituric acid assay whereas cell protection was measured in the HaCaT keratinocytes experiments. Electron paramagnetic resonance investigations revealed different extents of free radical production generated by iron ions, ascorbic acid and UV irradiation. In evaluating the results from this study new aspects of the mechanism of lipid damage caused by these three factors were suggested, transcending the simple redox behaviour of ascorbic acid.
Daubertand the Proper Role for the Courts in Health, Safety, and Environmental Regulation
Authors: McGarity Thomas O.
Published: July 2005

Assigning a Daubert-like gatekeeper role to courts engaged in judicial review of risk assessments prepared by federal agencies is a profoundly bad idea.

I describe the role of courts in reviewing regulatory agency decisionmaking and explore the potential impact of incorporating Daubert principles into administrative law. A Daubert form of judicial review will prevent agencies from employing a “weight of the evidence” approach, forcing them to adopt a “corpuscular” approach that rewards efforts by regulatees to find and exaggerate flaws in individual scientific studies.

Consequently, applying Daubert to federal agency decisionmaking will have a predictable impact on regulatory policy that runs directly counter to the precautionary policies that animate most health, safety, and environmental statutes.
Expert Evidence, the Adversary System, and the Jury
Authors: Vidmar Neil
Published: July 2005

Many assertions have been made about the competence of juries in dealing with expert evidence. I review the types of expert evidence that jurors hear and the impact of adversary legal procedure on the form and manner in which evidence is presented.

Empirical research indicates that jurors understand the adversary process, that they do not automatically defer to the opinions of experts, and that their verdicts appear to be generally consistent with external criteria of performance. Conflicts between the American adversary system and changes in trial procedures that might assist the jury in its task are also considered here.
What Has a Decade of Daubert Wrought?
Authors: Berger Margaret A.
Published: July 2005

There have been changes within the judicial system that may be attributable to opinions on the admissibility of expert testimony that began with the Supreme Court’s 1993 decision in Daubert v Merrell Dow Pharmaceuticals, Inc. After surveying Daubert and subsequent related Supreme Court opinions, I examine a number of questions.

Do the factors courts apply post-Daubert in ruling on the admissibility of expert testimony make scientific sense? Has Daubert had an impact on the willingness of scientists to become expert witnesses? What do we know about Daubert’s impact on improving science in the court room? What has been Daubert’s effect on access to the courts? Does Daubert further public policy objectives of protecting the public against harm?
Scientific Inferences in the Laboratory and the Law
Authors: Cranor Carl
Published: July 2005

Following the Supreme Court’s Daubert v Merrell Dow Pharmaceuticals, Inc decision, courts have struggled in reviewing scientific evidence and appear to have appreciated insufficiently the nature of scientific reasoning. To assist their evidentiary reviews, courts need to appreciate both scientific complexity and ignorance about human toxicity caused by the universe of chemical substances.

Conscientious, well-motivated, respectable experts can come to different conclusions about scientific evidence without making obvious mistakes and without being charlatans. So that justice is done between parties, courts need to allow for reasonable scientific disagreement to avoid excluding from trials respectable experts and all relevant scientific evidence.

The public health community can assist courts to understand ranges of scientific evidence and to recognize the reasonableness of scientific disagreements.
Regulatory Parallels to Daubert: Stakeholder Influence, “Sound Science,” and the Delayed Adoption of Health-Protective Standards
Authors: Neff Roni A. , Goldman Lynn R.
Published: July 2005

There is broad agreement that regulatory decisions should be based on evidence. But interested parties have used the “sound science” mantle to demand extended research, analysis, and review of evidence for the sole purpose of delaying health-protective regulation. This historical review shows how the forces behind the “sound science” reasoning leading to the Daubert v Merrell Dow Pharmaceuticals, Inc decision on science in the courtroom have operated in parallel in environmental regulation.

Like Daubert, certain “sound science” regulatory tools can be used to improve decision quality. However, these tools can also challenge the federal government’s ability to safeguard the public’s health and well-being. Most recently, political tampering with science provides the foundation for some policymakers to disregard science completely in the environmental regulatory process.