bluuebunny/crossref_metadata_2025 huggingface dataset:
Effects of hydrogen peroxide and apolipoprotein E isoforms on apolipoprotein E trafficking in HepG2 cells
Authors: Sabaretnam Tharani , Harris Matthew J , Kockx Maaike , Witting Paul K , Le Couteur David G , Kritharides Leonard
Published: September 2009

1. The major source of apolipoprotein E (apoE) is the liver. In the present study, the effects of oxidative stress and apoE isoforms on apoE distribution and trafficking were established using the HepG2 liver tumour cell line.

2. Hydrogen peroxide (0, 25, 250 and 1000 μmol/L) was associated with rapid and concentration‐dependent redistribution of apoE into the early endosomal compartment. This redistribution was achieved with a much lower concentration (25 μmol/L) than that needed to induce changes in intracellular apoE mRNA expression, apoE protein levels and markers of oxidative stress (250–1000 μmol/L).

3. Live cell imaging of apoE3–green fluorescent protein revealed a significant decrease in traffic velocity in response to oxidative stress.

4. The E4 isoform was associated with reduced trafficking velocity compared with the E3 isoform under basal conditions.

5. The results indicate that oxidative stress and apoE isoforms influence apoE trafficking and distribution within HepG2 cells. Altered apoE hepatocyte trafficking may provide a mechanistic link between oxidative stress, ageing and some diseases in older people.
Role of the median preoptic nucleus in the chronic hypotensive effect of losartan in sodium‐replete normal rats
Authors: Ployngam Trasida , Katz Stephen S , Collister John P
Published: September 2009

1. We have shown previously that the chronic hypotensive effect of the angiotensin II AT1receptor antagonist losartan is mediated, in part, by the subfornical organ (SFO). However, the neural pathway(s) mediating this central effect of losartan downstream from the SFO has not been completely elucidated.

2. The present study was designed to test the hypothesis that the median preoptic nucleus (MnPO) is a crucial part of the neural pathway necessary for the chronic hypotensive effect of losartan. To test this hypothesis, male Sprague‐Dawley rats were subjected to either Sham or electrolytic lesion of the MnPO (MnPOx). Rats were instrumented with radiotelemetric transducers and aortic flow probes for the continuous measurement of mean arterial pressure (MAP) and heart rate and cardiac output (CO), respectively. Total peripheral resistance (TPR) was calculated as MAP/CO. After 3 days of baseline measurements, rats were infused intraperitoneally with losartan (10 mg/kg per day) via an osmotic minipump at a rate of 5 μL/min.

3. The data revealed that, by Day 9 of losartan treatment, MAP had decreased 34 ± 2 mmHg in MnPOx rats (n = 9), whereas the MAP of Sham‐lesioned rats (n = 8) had only decreased 24 ± 3 mmHg. These findings were accompanied by a greater decrease in TPR in MnPOx compared with Sham rats (−0.464vs−0.237 mmHg/mL per min, respectively), whereas CO remained unchanged throughout the study protocol.

4. These results do not support the hypothesis that an intact MnPO is necessary to mediate the full chronic hypotensive effect of losartan in normal rats. Instead, they appear to suggest that the MnPO may play an important role in buffering the profound hypotension induced by losartan.
Calpains, skeletal muscle function and exercise
Authors: Murphy Robyn M
Published: September 2009

1. Skeletal muscle fibres contain ubiquitous (μ‐calpain and m‐calpain) and muscle‐specific (calpain‐3) Ca2+‐dependent proteases. The physiological roles of the calpains are not well understood, although ubiquitous calpains have been associated with apoptosis and myogenesis and calpain‐3 is likely involved in sarcomeric remodelling. A defect in the expression of calpain‐3 results in limb‐girdle muscular dystrophy Type 2A.

2. At resting [Ca2+]i, calpains are present predominantly in their full‐length, unautolysed/unactivated forms. Once activated, μ‐calpain and calpain‐3 appear in their autolysed forms and this measurement can be used to determine when in vivo activation occurs. Endogenously expressed μ‐calpain and calpain‐3 are activated within a physiological [Ca2+] range in a Ca2+‐ and time‐dependent manner.

3. In skeletal muscle, μ‐calpain is a freely diffusible protein that binds rapidly when [Ca2+]i is increased. Calpain‐3 is tightly bound in skeletal muscle fibres at the N2A line of the large elastic protein titin.

4. Overall, neither μ‐calpain nor calpain‐3 are activated immediately following sprint, endurance or eccentric exercise, despite the frequent episodes of high cytoplasmic [Ca2+] that would occur during these types of muscle contractions. Importantly, however, a substantial proportion of calpain‐3, but not μ‐calpain, is activated 24 h after a single bout of eccentric exercise.

5. In vitro studies have shown that calpain‐3 becomes activated if exposed for a prolonged period of time (> 1 h) to resting cytoplasmic [Ca2+] that are approximately two‐ to fourfold higher than normal. This suggests that the small but sustained increase in [Ca2+]i that likely occurs after eccentric contractions is both high and long enough to result in calpain‐3 activation and supports the role for calpain‐3 in sarcomeric remodelling.
Histone modifications and skeletal muscle metabolic gene expression
Authors: McGee Sean L , Hargreaves Mark
Published: September 2009

1. Skeletal muscle oxidative function and metabolic gene expression are co‐ordinately downregulated in metabolic diseases such as insulin resistance, obesity and Type 2 diabetes. Altering skeletal muscle metabolic gene expression to favour enhanced energy expenditure is considered a potential therapy to combat these diseases.

2. Histone deacetylases (HDACs) are chromatin‐remodelling enzymes that repress gene expression. It has been shown that HDAC4 and 5 co‐operatively regulate a number of genes involved in various aspects of metabolism. Understanding how HDACs are regulated provides insights into the mechanisms regulating skeletal muscle metabolic gene expression.

3. Multiple kinases control phosphorylation‐dependent nuclear export of HDACs, rendering them unable to repress transcription. We have found a major role for the AMP‐activated protein kinase (AMPK) in response to energetic stress, yet metabolic gene expression is maintained in the absence of AMPK activity. Preliminary evidence suggests a potential role for protein kinase D, also a Class IIa HDAC kinase, in this response.

4. The HDACs are also regulated by ubiquitin‐mediated proteasomal degradation, although the exact mediators of this process have not been identified.

5. Because HDACs appear to be critical regulators of skeletal muscle metabolic gene expression, HDAC inhibition could be an effective therapy to treat metabolic diseases.

6. Together, these data show that HDAC4 and 5 are critical regulators of metabolic gene expression and that understanding their regulation could provide a number of points of intervention for therapies designed to treat metabolic diseases, such as insulin resistance, obesity and Type 2 diabetes.
Novel role for β‐adrenergic signalling in skeletal muscle growth, development and regeneration
Authors: Ryall James G , Church Jarrod E , Lynch Gordon S
Published: September 2009

1. In adult mammals, skeletal muscle mass is maintained through a precise balance of protein synthesis and protein degradation, whereas during development cellular (not protein) turnover predominates. When protein balance is shifted towards synthesis, skeletal muscle hypertrophy ensues. In contrast, increased protein degradation leads to skeletal muscle atrophy. Insulin‐like growth factor (IGF)‐I is among the best documented of the growth factors and regulates skeletal muscle mass by increasing protein synthesis and decreasing protein degradation. However, an IGF‐I‐independent growth pathway has been identified that involves the activation of β‐adrenoceptors and subsequent skeletal muscle growth, development and hypertrophy.

2. Although the importance of β‐adrenergic signalling in the heart has been well documented and continues to receive significant attention, it is only more recently that we have started to appreciate the importance of this signalling pathway in skeletal muscle structure and function. Studies have identified an important role for β‐adrenoceptors in myogenesis and work from our laboratory has identified a novel role for β‐adrenoceptors in regulating skeletal muscle regeneration after myotoxic injury. In addition, new data suggest that β‐adrenoceptors are markedly upregulated during differentiation of C2C12 cells.

3. It is now clear that β‐adrenoceptors play an important role in regulating skeletal muscle structure and function. Importantly, a clearer understanding of the pathways regulating skeletal muscle mass may lead to the identification of novel therapeutic targets for the treatment of muscle wasting disorders, including sarcopenia, cancer cachexia and the muscular dystrophies.
Serum ornithine carbamyltransferase reflects hepatic damage in diabetic obese mice
Authors: Murayama Hiroshi , Ikemoto Masaki , Hamaoki Masaru
Published: September 2009

Background and Aim:  As ornithine carbamyltransferase (OCT) has proved to be a sensitive serum marker in the detection of hepatotoxicity in several models, it is important to confirm its application to the diagnosis of non‐alcoholic fatty liver disease.

Methods:  C57BL/6, KK‐Ta and KK‐Ay mice were fed a high‐fat diet for 8 weeks and serum enzyme markers were examined. Serum OCT and alanine aminotransferase (ALT) were also measured in diabetic obese ob/ob and db/db mice fed a normal diet. Liver damage in these mice was evaluated by the hepatic content of tumor necrosis factor‐alpha.

Results:  Serum levels of OCT increased in KK‐Ay fed a high‐fat diet compared with the normal diet‐fed group, whereas C57BL/6 and KK‐Ta mice were not affected. In ob/ob mice, the relative increase was always greater in OCT than in ALT. In contrast, in db/db mice, the relative increase was always greater in ALT. Hepatic tumor necrosis factor‐alpha was significantly elevated in ob/ob mice, but not in db/db mice.

Conclusions:  Serum OCT seemed to reflect tumor necrosis factor‐alpha‐mediated hepatic damage when compared with ALT in diabetic obese mice and could be useful in the application for non‐alcoholic fatty liver disease with features of metabolic syndrome, such as obesity and diabetes.
Self‐perception levels of mothers dealing with infant care problems for babies 0–12 months old
Authors: Bayhan Pınar , Yükselen Arzu I. , Cetin Zeynep
Published: September 2009

Background:  Babies need the presence of an adult, especially their mothers, from the moment they are born in order to have their needs fulfilled. The significance of the care, particularly during the newborn and the babyhood period, increases gradually as the children grow older. The adequate and efficient fulfillment of needs during the newborn and babyhood period are fundamental in terms of child development. On the other hand, many mothers don't know what to do about problematic situations related to infant care that they might encounter when they have a newborn baby.

Methods:  The self‐perception of 864 mothers, in various educational level groups, with 432 male and 432 female babies, was analyzed in regards to dealing with problems that arise related to infant care. A questionnaire, developed by Pridham and Chang (1991), was filled out during interviews with the mothers. The analyses of the data obtained as the result of the study were evaluated with the Kruskal–Wallis test while the statistically significant findings were dually compared using the Mann–Whitney test.

Results:  At the conclusion of the study it was determined that the gender of the baby did not effect the mother's self‐perception during problem solving, whereas their educational levels created remarkable differences amongst their responses.
Posterior scleral reinforcement in the treatment of macular retinoschisis in highly myopic patients
Authors: Zhu Zicheng , Ji Xueying , Zhang Jinsong , Ke Genjie
Published: September 2009

Abstract

The objective of this study was to evaluate the clinical curative effect of posterior scleral reinforcement for macular retinoschisis in highly myopic patients. Twenty‐four highly myopic eyes with macular retinoschisis were treated with posterior scleral reinforcement surgery from September 2005 to March 2007 in our hospital. Visual field, best corrected vision acuity (BCVA), refractive error, optical coherence tomography and A/B Scan ultrasound graphy results were retrospectively analysed. The central visual field in 18 eyes was improved after surgery; optical coherence tomography showed complete resolution of the myopic foveoschisis in 20 (83.33%) of the 24 eyes after surgery. The postoperative BCVA was improved by 0.1 or more in 18 eyes (75%), and remained within 0.1 of the preoperative BCVA in five eyes (20.83%) at the end of follow‐up. Compared with the preoperative data of 23 eyes, the final magnitude of myopia after surgery was significantly decreased (t = 3.527, P = 0.002). In conclusion, this procedure can effectively treat highly myopic patients with macular retinoschisis without macular hole or retinal detachment, and might be better for maintaining central vision and preventing the occurrence of complications.
Management of exudative retinal detachment in choroidal melanoma
Authors: Gibran Syed K , Kapoor Kapil G
Published: September 2009

Abstract

Exudative retinal detachment is the most common source of visual loss associated with malignant melanoma of the uveal tract. Management has historically been conservative, leading to irreversible visual loss from photoreceptor damage during the several months needed for post‐radiation resolution. The purpose of this paper is to describe timely vitreoretinal surgical intervention for exudative retinal detachments associated with choroidal melanomas. This was an interventional case series including six consecutive patients with malignant melanoma who experienced VA reduction secondary to associated exudative retinal detachment. Patients underwent complete ophthalmic evaluation and B‐scan ultrasound. Treatment included proton‐beam radiation or brachytherapy, prognostic transretinal tumour biopsy with 25‐gauge vitrector and surgical treatment of exudative retinal detachment, including vitrectomy and drainage of subretinal fluid at the time of irradiation. Successful management of exudative retinal detachments associated with choroidal melanomas was observed in all cases, with significant restoration of vision. Steady regression of tumour thickness was noted clinically and ultrasonographically, without extrascleral extension or metastasis, and with no recurrence of exudative retinal detachment found over follow up. In the present study, the investigators have showed effective surgical treatment of exudative retinal detachment associated with malignant melanoma. These patients had significant restoration of vision, confirming that timely intervention of exudative retinal detachment associated with malignant melanoma can reverse visual loss in these patients. These findings are in contrast to previous reports of irreversible visual loss after exudative retinal detachments, and suggest that photoreceptor atrophy might play a role in visual loss associated with chronic exudative retinal detachments.
Widespread known and novel phosphonate utilization pathways in marine bacteria revealed by functional screening and metagenomic analyses
Authors: Martinez Asuncion , Tyson Gene W. , DeLong Edward F.
Published: September 2009

Phosphonates (Pn), compounds with a direct C–P bond instead of the more common C–O–P ester bond, constitute a significant fraction of marine dissolved organic phosphorus and recent evidence suggests that they may be an alternative source of P for marine microorganisms. To further characterize the microorganisms and pathways involved in Pn utilization, we screened bacterioplankton genomic libraries for their ability to complement an Escherichia coli strain unable to use Pns as a P source. Using this approach we identified a phosphonatase pathway as well as a novel pair of genes that allowed utilization of 2‐aminoethylphosphonate (2‐AEPn) as the sole P source. These pathways are present in diverse bacteria common in marine plankton including representatives of Proteobacteria, Planctomycetes and Cyanobacteria. Analysis of metagenomic databases for Pn utilization genes revealed that they are widespread and abundant among marine bacteria, suggesting that Pn metabolism is likely to play an important role in P‐depleted surface waters, as well as in the more P‐rich deep‐water column.
Effects of Kindermusik training on infants’ rhythmic enculturation
Authors: Gerry David W. , Faux Ashley L. , Trainor Laurel J.
Published: September 2009

Phillips‐Silver and Trainor (2005) demonstrated a link between movement and the metrical interpretation of rhythm patterns in 7‐month‐old infants. Infants bounced on every second beat of a rhythmic pattern with no auditory accents later preferred to listen to an accented version of the pattern with accents every second beat (duple or march meter), whereas infants bounced on every third beat of the same rhythmic pattern preferred to listen to a version with accents every third beat (triple or waltz meter). The present study compared infants participating in Kindermusik classes with infants not participating in music classes. In Kindermusik classes infants receive enriched experience moving to music. Following Western musical norms, the majority of the music samples in the classes are in duple meter. During the preference test, Kindermusik infants listened longer overall, indicating heightened interest in musical rhythms. Both groups listened longer to the accented version that matched how they had been bounced, but only the Kindermusik group showed a stronger preference in the case of duple bouncing than in the case of triple bouncing. We conclude that musical classes for infants can accelerate the development of culture‐specific metrical perception.
See no evil: moral sensitivity in the formulation of business problems
Authors: Pedersen Lars Jacob Tynes
Published: September 2009

This paper explores moral sensitivity in a learning perspective, and a framework is developed for the understanding of how moral sensitivity can be developed through reiterative problem solving in the face of diverse ethical problems. Factors that may inhibit the individual's ability to conceive of moral issues are discussed, and perspectives from moral psychology are integrated with theory on problem formulation. It is argued that (1) the individual's moral sensitivity is pivotal for ethical problem solving, because problem formulation is paramount for further reflection and behaviour; (2) ethical behaviour must be understood both (a) in terms of the individual's psychological make‐up that determines psychological response to moral features and (b) in terms of external constraints on the individual's moral sensitivity; and (3) the development of moral sensitivity can be promoted by actively and consciously pursuing disciplined imagination in multi‐perspective formulations of problems.
Popularity and Acceptance as Distinct Dimensions of Social Standing for Chinese Children in Hong Kong
Authors: Schwartz David , Tom Shelley R. , Chang Lei , Xu Yiyuan , Duong Mylien T. , Kelly Brynn M.
Published: September 2009

This study attempted to validate distinctions between popularity and social acceptance in the cultural context of Hong Kong. We recruited 280 Chinese children (132 girls, 148 boys, mean age = 9.5) from Hong Kong primary schools. These children completed a peer nomination inventory assessing popularity, social acceptance, social rejection, aggression, peer victimization, and social behavior. Consistent with research conducted in western samples, we found that social acceptance was correlated primarily with positive behavioral characteristics (i.e., assertiveness‐leadership and low levels of submissiveness‐withdrawal). In contrast, popularity was associated with a more mixed pattern of features including high levels of aggression. The overall pattern of findings closely replicates past research conducted in North American and European settings.
The Limits of Transparency
Authors: Cukierman Alex
Published: September 2009

This paper probes the limits of transparency in monetary policymaking along two dimensions: feasibility and desirability. It argues that, due to limited knowledge about the economy, even central banks (CBs) that are considered champions of openness are not very clear about their measurement of the output gap and about their beliefs regarding the effect of policy on inflationary expectations. Consequently, feasibility constraints on transparency are more serious than stylized models of the transmission mechanism would imply. In addition, no CB has made clear statements about its objective function, including in particular the relative weight on output versus inflation stabilization, the policy discount factor and the shape of losses from the inflation and the output gaps over the possible ranges of realizations of those variables.

The paper also argues that there is a trade‐off between full transparency and full utilization of information in setting policy and that excessive transparency may facilitate the exertion of political pressures on the CB.

The last section of the paper abstracts from feasibility constraints and discusses the desirable levels of openness in various areas of the policymaking process. It is argued that the strongest case against immediate transparency arises when the CB has private information about problems within segments of the financial system. Premature release of information may, in such a case, destroy efficient risk‐sharing arrangements and long‐term investments by triggering a run on the financial system. This is illustrated within the context of the classic Diamond–Dybvig model of bank runs. The paper also probes the desirable levels of transparency in other areas of the policymaking process like the bank's objective function, the bank's output target, forecasts of economic shocks, disagreements within the CB board and the publication of CB interest‐rate forecasts.
Forecasting the Direction of Policy Rate Changes: The Importance of ECB Words
Authors: Rosa Carlo
Published: September 2009

This paper evaluates the predictive power of different information sets for the European Central Bank (ECB) interest‐rate‐setting behaviour. We employ an ordered probit model, i.e. a limited dependent variable framework, to take into account the discreteness displayed by policy rate changes. The results show that the forecasting ability of standard Taylor‐type variables, such as inflation and output gap, is fairly low both in‐sample and out‐of‐sample, and is comparable to the performance of the random walk model. Instead by using broader information sets that include measures of core inflation, exchange rates, monetary aggregates and financial conditions, the accuracy of the forecasts about ECB future actions substantially improves. Moreover, ECB rhetoric considerably contributes to a better understanding of its policy reaction function. Finally, we find that that the ECB has been fairly successful in educating the public to anticipate the overall future direction of its monetary policy, but has been less successful in signalling the exact timing of rate changes.
The International Financial Crisis Viewed by Experts
Authors: Forte Antonio , Pesce Giovanni
Published: September 2009

The occurrence of the international financial crisis and the spread out of its effects on the global economy prompted experts around the world to think about how to manage the crisis and which measures to implement in order to restore normal economic and financial conditions. In this paper, we present and discuss the results of an international expert survey. We use these experts’ perceptions to pursue a twofold target to understand their perceptions about the causes of the crisis, and of the policies to solve it. Interestingly, experts seem to broadly concur on what caused the crisis but their perceptions diverge regarding the policies. Furthermore, substantial differences in perceptions emerge between the Euro Area and the United States. We also find that the Federal Reserve and the European Central Bank monetary policies during the crisis are judged barely adequate. Finally, different views distinguish academicians from other experts.
From “Shared Responsibility” to a Migration Agreement? The Limits for Cooperation in the Mexico‐United States Case (2000–2008)1
Authors: Delano Alexandra
Published: September 2009

Why were the Mexican and United States governments unable to establish formal cooperation for the management of migration flows even after agreeing on the need for a “shared responsibility” approach and establishing an agenda for negotiations on a bilateral agreement in the spring of 2001? Conventional wisdom is that the terrorist attacks of September 11th were the main reason for the shift from a bilateral to a unilateral approach to the management of US‐Mexico migration flows. Although this event changed the US government’s foreign policy priorities, in order to understand the reasons why the proposal for a migration agreement failed, it is necessary to look beyond the security context that permeated the US agenda after September 11th and analyse the underlying structural, domestic and ideological factors that influenced the governments’ positions during and after the negotiations. By examining the context of power asymmetry in the US‐Mexico relationship, the domestic politics that surround the issue and public perceptions of immigration in the United States, this paper identifies the challenges implied in efforts to expand bilateral cooperation over migration issues in the NAFTA framework. The fact that both countries’ migration policies are mostly pursued unilaterally despite the acceptance of a “shared responsibility” raises key questions regarding the limits of regional integration and bilateral or multilateral cooperation for the management of migration.
Cost‐effectiveness of a barrier‐strengthening moisturizing cream as maintenance therapy vs. no treatment after an initial steroid course in patients with atopic dermatitis in Sweden – with model applications for Denmark, Norway and Finland
Authors: Hjalte F , Asseburg C , Tennvall GR
Published: September 2009

Background  Atopic dermatitis (AD) affects health and quality of life and it has great impact on both health‐care costs and costs to the society.

Objectives  The objective of this study was to develop a model to analyse the cost‐effectiveness of a barrier‐strengthening moisturizing cream as maintenance therapy compared with no treatment after initial treatment with betamethasone valerate in adult patients with AD in Sweden. A further aim was to apply a similar health‐economic analysis for Denmark, Norway and Finland.

Methods  A Markov simulation model was developed including data from three sources: (i) efficacy data from a randomized controlled trial including patients with moderate AD treated with either a moisturizing cream or no treatment, (ii) resource utilization and quality of life data, and (iii) unit prices from official price lists. A societal perspective was used and the analysis was performed according to treatment practice in Sweden. The model simulation was also applied for Denmark, Norway and Finland with inclusion of country‐specific unit costs. Sensitivity analyses were performed to test the robustness of the results.

Results  The results from the present analyses of treatment for patients with moderate AD indicate that maintenance treatment with a moisturizing cream during eczema‐free periods could be cost‐effective in a societal perspective. Similar results were obtained for Sweden, Denmark, Norway and Finland.

Conclusions  According to the analysis, treatment with a moisturizing cream was found to be a cost‐effective option compared with no treatment in eczema‐free periods in adult patients with AD in the four Nordic countries.
Managing Earnings Surprises in Japan: Perspectives from Main Bank Relationships and Institutional Ownership
Authors: Baik Bok , Choi Wooseok
Published: September 2009

Abstract:  In this study, we examine the impact of main bank relationships and institutional ownership on management's incentives to meet or beat analysts’ expectations in Japan. We hypothesize that close main bank relationships reduce managers’ incentives to meet or beat analysts’ expectations since investors place less weight on the need to achieve capital market‐based performance benchmarks. Consistent with our prediction, we find that firms with close main bank relationships are less likely to meet or beat analysts’ expectations. In contrast, we find that the incidence of meeting or beating analysts’ consensus forecasts is greater for firms with institutional shareholders, suggesting that such investors place greater importance on achieving capital market–based performance benchmarks. Overall, our findings support the notion that banks and institutional investors play a significant role in firms’ financial reporting behavior.
Anxiety and depression are risk factors rather than consequences of functional somatic symptoms in a general population of adolescents: The TRAILS study
Authors: Janssens Karin A.M. , Rosmalen Judith G.M. , Ormel Johan , Van Oort Floor V. A. , Oldehinkel Albertine J.
Published: September 2009

Background:  It is well known that functional somatic symptoms (FSS) are associated with anxiety and depression. However, evidence is lacking about how they are related to FSS. The aim of this study was to clarify these relationships and examine whether anxiety and depression are distinctly related to FSS. We hypothesized that anxiety contributes to the development of FSS and that depression is a consequence of FSS.

Methods:  FSS, anxiety, and depression were measured in adolescents (N = 2230, 51% women) by subscales of the Youth Self‐Report during three assessment waves (adolescents successively aged: 10–12, 12–14, and 14–17) and by corresponding subscales of the Child Behavior Checklist. Using structural equation models, we combined trait and state models of FSS with those of anxiety and depression, respectively. We identified which relationships (contemporaneous and two‐year lagged) significantly connected the states of FSS with the states of anxiety and depression.

Results:  Trait variables were all highly interrelated (r = .54–.63). Contrary to our hypothesis, both state anxiety (β = .35) and state depression (β = .45) had a strong contemporaneous effect on state FSS. In turn, state FSS had a weak two‐year lagged effect on state anxiety (β = .11) and an even weaker effect on state depression (β = .06).

Conclusions:  While the effect of anxiety and depression on FSS is strong and immediate, FSS exert a weaker and delayed influence on anxiety and depression. Further research should be done to detect the exact ways in which anxiety and depression lead to FSS, and FSS lead to anxiety and depression.
Reversal of temperature‐induced conformational changes in the amyloid‐beta peptide, Aβ40, by the β‐sheet breaker peptides 16–23 and 17–24
Authors: Hatip Funda F. Bölükbaşı , Suenaga Midori , Yamada Tatsuo , Matsunaga Yoichi
Published: September 2009

Background and purpose: Aggregates of the protein amyloid‐beta (Aβ) play a crucial role in the pathogenesis of Alzheimer's disease (AD). Most therapeutic approaches to AD do not target Aβ, so determination of the factor(s) that facilitate aggregation and discovering agents that prevent aggregation have great potential therapeutic value.

Experimental approach: We investigatedex vivothe temperature‐sensitive regions of Aβ1–40 (Aβ40) and their interactions with octapeptides derived from sequences within Aβ40 –β‐sheet breaker peptides (βSBP) – using enzyme‐linked immunosorbent assay, and dot blot and far‐UV circular dichroism (CD) spectroscopy. We measured changes within the physiological limits of temperature, using antibodies targeting epitopes 1–7, 5–10, 9–14 and 17–21 within Aβ40.

Key results: Temperature‐dependent conformational changes were observed in Aβ40 at epitopes 9–14 and 17–21 at 36–38 and 36–40°C respectively. The βSBPs 16–23 and 17–24, but not 15–22 and 18–25, could inhibit the changes. Moreover, βSBPs 16–23 and 17–24 increased digestion of Aβ40 by protease K, indicating a decreased aggregation of Aβ40, whereas βSBPs 15–22 and 18–25 did not increase this digestion. CD spectra revealed that β‐sheet formation in Aβ40 at 38°C was reduced with βSBPs 16–23 and 17–24.

Conclusions and implications: The epitopes 9–14 and 17–21 are the temperature‐sensitive regions within Aβ40. The βSBPs, Aβ16–23 and 17–24 reversed temperature‐induced β‐sheet formation, and decreased Aβ40 aggregation. The results suggest that the 17–23 epitope of Aβ40 is crucially involved in preventing Aβ40 aggregation and consequent deposition of Aβ40 in AD brain.
Lipoxins: resolutionary road
Authors: Maderna Paola , Godson Catherine
Published: September 2009

The resolution of inflammation is an active process controlled by endogenous mediators with selective actions on neutrophils and monocytes. The initial phase of the acute inflammatory response is characterized by the production of pro‐inflammatory mediators followed by a second phase in which lipid mediators with pro‐resolution activities may be generated. The identification of these mediators has provided evidence for the dynamic regulation of the resolution of inflammation. Among these endogenous local mediators of resolution, lipoxins (LXs), lipid mediators typically formed during cell–cell interaction, were the first to be recognized. More recently, families of endogenous chemical mediators, termed resolvins and protectins, were discovered. LXs and aspirin‐triggered LXs are considered to act as ‘braking signals’ in inflammation, limiting the trafficking of leukocytes to the inflammatory site. LXs are actively involved in the resolution of inflammation stimulating non‐phlogistic phagocytosis of apoptotic cells by macrophages. Furthermore, LXs have emerged as potential anti‐fibrotic mediators that may influence pro‐fibrotic cytokines and matrix‐associated gene expression in response to growth factors. Here, we provide a review and an update of the biosynthesis, metabolism and bioactions of LXs and LX analogues, and the recent studies on their therapeutic potential as promoters of resolution and fibro‐suppressants.

This article is part of a themed issue on Mediators and Receptors in the Resolution of Inflammation. To view this issue visithttp://www3.interscience.wiley.com/journal/121548564/issueyear?year=2009
Lactacystin requires reactive oxygen species and Bax redistribution to induce mitochondria‐mediated cell death
Authors: Perez‐Alvarez Sergio , Solesio Maria E , Manzanares Jorge , Jordán Joaquín , Galindo María F
Published: September 2009

Background and purpose:  The proteasome inhibitor model of Parkinson's disease (PD) appears to reproduce many of the important behavioural, imaging, pathological and biochemical features of the human disease. However, the mechanisms involved in the lactacystin‐induced, mitochondria‐mediated apoptotic pathway remain poorly defined.

Experimental approach:  We have used lactacystin as a specific inhibitor of the 20S proteasome in the dopaminergic neuroblastoma cell line SH‐SY5Y. We over‐expressed a green fluorescent protein (GFP)–Bax fusion protein in these cells to study localization of Bax. Free radical scavengers were used to assess the role of reactive oxygen species (ROS) in these pathways.

Key results:  Lactacystin triggered a concentration‐dependent increase in cell death mediated by the mitochondrial apoptotic pathway, and induced a change in mitochondrial membrane permeability accompanied by cytochrome c release. The participation of Bax protein was more critical than the formation of the permeability transition pore in mitochondria. GFP–Bax over‐expression demonstrated Bax redistribution from the cytosol to mitochondria after the addition of lactacystin. ROS, but not p38 mitogen‐activated protein kinase, participated in lactacystin‐induced mitochondrial Bax translocation. Lactacystin disrupted the intracellular redox state by increasing ROS production and depleting endogenous antioxidant systems such as glutathione (GSH). Pharmacological depletion of GSH, using l‐buthionine sulphoxide, potentiated lactacystin‐induced cell death. Lactacystin sensitized neuroblastoma cells to oxidative damage, induced by subtoxic concentrations of 6‐hydroxydopamine.

Conclusions and implications:  The lactacystin‐induced, mitochondrial‐mediated apoptotic pathway involved interactions between ROS, GSH and Bax. Lactacystin could constitute a potential factor in the development of sporadic PD.
Acute dilation to α2‐adrenoceptor antagonists uncovers dual constriction and dilation mediated by arterial α2‐adrenoceptors
Authors: Crassous PA , Flavahan S , Flavahan NA
Published: September 2009

Background and purpose: In mouse tail arteries, selective α2‐adrenoceptor antagonism with rauwolscine caused powerful dilation during constriction to the α1‐adrenoceptor agonist phenylephrine. This study therefore assessed phenylephrine's selectivity at vascular α‐adrenoceptors and the mechanism(s) underlying dilation to rauwolscine.

Experimental approach: Mouse isolated tail arteries were assessed using a pressure myograph.

Key results: The α2‐adrenoceptor agonist UK14,304 caused low‐maximum constriction that was inhibited by rauwolscine (3 × 10−8 M) but not by the selective α1‐adrenoceptor antagonist prazosin (10−7 M). Concentration–effect curves to phenylephrine, cirazoline or noradrenaline were unaffected by rauwolscine but were inhibited by prazosin, which was more effective at high compared with low levels of constriction. In the presence of prazosin, rauwolscine inhibited the curves and was more effective at low compared with high levels of constriction. Although rauwolscine alone did not affect concentration–effect curves to phenylephrine, noradrenaline or cirazoline, it caused marked transient dilation when administered during constriction to these agonists. Dilation was mimicked by another α2‐adrenoceptor antagonist (RX821002, 3 × 10−8 M), was dependent on agonist selectivity, and did not occur during adrenoceptor‐independent constriction (U46619). During constriction to UK14,304 plus U46619, rauwolscine or rapid removal of UK14,304 caused transient dilation that virtually abolished the combined constriction. Endothelial denudation reduced these dilator responses.

Conclusions and implications: Inhibition of α2‐adrenoceptors caused transient dilation that was substantially greater than the contribution of α2‐adrenoceptors to the constriction. This reflects a slowly reversing α2‐adrenoceptor‐mediated endothelium‐dependent dilation and provides a rapid, sensitive test of α2‐adrenoceptor activity. This approach also clearly emphasizes the poor selectivity of phenylephrine at vascular α‐adrenoceptors.
Effects of inactivation‐resistant agonists on the signalling, desensitization and down‐regulation of bradykinin B2receptors
Authors: Bawolak Marie‐Thérèse , Fortin Sébastien , Bouthillier Johanne , Adam Albert , Gera Lajos , C.‐Gaudreault René , Marceau François
Published: September 2009

Background and purpose: A peptide bradykinin (BK) B2receptor agonist partially resistant to degradation, B‐9972, down‐regulates this receptor subtype. We have used another recently described non‐peptide agonist, compound 47a, as a tool to study further the effects of metabolically more stable and thus persistent, agonists of the BK B2receptor on signalling, desensitization and down‐regulation of this receptor.

Experimental approach and key results: Compound 47a was a partial agonist at the B2receptor in the human umbilical vein, where it shared with B‐9972 a very slow relaxation on washout, and in HEK 293 cell lines expressing tagged forms [myc, green fluorescent protein (GFP)] of the rabbit B2receptor. Compound 47a desensitized the umbilical vein to BK. In the cellular systems, the inactivation‐resistant agonists induced [Ca2+]itransients as brief as those of BK but affected other functions with a longer duration than BK [12 h; receptor endocytosis, endosomal β‐arrestin1/2translocation, protein kinase C‐dependent extracellular signal‐regulated kinases (ERK)1/2 phosphorylation and c‐Fos expression]. The B2receptor–GFP was degraded in cells exposed to B‐9972 or compound 47a for 12 h. The non‐peptide B2receptor antagonist LF 16‐0687 prevented all effects of compound 47a, which were also absent in cells lacking recombinant B2receptors.

Conclusion and implications: Inactivation‐resistant agonists revealed a long‐lasting assembly of the agonist–B2receptor–β‐arrestin complexes in endosomal structures and induce ‘biased signalling’ (in terms of activation of ERK and c‐Fos) as a function of time. Further, B‐9972 and compound 47a, unlike BK, efficiently down‐regulated BK B2receptors.
Impact of OATP transporters on pharmacokinetics
Authors: Kalliokoski A , Niemi M
Published: September 2009

Membrane transporters are now recognized as important determinants of the transmembrane passage of drugs. Organic anion transporting polypeptides (OATP) form a family of influx transporters expressed in various tissues important for pharmacokinetics. Of the 11 human OATP transporters, OATP1B1, OATP1B3 and OATP2B1 are expressed on the sinusoidal membrane of hepatocytes and can facilitate the liver uptake of their substrate drugs. OATP1A2 is expressed on the luminal membrane of small intestinal enterocytes and at the blood‐brain barrier, potentially mediating drug transport at these sites. Several clinically used drugs have been identified as substrates of OATP transporters (e.g. many statins are substrates of OATP1B1). Some drugs may inhibit OATP transporters (e.g. cyclosporine) causing pharmacokinetic drug–drug interactions. Moreover, genetic variability in genes encoding OATP transporters can result in marked inter‐individual differences in pharmacokinetics. For example, a single nucleotide polymorphism (c.521T > C, p.Val174Ala) in theSLCO1B1gene encoding OATP1B1 decreases the ability of OATP1B1 to transport active simvastatin acid from portal circulation into the liver, resulting in markedly increased plasma concentrations of simvastatin acid and an enhanced risk of simvastatin‐induced myopathy.SLCO1B1polymorphism also affects the pharmacokinetics of many other, but not all (fluvastatin), statins and that of the antidiabetic drug repaglinide, the antihistamine fexofenadine and the endothelin A receptor antagonist atrasentan. This review compiles the current knowledge about the expression and function of human OATP transporters, their substrate and inhibitor specificities, as well as pharmacogenetics.
The Xhosa Cattle‐Killing Movement in History and Literature
Authors: Offenburger Andrew
Published: September 2009

In South Africa’s Eastern Cape frontier zone, a millenarian movement known as the Xhosa Cattle‐Killing (1856–1857) devastated local populations and stunned observers. How could the messages of its prophetess, Nongqawuse, and the exhortations of her uncle, Mhlakaza, lead to the slaughter of hundreds of thousands of cattle, to the death of tens of thousands of people, and to the subjugation of the Xhosa? Historians and authors of literary works have attempted to answer this question, and their explanations have followed the contours of South African history through three general phases. The first (1857–1947) characterized the movement as a failed revolt against British expansion and a necessary step in social and religious Darwinism. The second period (1948–1988) saw the continuation of these interpretations, and, with National Party rule and the rise of the Black Consciousness Movement, an increasingly radical group of historians brought about politicized and alternative interpretations embedded in Xhosa oral history. The third phase (1989–) began with the publication of Jeff Peires’The Dead Will Arise, which renewed interest in the history and has inspired a new wave of historical critique.
Zolmitriptan Nasal Spray in the Acute Treatment of Cluster Headache: A Meta‐Analysis of Two Studies
Authors: Hedlund Cecilia , Rapoport Alan M. , Dodick David W. , Goadsby Peter J.
Published: September 2009

Objective.— To conduct an individual subject meta‐analysis of available controlled studies of zolmitriptan nasal spray in the acute treatment of cluster headache.

Background.— Two double‐blind, placebo‐controlled, randomized, crossover studies of zolmitriptan nasal spray in the acute treatment of cluster headache, with similar patient populations, protocol designs, doses, and clinical endpoints have been published.

Methods.— In both double‐blind studies, each patient was to treat 3 attacks, 1 with placebo, 1 with zolmitriptan 5 mg, and 1 with zolmitriptan 10 mg in a randomized, crossover manner. Headache intensity was rated on a 5‐point scale (none to very severe). The primary endpoint was headache relief at 30 minutes post dose: reduction from moderate, severe, or very severe pain to mild or none. A multilevel, random‐effects, logistic regression model was used to analyze the data.

Results.— A total of 121 patients (100 male; 64.5% with episodic cluster headache) provided efficacy data for at least 1 attack. Zolmitriptan 5 mg and 10 mg were significantly more effective at providing headache relief at 30 minutes post treatment than placebo (odds ratio 3.48; 95% confidence interval 1.49‐8.10 and odds ratio 8.68; 95% confidence interval: 3.35‐22.5, respectively). For episodic cluster headache, response rates were 35.6%, 51.7%, and 73.7% for placebo, zolmitriptan 5 mg (odds ratio 2.5; P = .06 vs placebo), and 10 mg (odds ratio 9.9; P < .001 vs placebo), respectively. For chronic cluster headache, response rates were 17.2%, 41.9%, and 40.7% for placebo, zolmitriptan 5 mg (odds ratio 8.1; P = .035), and 10 mg (odds ratio 7.6; P = .046), respectively. Zolmitriptan was well tolerated in both studies with no serious adverse events reported.

Conclusion.— Zolmitriptan nasal spray at a dose of 5 mg and 10 mg is efficacious in the acute treatment of episodic and chronic cluster headache.