bluuebunny/crossref_metadata_2025 huggingface dataset:
Creditor Rights and R&D Expenditures
Authors: Seifert Bruce , Gonenc Halit
Published: September 2011

Manuscript Type: Empirical

Research Question/Issue: This study examines the impact of creditor rights on R&D intensity (R&D/total assets). We argue that managers in countries with strong creditor rights have more incentives to reduce cash flow risk and therefore limit expenditures on R&D more than managers located in countries with weak creditor rights.

Research Findings/Insights: Using a sample of over 21,000 firms from 41 countries, our research is one of the first to document that strong creditor rights are indeed associated with reduced R&D intensity. This negative relationship is observed in market‐based countries, but not in bank‐based countries. Moreover, the results show that the negative effect of creditor rights on R&D intensity is usually stronger (more negative) for firms facing or near financial distress. We observe that the determinants for R&D intensity consist of both country and firm level variables and firm level variables appear to be more important in explaining the variance of R&D intensity.

Theoretical/Academic Implications: This study documents an important link between creditor rights and R&D intensity. Our empirical procedure specifically accounts for the fact that R&D intensity and debt are likely to be jointly determined.

Practitioner/Policy Implications: This research is important to policy makers interested in understanding the determinants of firms' R&D intensity. In particular, our study suggests a possible harmful effect of strong creditor rights, namely the possibility that R&D intensity will be lowered.
Non‐stationary Cross‐Covariance Models for Multivariate Processes on a Globe
Authors: JUN MIKYOUNG
Published: September 2011

Abstract.  In geophysical and environmental problems, it is common to have multiple variables of interest measured at the same location and time. These multiple variables typically have dependence over space (and/or time). As a consequence, there is a growing interest in developing models for multivariate spatial processes, in particular, the cross‐covariance models. On the other hand, many data sets these days cover a large portion of the Earth such as satellite data, which require valid covariance models on a globe. We present a class of parametric covariance models for multivariate processes on a globe. The covariance models are flexible in capturing non‐stationarity in the data yet computationally feasible and require moderate numbers of parameters. We apply our covariance model to surface temperature and precipitation data from an NCAR climate model output. We compare our model to the multivariate version of the Matérn cross‐covariance function and models based on coregionalization and demonstrate the superior performance of our model in terms of AIC (and/or maximum loglikelihood values) and predictive skill. We also present some challenges in modelling the cross‐covariance structure of the temperature and precipitation data. Based on the fitted results using full data, we give the estimated cross‐correlation structure between the two variables.
International Growth Spillovers, Geography and Infrastructure
Authors: Roberts Mark , Deichmann Uwe
Published: September 2011

There is significant academic evidence that growth in one country has a positive impact on growth in neighbouring countries. This paper contributes to this literature by analysing the heterogeneous strength of growth spillovers across world regions and by investigating the contribution of transport and communication infrastructure to explain this heterogeneity and promote neighbourhood effects. By defining neighbourhood on the basis of membership of regional trade agreements, we focus on spillovers that work through regional integration and trade. The analysis finds significant evidence for heterogeneity in growth spillovers, which are strong between OECD countries and essentially absent in sub‐Saharan Africa (SSA). We further find strong interaction between infrastructure and being a landlocked country. This suggests that growth spillovers from regional ‘success stories’ in SSA and other lagging world regions will depend on first strengthening the channels through which such spillovers can spread – most importantly connective infrastructure such as transport and telecommunication links.
UK research expenditure on dementia, heart disease, stroke and cancer: are levels of spending related to disease burden?
Authors: Luengo‐Fernandez R. , Leal J. , Gray A. M.
Published: September 2011

Background and purpose:  A UK government review recommended that the impact of disease on the population and economy should be assessed to inform health research priorities. This study aims to quantify UK governmental and charity research funding for dementia, cancer, coronary heart disease (CHD) and stroke in 2007/08 and assess whether the levels of research expenditure are aligned with disease and economic burden.

Methods:  We identified UK governmental agencies and charities providing health research funding and determined their levels of funding for dementia, cancer, CHD and stroke. Research funding levels were compared to the number of cases, disability‐adjusted life years (DALYs) and economic burden. Economic costs were estimated using data on morbidity, mortality, health and social care use, private costs and other related indicators.

Results:  Research funding to the four diseases was £833 million, of which £590 million (71%) was devoted to cancer, £169 million (20%) to CHD, £50 million (6%) to dementia and £23 million (4%) to stroke. Cancer received £482 in research funding per 1000 DALYs lost, CHD received £266, dementia received £166, with stroke receiving £71. In terms of economic burden, for every £1 million of health and social care costs attributable to each disease, cancer received £129 269 in research funding, CHD received £73 153, stroke received £8745 and dementia received £4882.

Conclusions:  Most health research funding in the UK is currently directed towards cancer. When compared to their burden, our analysis suggests that research spending on dementia and stroke is severely underfunded in comparison with cancer and CHD.
Welfare risks in early adulthood: A longitudinal analysis of social assistance transitions in Norway
Authors: Lorentzen Thomas , Dahl Espen , Harsløf Ivan
Published: September 2011

Lorentzen T, Dahl E, Harsløf I. Welfare risks in early adulthood: a longitudinal analysis of social assistance transitions in Norway

This study assessed the significance of critical life events and socio‐economic background in relation to the likelihood of young Norwegians receiving social assistance, asking how each of these factors contributes both independently and interactively. The data set was derived from a nationwide, longitudinal register and includes the entire 18‐year‐old cohort in 1993. A discrete‐time proportional hazard rate analysis controlling for unobserved heterogeneity was applied. The results indicate that both socio‐economic background and indicators of critical life events have strong independent effects on the likelihood of receiving social assistance. Significant interaction effects between socio‐economic background and certain indicators of critical life events were detected. However, contrary to our expectations, under certain circumstances, coming from a group with low socio‐economic status does not seem to ameliorate the effect of being exposed to critical life events.
Aufkommens- und Verteilungsfolgen des Ersatzes des deutschen einkommensteuerlichen Formeltarifs durch einen Stufentarif
Authors: Houben Henriette , Maiterth Ralf , Müller Heiko
Published: September 2011

A simplification of the German tax law is the major intend when proposing a graduated tax rate to replace the current German formula based tax scale. A plain tax rate structure requires catchy tax brackets (e.g. in 5.000 € or 10.000 € steps) and tax rates (e.g. tax rate differences of 5% or 10%). Our empirical analysis shows that such a graduated tax rate causes significant distributional effects and, depending on the particular form, affects different groups of tax payers in different ways. This holds in particular for the two graduated tax rate proposals from the German Liberal Party which additionally provoke substantial revenue losses. A graduated tax rate with little revenue and distributional effects compared to the current formula based tax scale lacks a plain structure and hence conflicts with the objective of tax simplification.
The effects of including a callous–unemotional specifier for the diagnosis of conduct disorder
Authors: Kahn Rachel E. , Frick Paul J. , Youngstrom Eric , Findling Robert L. , Youngstrom Jennifer Kogos
Published: September 2011

Background:  ‘With Significant Callous–Unemotional Traits’ has been proposed as a specifier for conduct disorder (CD) in the upcoming revision of the Diagnostic and Statistical Manual of Mental Disorders (DSM‐V). The impact of this specifier on children diagnosed with CD should be considered.

Methods:  A multi‐site cross‐sectional design with volunteers (n = 1136) in the third–seventh grades and 566 consecutive referrals (ages 5–18) to a community mental health center were used to estimate the prevalence rates of CD with and without the proposed specifier. In addition, the degree of emotional and behavioral (especially physical aggression) disturbance and level of impairment in youth with and without CD and with and without the specifier was evaluated.

Results:  In the community sample, 10%–32% of those with CD and 2%–7% of those without CD met the callous–unemotional (CU) specifier threshold depending on informant. In the clinic‐referred sample, 21%–50% of those with CD and 14%–32% without CD met the CU specifier threshold depending on informant. Those with CD and the specifier showed higher rates of aggression in both samples and higher rates of cruelty in the clinic‐referred sample.

Conclusions:  Results indicate between 10% and 50% of youth with CD would be designated with the proposed CU specifier. Those with CD and the specifier appear to be more severe on a number of indices, including aggression and cruelty.
Genetic diversity in North American captive Asian elephants
Authors: Lei R. , Brenneman R. A. , Schmitt D. L. , Louis E. E.
Published: September 2011

To assess genetic diversity in North American captive Asian elephants Elephas maximus, one mitochondrial DNA (mtDNA) segment was sequenced in combination with multilocus genotypes generated from 20 nuclear microsatellite loci for 201 individuals. The analysis of 627 bp of the C‐terminal of cyt b and the hypervariable left domain of the noncoding control region (labeled as MDL fragment) sequences revealed the existence of two mtDNA lineages (α and β clade). Analysis of the MDL confirmed that North American captive Asian elephants belong to either the previously characterized α or β clade. An average nucleotide diversity of 0.017 was observed for the Asian elephant mtDNA MDL fragment sequences. Regardless whether an individual possessed mtDNA α or β clade haplotype, all individuals belonged to one nuclear gene lineage for the two X‐linked (BGN and PHKA2) and one Y‐linked (AMELY) genes sequenced. Analysis of multilocus genotypes indicated an average observed and expected heterozygosities were 0.543 and 0.539 in wild‐sourced and 0.579 and 0.547 in the captive‐born Asian elephants, respectively. No subdivision among the sampled individuals was detected, including data partitioned by mtDNA clades. Aside from parent–offspring dyads, no further relationships were detected among wild‐sourced and captive‐born Asian elephants (average relatedness value <0.000).
My Space/Mi Espacio: Evangelical Christianity and Identity Politics in Mexico
Authors: MISRA AMALENDU
Published: September 2011

This article analyses evangelical identity politics and more generally religious competition in contemporary Mexico through a specific focus on the construction, dissemination and imagination of space. The imagination and occupation of a particular space determines the specific identity of its followers. Since the identity–space construct is primarily anchored in the political, religious, economic and funerary contexts in most societies, these four rubrics are woven together to assess of the evangelical Christian space–identity construct. The paper furthers research on religious space creation, dissemination and demarcation amongst evangelical Christians in Mexico, and it emphasises the extent to which the strategies of spatial expansion can lead to rigorous intra‐faith competition and conflict.
Unfolding the universe of newborn health interventions: the role of innovative community‐based strategies
Authors: Lassi ZS , Bhutta ZA
Published: September 2011

Please cite this paper as: Lassi ZS, Bhutta ZA. Unfolding the universe of newborn health interventions: the role of innovative community‐based strategies. BJOG 2011;118 (Suppl. 2):18–21.
Role of presenilin1 in structural plasticity of cortical dendritic spines in vivo
Authors: Jung Christian K. E. , Fuhrmann Martin , Honarnejad Kamran , Van Leuven Fred , Herms Jochen
Published: September 2011

J. Neurochem. (2011) 119, 1064–1073.

Mutations in presenilins are the major cause of familial Alzheimer’s disease (FAD), leading to impairments of memory and synaptic plasticity followed by age‐dependent neurodegeneration. Presenilins are the catalytic subunits of γ‐secretase, which itself is critically involved in the processing of amyloid precursor protein to release neurotoxic amyloid β (Aβ). Besides Aβ generation, there is growing evidence that presenilins play an essential role in the formation and maintenance of synapses. To further elucidate the effect of presenilin1 (PS1) on synapses, we performed longitudinal in vivo two‐photon imaging of dendritic spines in the somatosensory cortex of transgenic mice over‐expressing either human wild‐type PS1 or the FAD‐mutated variant A246E (FAD‐PS1). Interestingly, the consequences of transgene expression were different in two subtypes of cortical dendrites. On apical layer 5 dendrites, we found an enhanced spine density in both mice over‐expressing human wild‐type presenilin1 and FAD‐PS1, whereas on basal layer 3 dendrites only over‐expression of FAD‐PS1 increased the spine density. Time‐lapse imaging revealed no differences in kinetically distinct classes of dendritic spines nor was the shape of spines affected. Although γ‐secretase‐dependent processing of synapse‐relevant proteins seemed to be unaltered, higher expression levels of ryanodine receptors suggest a modified Ca2+ homeostasis in PS1 over‐expressing mice. However, the conditional depletion of PS1 in single cortical neurons had no observable impact on dendritic spines. In consequence, our results favor the view that PS1 influences dendritic spine plasticity in a gain‐of‐function but γ‐secretase‐independent manner.
The chemokine BRAK/CXCL14 regulates synaptic transmission in the adult mouse dentate gyrus stem cell niche
Authors: Banisadr Ghazal , Bhattacharyya Bula J. , Belmadani Abdelhak , Izen Sarah C. , Ren Dongjun , Tran Phuong B. , Miller Richard J.
Published: September 2011

J. Neurochem. (2011) 10.1111/j.1471‐4159.2011.07509.x

The chemokine BRAK/CXCL14 is an ancient member of the chemokine family whose functions in the brain are completely unknown. We examined the distribution of CXCL14 in the nervous system during development and in the adult. Generally speaking, CXCL14 was not expressed in the nervous system prior to birth, but it was expressed in the developing whisker follicles (E14.5) and subsequently in the hair follicles and skin. Postnatally, CXCL14 was also highly expressed in many regions of the brain, including the cortex, basal ganglia, septum and hippocampus. CXCL14 was also highly expressed in the dorsal root ganglia. We observed that in the hippocampal dentate gyrus (DG) CXCL14 was expressed by GABAergic interneurons. We demonstrated that CXCL14 inhibited GABAergic transmission to nestin‐EGFP‐expressing neural stem/progenitor cells in the adult DG. CXCL14 inhibited both the tonic and phasic effects of synaptically released GABA. In contrast CXCL12 enhanced the effects of GABA at these same synapses. CXCL14 increased [Ca2+]i in neural stem cells cultured from the postnatal brain indicating that they expressed the CXCL14 receptor. These observations are consistent with the view that CXCL12 and CXCL14 may normally act as positive and negative regulators of the effects of GABA in the adult DG stem cell niche.
Environmental constraints defining the distribution, composition, and evolution of chlorophototrophs in thermal features of Yellowstone National Park
Authors: HAMILTON T. L. , VOGL K. , BRYANT D. A. , BOYD E. S. , PETERS J. W.
Published: September 2011

Chlorophotoautotrophy, the use of chlorophylls to convert light energy into chemical energy for carbon dioxide fixation, is the primary metabolic process linking the inorganic and organic carbon pools on Earth. To understand the potential effects of various environmental constraints on the evolution of chlorophototrophy better, we studied the distribution, diversity, and abundance of chlorophylls and genes involved in their synthesis along geothermal gradients in Yellowstone National Park, Wyoming. Genes involved in chlorophyll biosynthesis were constrained to temperatures of less than ∼70 °C and were only detected at this elevated temperature when the pH was in the circumneutral to alkaline range. The upper temperature limit for the detection of chlL/bchL1 and bchY2 decreased systematically with increasingly acidic pH, an observation likely attributable to sulfide, which upon oxidation, generates acidic spring water and reduces the availability of bicarbonate the preferred source of inorganic carbon for phototrophs. Spring pH was also the best predictor of the phylogenetic diversity of chlL/bchL communities. The phylogenetic similarity of chlL/bchL genes between sites was significantly correlated with that of chlorophylls. The predominance of chlorophyll a and bacteriochlorophyll a among extracted pigments was consistent with predominance of chlL/bchL genes affiliated with the Cyanobacteria and Chloroflexiales, respectively, and might be related to the fact that the majority of these organisms are photoautotrophs. Together, these results suggest that a combination of temperature, pH, and/or sulfide influences the distribution, diversity, and evolution of chlorophotrophs and the chlorophylls that they synthesize.
The incidence of plateau at 2max is affected by a bout of prior‐priming exercise
Authors: Gordon Dan , Schaitel Kari , Pennefather Amy , Gernigon Marie , Keiller Don , Barnes Richard
Published: September 2011

The purpose of this study was to determine the effect of 6 min of prior‐priming exercise on the incidence of plateau at 2max. Twelve trained cyclists (age, 21 ± 3 years; height, 175·0 ± 8·0 cm; weight, 69·0 ± 10·4 kg; maximal oxygen uptake (2max), 56·3 ± 6·9 ml kg−1 min−1) completed three incremental tests to volitional exhaustion, which were classified as unprimed (UP), heavy‐primed (HP) and severe‐primed (SP), at a work rate of 1 W 2 s−1, from an initial workload of 100 W, for the determination of 2max. 2max trial in the HP and SP conditions was preceded by a period of 4‐min unloaded cycling followed by a further 6 min of constant load cycling at Δ50%2 gas exchange threshold (GET)‐ 2max (HP) and Δ75%2 GET‐2max (SP). Expired air was recorded on a breath‐by‐breath basis during all trials. The criteria adopted for a plateau in2max was a Δ2 over the final two consecutive 30‐s sampling periods ≤2·1 ml kg−1 min−1. There was a significant increase in plateau responses between the UP (50%) and HP (100%) conditions (P = 0·001) coupled with a significant change in the slope of the regression line during the final 60 s of the 2max test, UP and HP (P = 0·0299) and UP and SP (P = 0·0296). These data suggest that a bout of prior‐priming exercise promotes an increased incidence of plateau responses at VO2max. It is suggested that future studies address how such an approach can be adopted without prior knowledge of GET.
The effects of spherical aberration on static accommodative responses in emmetropes and myopes
Authors: Wu Ying , Jiang Bai‐Chuan
Published: September 2011

Citation information: Wu Y & Jiang B‐C. The effects of spherical aberration on static accommodative responses in emmetropes and myopes. Ophthalmic Physiol Opt 2011, 31, 595–602. doi: 10.1111/j.1475‐1313.2011.00870.x

Purpose:  To compare the effects of spherical aberration (SA) on accommodative responses between emmetropes (EMs), stable myopes (SMs), and progressing myopes (PMs).

Methods:  The accommodative responses (AR) induced by negative lenses from 0 to −5 D in 1 D steps were measured with a Complete Ophthalmic Analysis System (COAS) for 10 emmetropes (EMs), 13 stable myopes (SMs), and 9 progressing myopes (PMs). Three types of AR were calculated from wavefront aberration data based on ocular foci within a paraxial area, natural pupil area, and a 3.5 mm‐diameter annular pupil area. The accommodative stimulus response curves (ASRCs) were compared between the three groups and between the three AR conditions.

Results:  The difference in the slope of ASRC was significant between the three AR conditions (p < 0.0001) but it was not significant between the three refractive groups. In each group, the slope of ASRC for the accommodative response measured within the paraxial area of the pupil (paraxial AR) was significantly steeper than that measured for the natural pupil (total AR) and also for that estimated for the 3.5 mm‐diameter annular pupil (p < 0.01). The difference in the y‐intercept of ASRC between the three AR conditions was also significant (p = 0.02) but not between the three refractive groups. The y‐intercept of ASRC for paraxial AR was more positive than that for total AR in SMs (p < 0.01) and in PMs (p < 0.05); the y‐intercept of ASRC for the 3.5 mm peripheral AR was more positive than that for total AR in SMs (p < 0.05).

Conclusions:  The spherical aberration of the eye has a significant effect on the slope of ASRC and is less in PMs than in EMs and SMs.
Does Decreased Access to Emergency Departments Affect Patient Outcomes? Analysis of Acute Myocardial Infarction Population 1996–2005
Authors: Shen Yu‐Chu , Hsia Renee Y.
Published: September 2011

Objective

We analyze whether decreased emergency department (ED) access results in adverse patient outcomes or changes in the patient health profile for patients with acute myocardial infarction (AMI).

Data

We merge Medicare claims, American Hospital Association annual surveys, Medicare hospital cost reports, and location information for 1995–2005.

Study Design

We define four ED access change categories and estimate a ZIP Code fixed‐effects regression models on the following AMI outcomes: mortality rates, age, and probability of percutaneous transluminal coronary angioplasty (PTCA) on day of admission.

Principal Findings

We find a small increase in 30‐day to 1‐year mortality rates among patients in communities that experience a <10‐minute increase in driving time. Among patients in communities with >30‐minute increases, we find a substantial increase in long‐term mortality rates, a shift to younger ages (suggesting that older patients die en route), and a higher probability of immediate PTCA. Most of the adverse effects disappear after the transition years.

Conclusions

Deterioration in geographic access to ED affects a small segment of the population, and most adverse effects are transitory. Policy planners can minimize the adverse effects by providing assistance to ensure adequate capacity of remaining EDs, and facilitating the realignment of health care resources during the critical transition periods.
A Comparison of Health Care Use for Physician‐Referred and Self‐Referred Episodes of Outpatient Physical Therapy
Authors: Pendergast Jane , Kliethermes Stephanie A. , Freburger Janet K. , Duffy Pamela A.
Published: September 2011

Objective

To compare patient profiles and health care use for physician‐referred and self‐referred episodes of outpatient physical therapy (PT).

Data Source

Five years (2003–2007) of private health insurance claims data, from a Midwest insurer, on beneficiaries aged 18–64.

Study Design

Retrospective analyses of health care use of physician‐referred (N = 45,210) and self‐referred (N = 17,497) ambulatory PT episodes of care was conducted, adjusting for age, gender, diagnosis, case mix, and year.

Data Collection/Extraction

Physical therapy episodes began with the physical therapist initial evaluation and ended on the last date of service before 60 days of no further visits. Episodes were classified as physician‐referred if the patient had a physician claim from a reasonable referral source in the 30 days before the start of PT.

Principal Findings

The self‐referred group was slightly younger, but the two groups were very similar in regard to diagnosis and case mix. Self‐referred episodes had fewer PT visits (86 percent of physician‐referred) and lower allowable amounts ($0.87 for every $1.00), after covariate adjustment, but did not differ in related health care utilization after PT.

Conclusions

Health care use during PT episodes was lower for those who self‐referred, after adjusting for key variables, but did not differ after the PT episode.
The Health Care Cost Implications of Overweight and Obesity during Childhood
Authors: Au Nicole
Published: September 2011

Objective

To investigate whether childhood overweight at age 4–5 increases publicly funded health care costs during childhood, and to explore the role of timing and duration of overweight on health costs.

Data Sources

The Longitudinal Study of Australian Children (2004–2008) and linked records from Medicare, Australia's public health insurance provider (2004–2009).

Study Design

The influence of overweight status on non‐hospital Medicare costs incurred by children over a 5‐year period was estimated using two‐part models and one‐part generalized linear models (GLM). All models controlled for demographic, socioeconomic, and parental characteristics.

Principal Findings

Being overweight at age 4–5 is associated with significantly higher pharmaceutical and medical care costs. The results imply that for all children aged 4 and 5 in 2004–2005, those who were overweight had a combined 5‐year Medicare bill that was AUD$9.8 million higher than that of normal weight children. Results from dynamic analyses show that costs of childhood overweight occur contemporaneously, and the duration of overweight is positively associated with medical costs for children who became overweight after age 5.

Conclusions

This study reveals that the financial burden to the public health system of childhood overweight and obesity occurs even during the first 5 years of primary school.
Racialized Customer Service in Restaurants: A Quantitative Assessment of the Statistical Discrimination Explanatory Framework*
Authors: Brewster Zachary W.
Published: September 2011

Despite popular claims that racism and discrimination are no longer salient issues in contemporary society, racial minorities continue to experience disparate treatment in everyday public interactions. The context of full‐service restaurants is one such public setting wherein racial minority patrons, African Americans in particular, encounter racial prejudices and discriminate treatment. To further understand the causes of such discriminate treatment within the restaurant context, this article analyzes primary survey data derived from a community sample of servers (N = 200) to assess the explanatory power of one posited explanation—statistical discrimination. Taken as a whole, findings suggest that while a statistical discrimination framework toward understanding variability in servers’ discriminatory behaviors should not be disregarded, the framework’s explanatory utility is limited. Servers’ inferences about the potential profitability of waiting on customers across racial groups explain little of the overall variation in subjects’ self‐reported discriminatory behaviors, thus suggesting that other factors not explored in this research are clearly operating and should be the focus of future inquires.
Testing Parsons: Evidence from an Organizational Subunit and Implications for Structural Functional Theorizing*
Authors: Powers Charles H. , Fernandez Marilyn
Published: September 2011

Talcott Parsons’ ideas are shown to have operational meaning when applied to organizations in two respects. (1) Parsons’ typology of system needs provides a meaningful way of categorizing administrative rules (protocols) developed by the subunit under study, and (2) “phase dominance,” anticipated by structural functionalists, is tested. Our analysis adds to Parsons’ framework (a) by helping to clarify the distinctive (and generally unappreciated) role that can be played by ground‐level administrative units in the process of adaptive change within large and complex organizations, and (b) by informing our understanding of organizational alignment with external societal forces.
Ursolic acid induces apoptosis in human leukaemia cells and exhibits anti‐leukaemic activity in nude mice through the PKB pathway
Authors: Gao Ning , Cheng Senping , Budhraja Amit , Gao Ziyi , Chen Jieping , Liu E‐Hu , Huang Cheng , Chen Deying , Yang Zailin , Liu Qun , Li Ping , Shi Xianglin , Zhang Zhuo
Published: September 2011

BACKGROUND AND PURPOSE Ursolic acid (UA) has been extensively used as an anti‐leukaemic agent in traditional Chinese medicine. In the present study, we investigated the ability of UA to induce apoptosis in human leukaemia cells in relation to its effects on caspase activation, Mcl‐1 down‐regulation and perturbations in stress‐induced signalling pathways such as PKB and JNK.

EXPERIMENTAL APPROACH Leukaemia cells were treated with UA after which apoptosis, caspase activation, PKB and JNK signalling pathways were evaluated. The anti‐tumour activity of UA was evaluated using xenograft mouse model.

KEY RESULTS UA induced apoptosis in human leukaemia cells in a dose‐ and time‐dependent manner; this was associated with caspase activation, down‐regulation of Mcl‐1 and inactivation of PKB accompanied by activation of JNK. Enforced activation of PKB by a constitutively active PKB construct prevented UA‐mediated JNK activation, Mcl‐1 down‐regulation, caspase activation and apoptosis. Conversely, UA lethality was potentiated by the PI3‐kinase inhibitor LY294002. Interruption of the JNK pathway by pharmacological or genetic (e.g. siRNA) attenuated UA‐induced apoptosis. Furthermore, UA‐mediated inhibition of tumour growth in vivo was associated with induction of apoptosis, inactivation of PKB as well as activation of JNK.

CONCLUSIONS AND IMPLICATIONS Collectively, these findings suggest a hierarchical model of UA‐induced apoptosis in human leukaemia cells in which UA induces PKB inactivation, leading to JNK activation and culminating in Mcl‐1 down‐regulation, caspase activation and apoptosis. These findings indicate that interruption of PKB/JNK pathways may represent a novel therapeutic strategy in haematological malignancies.
The structure and function of the glucagon‐like peptide‐1 receptor and its ligands
Authors: Donnelly Dan
Published: September 2011

Glucagon‐like peptide‐1(7‐36)amide (GLP‐1) is a 30‐residue peptide hormone released from intestinal L cells following nutrient consumption. It potentiates the glucose‐induced secretion of insulin from pancreatic beta cells, increases insulin expression, inhibits beta‐cell apoptosis, promotes beta‐cell neogenesis, reduces glucagon secretion, delays gastric emptying, promotes satiety and increases peripheral glucose disposal. These multiple effects have generated a great deal of interest in the discovery of long‐lasting agonists of the GLP‐1 receptor (GLP‐1R) in order to treat type 2 diabetes. This review article summarizes the literature regarding the discovery of GLP‐1 and its physiological functions. The structure, function and sequence–activity relationships of the hormone and its natural analogue exendin‐4 (Ex4) are reviewed in detail. The current knowledge of the structure of GLP‐1R, a Family B GPCR, is summarized and discussed, before its known interactions with the principle peptide ligands are described and summarized. Finally, progress in discovering non‐peptide ligands of GLP‐1R is reviewed. GLP‐1 is clearly an important hormone linking nutrient consumption with blood sugar control, and therefore knowledge of its structure, function and mechanism of action is of great importance.

LINKED ARTICLES This article is part of a themed section on Secretin Family (Class B) G Protein‐Coupled Receptors. To view the other articles in this section visit http://dx.doi.org/10.1111/bph.2012.166.issue‐1
L‐Tryptophan ethyl ester dilates small mesenteric arteries by inhibition of voltage‐operated calcium channels in smooth muscle
Authors: Jadhav Ashok , Liang Wenbin , Balsevich John , Bastin Guillaume , Kroetsch Jeff , Heximer Scott , Backx Peter H , Gopalakrishnan Venkat
Published: September 2011

BACKGROUND AND PURPOSE L‐tryptophan (L‐W) is a precursor of the vasoconstrictor, 5‐HT. However, acute administration of L‐W ethyl ester (L‐Wee) lowered blood pressure. The mechanism of action is unknown. This study compares the vascular effects of L‐W and L‐Wee in intact animals, isolated aortic rings, small mesenteric arteries (MA) and explores possible mechanisms by studies in vascular smooth muscle cells (VSMC) of MA.

EXPERIMENTAL APPROACH Effects of L‐W or L‐Wee (5–50 mg kg−1, i.v.) on mean arterial pressure (MAP) and heart rate (HR) were determined in male Sprague‐Dawley rats. The effects of L‐W and L‐Wee on basal tone and of phenylephrine‐ or KCl‐induced contractions of aortic and MA rings were assessed. Effects of L‐Wee and L‐W on voltage‐operated calcium channels (VOCC) of VSMC of MA were also examined in patch‐clamp studies.

KEY RESULTS Administration of L‐Wee, but not L‐W, evoked a rapid and transient dose‐dependent decrease in MAP and HR. While both agents failed to affect basal tone, L‐Wee decreased, concentration‐dependently, (Imax > 98%) tension responses to phenylephrine and KCl in an endothelium‐independent manner in aorta (IC50 2 mM) and MA (IC50 17 µM). L‐Wee evoked concentration‐dependent inhibition of VOCC currents (IC50 12 µM; Imax 90%) in VSMC of MA.

CONCLUSIONS AND IMPLICATIONS Esterified L‐W (L‐Wee), but not L‐W, preferentially relaxed resistance vessels rather than conduit vessels. These effects were associated with blockade of VOCC by L‐Wee. Our findings suggest that the falls in MAP and HR induced by L‐Wee were due to blockade of VOCC by L‐Wee.
Modulation of mouse gastrointestinal motility by allyl isothiocyanate, a constituent of cruciferous vegetables (Brassicaceae): evidence for TRPA1‐independent effects
Authors: Capasso Raffaele , Aviello Gabriella , Romano Barbara , Borrelli Francesca , De Petrocellis Luciano , Di Marzo Vincenzo , Izzo Angelo A
Published: September 2011

BACKGROUND AND PURPOSE Allyl isothiocyanate (AITC, mustard oil), a constituent of many common cruciferous vegetables (Brassicaceae), activates transient receptor potential of ankyrin type‐1 (TRPA1) channels, claimed to regulate gastrointestinal contractility. In this study, we have investigated the effect of AITC on intestinal motility.

EXPERIMENTAL APPROACH Effects of AITC were investigated in vivo on upper gastrointestinal transit in mice and in mouse isolated ileum [contractions induced by electrical field stimulation (EFS), acetylcholine and spontaneous contractility]. The contractor activity of AITC was studied in mouse isolated colon. The ability of TRPA1 channel antagonists to block AITC‐induced elevation of intracellular Ca2+[Ca2+]i was assessed in HEK293 cells transfected with rat TRPA1 channels.

KEY RESULTS AITC increased [Ca2+]i in HEK293 cells, reduced ileal contractility (acetylcholine‐, EFS‐induced contractions and spontaneous contractility), but contracted the isolated colon. Gentamicin and camphor (non‐selective TRPA1 channel antagonists), HC‐030031 and AP18 (selective TRPA1 channel agonists) inhibited AITC‐induced effects in HEK293 cells but not in the ileum or colon. AITC‐induced contractions were reduced by tetrodotoxin and strongly reduced by nifedipine, cyclopiazonic acid and ryanodine. In vivo, AITC reduced (following i.p. administration) or increased (following intragastric administration) upper gastrointestinal transit in mice These effects were not affected by HC‐030031.

CONCLUSION AND IMPLICATIONS AITC, depending, in vitro, on the regions of gut examined and, in vivo, on the route of administration, exerted both stimulatory and inhibitory effects on intestinal motility, which were not sensitive to TRPA1 channel antagonists. The proposition that TRPA1 channels are the primary targets for AITC to induce contraction should be revised.
Hydrogen sulphide‐releasing diclofenac derivatives inhibit breast cancer‐induced osteoclastogenesis in vitro and prevent osteolysis ex vivo
Authors: Frantzias J , Logan JG , Mollat P , Sparatore A , Del Soldato P , Ralston SH , Idris AI
Published: September 2011

BACKGROUND AND PURPOSE Hydrogen sulphide (H2S) and prostaglandins are both involved in inflammation, cancer and bone turnover, and non‐steroidal anti‐inflammatory drugs (NSAIDs) and H2S donors exhibit anti‐inflammatory and anti‐tumour properties. H2S‐releasing diclofenac (S‐DCF) derivatives are a novel class of NSAIDs combining the properties of a H2S donor with those of a conventional NSAID.

EXPERIMENTAL APPROACH We studied the effects of the S‐DCF derivatives ACS15 and ACS32 on osteoclast and osteoblast differentiation and activity in vitro, human and mouse breast cancer cells support for osteoclast formation and signalling in vitro, and osteolysis ex vivo.

KEY RESULTS The S‐diclofenac derivatives ACS15 and ACS32 inhibited the increase in osteoclast formation induced by human MDA‐MB‐231 and MCF‐7 and mouse 4T1 breast cancer cells without affecting breast cancer cell viability. Conditioned media from human MDA‐MB‐231 cells enhanced IκB phosphorylation and osteoclast formation and these effects were significantly inhibited following treatment by ACS15 and ACS32, whereas the parent compound diclofenac had no effects. ACS15 and ACS32 inhibited receptor activator of NFκB ligand‐induced osteoclast formation and resorption, and caused caspase‐3 activation and apoptosis in mature osteoclasts via a mechanism dependent on IKK/NFκB inhibition. In calvaria organ culture, human MDA‐MB‐231 cells caused osteolysis, and this effect was completely prevented following treatment with ACS15 and ACS32.

CONCLUSIONS AND IMPLICATIONS S‐diclofenac derivatives inhibit osteoclast formation and activity, suppress breast cancer cell support for osteoclastogenesis and prevent osteolysis. This suggests that H2S‐releasing diclofenac derivatives exhibit anti‐resorptive properties, which might be of clinical value in the treatment of osteolytic bone disease.
Friendship and religion in the Republic of Letters; the return of Justus Lipsius to Catholicism (1591)
Authors: MACHIELSEN JAN
Published: September 2011

jan machielsen, Friendship and religion in the Republic of Letters; The return of Justus Lipsius to Catholicism (1591)

The return of the Flemish humanist Justus Lipsius (1547–1606) to the Spanish Netherlands and his reconciliation with Catholicism (1591) have defined his image for posterity. Debates about the sincerity of Lipsius' religious beliefs have continued to the present day. Scholars have presented Lipsius' departure from Leiden as the result of external pressure, as effortless, and conducted in secret. By contrast, this article shows that Lipsius' public engagement in the Republic of Letters was instrumental in enabling his reconciliation with Catholicism. Lipsius employed both published and private letters and the rhetoric of friendship to win support for his return to the Southern Netherlands. After his arrival, Lipsius' correspondence and friendship with the Flemish‐Spanish Jesuit Martin Delrio (1551–1608) served as a public platform on which the humanist acted out his reconciliation. The article concludes with a discussion as to why Lipsius only published a fraction of his letters to Delrio.
A possible involvement of p62/sequestosome‐1 in the process of biliary epithelial autophagy and senescence in primary biliary cirrhosis
Authors: Sasaki Motoko , Miyakoshi Masami , Sato Yasunori , Nakanuma Yasuni
Published: September 2011

Background and Aims

Given autophagy is involved in the pathogenesis in primary biliary cirrhosis (PBC), we examined an involvement of p62 sequestosome‐1 (p62), a specific cargo for autophagy, in the process of autophagy and cellular senescence in PBC.

Methods

We examined immunohistochemically the expression of p62 in livers taken from patients with PBC (n = 46) and control livers (n = 78) and its colocalization with microtubule‐associated proteins‐light chain 3β (LC3), lysosome‐associated membrane protein‐1 (LAMP‐1) and senescent markers (p16INK4a and p21WAF1/Cip1). We examined the expression of p62 and LC3 in cultured biliary epithelial cells (BECs) treated with various stress. The effect of p62 knockdown with siRNA on stress‐induced autophagy and cellular senescence was also assessed.

Results

The expression of p62 was specifically seen in cytoplasmic aggregates in BECs in the inflamed and damaged small bile ducts (SBDs) in PBC, when compared with non‐inflamed ones in PBC and in control livers (P < 0.01). The co‐expression of p62 with LC3, LAMP‐1 and senescent markers was seen in the inflamed SBDs in PBC, but the intracytoplasmic localization was different. The expression of p62 and LC3 was significantly upregulated in BECs treated with various stress (P < 0.01) and pretreatment with bafilomycin A1 enhanced the accumulation of p62‐positive aggregates in BECs with serum deprivation. The knockdown of p62 decreased stress‐induced autophagy and cellular senescence.

Conclusion

The aggregation of p62 is specifically increased in the damage bile ducts in PBC and may reflect dysfunctional autophagy, followed by cellular senescence in the pathogenesis of bile duct lesions in PBC.
A Novel Hemoglobin‐Based Oxygen Carrier, Polymerized Porcine Hemoglobin, Inhibits H2O2‐Induced Cytotoxicity of Endothelial Cells
Authors: Zhang Wei , Yan Kunping , Dai Penggao , Tian Jingjing , Zhu Hongli , Chen Chao
Published: September 2011

Hemoglobin‐based oxygen carriers (HBOCs), with their capacity for delivering oxygen, could potentially function as red blood cell substitutes or primary resuscitation solutions. However, there has been some concern regarding redox‐related safety issues of HBOCs. The present study describes a novel function of polymerized porcine hemoglobin (pPolyHb) in protecting a human umbilical vein endothelial cell line from H2O2‐induced cytotoxicity. Through the examination of H2O2 consumption and ferrylhemoglobin formation, we found that pPolyHb exhibits antioxidant activity, suggesting that pPolyHb may protect cells from free radical‐induced cell damage. Additionally, we investigated the effect of pPolyHb on H2O2‐induced cell cytotoxicity, and found that pPolyHb significantly inhibits H2O2‐mediated endothelial cell damage as well as apoptosis. Thus, pPolyHb may be developed as a new HBOC in the future.
Seizure outcomes following multilobar epilepsy surgery
Authors: Sarkis Rani A. , Jehi Lara , Najm Imad M. , Kotagal Prakash , Bingaman William E.
Published: September 2011

Purpose: Outcomes following unilobar surgeries for refractory epilepsy have been well described. However, little is known about long‐term seizure outcomes following multilobar resections. The aim of the current study was to identify long‐term seizure control and predictors of seizure recurrence in this patient population.

Methods: Records of patients who underwent multilobar epilepsy surgery at the Cleveland Clinic between 1994 and 2010 were retrospectively reviewed. A postoperative follow‐up of at least 6 months was required. Patients were classified as seizure free if they achieved an Engel class I at last follow‐up. Long‐term chances of seizure freedom were illustrated using a survival analysis, and predictors of recurrence were identified using Cox proportional hazard modeling.

Key Findings: Sixty‐three patients with medically intractable epilepsy underwent multilobar surgical resections during the study period (mean follow‐up of 4.6 years). Predominant resection types included extended occipital (temporoparietooccipital, parietooccipital, temporooccipital: 57%), frontotemporal (21%), and temporoparietal (17%). Mean age at surgery was 21.4 years and mean age at seizure onset was 10.1 years. Fifty‐six percent of the patients underwent extraoperative invasive electroencephalography (EEG) evaluations. At 6 postoperative months, 71% (95% confidence interval (CI) 65–77) were seizure‐free (SF), 64% (CI 58–70) were SF at 1 year, 52% (CI 46–59) were SF at 5 years, and 41% (CI 32–50) remained SF at 10 years. Forty‐one patients had at least one breakthrough seizure after surgery (median timing of recurrence 6.1 months), with an Engel class 1 achieved again by last follow‐up in 12 of these 41 cases. Nine patients required a reoperation. Patients who underwent extended occipital/posterior quadrant resections had more favorable outcomes as compared to the other groups. With multivariate analysis, the type of resection (p = 0.03), preoperative auras (p = 0.03), an incomplete resection (0.03), and the presence of postoperative spikes (p = 0.0003) correlated with seizure recurrence. The risk of seizure recurrence for an incomplete resection was 2.3 (CI 1.53–3.36), preoperative aura 2.3 (CI 1.34–3.87), and postoperative spikes on surface EEG 2.5 (CI 1.29–4.71).

Significance: A favorable outcome can be achieved in 41% of patients undergoing multilobar resections for epilepsy surgery at 10 years of follow‐up. Close to one‐third of patients who have breakthrough seizures after surgery are able to regain seizure freedom by last follow‐up. Predictors of recurrence include resection type (frontotemporal and parietotemporal resections did worse), presence of preoperative aura, an incomplete surgical resection, and the presence of postoperative interictal discharges on EEG.
Economic Impact of Potential Drug–Drug Interactions among Osteoarthritis Patients Taking Opioids
Authors: Pergolizzi Joseph V. , Labhsetwar Sumedha A. , Puenpatom R. Amy , Ben‐Joseph Rami , Ohsfeldt Robert , Summers Kent H.
Published: September 2011

Patients with osteoarthritis (OA) taking at least one CYP450‐metabolized opioid concurrently with another CYP450‐metabolized medication experience a drug–drug exposure (DDE), which puts them at risk of a pharmacokinetic drug–drug interaction (PK DDI). This study compared patients with and without such an incident DDE to determine healthcare utilization and associated payments. Using a retrospective database analysis, the impact of DDEs was evaluated in terms of associated clinical events, healthcare services utilization (office visits, outpatient visits, ED visits, hospitalization), and payments in patient populations based on age (those under age 65 and those 65 years of age and older), during the 6 months after exposure. DDE patients had significantly more inpatient hospitalizations than no‐DDE patients. Mean total payments at 6 months were significantly higher for both younger and older patients with DDE compared to similar patients without DDE ($9,469, SD = $12,192 vs. $8,382, SD = $14,078, respectively, for younger patients, resulting in a difference of $1,087, P < 0.004, and $9,829, SD = $11,721 vs. $8,622, SD = $10,131, respectively, for older patients, resulting in a difference of $1,207, P = 0.001). In both age groups, DDE patients had significantly higher payments for nonopioid prescription drugs ($1,824 SD = $2,420 vs. $1,362, SD = $1,891, respectively, for younger patients, resulting in a difference of $462, P < 0.001, and $2,197 SD = $2,332 vs. $2,013, SD = $2,437, respectively, for older patients, resulting in a difference of $184, P = 0.020). Overall, patients with OA who experienced DDEs had significantly greater utilization rates of healthcare resources and higher associated payments in the 6‐month observation period following the exposure, compared to patients without DDEs, consistent with the risk of PK DDIs associated with DDEs. ▪