bluuebunny/crossref_metadata_2025 huggingface dataset:
A novel fluorophosphonate inhibitor of the biosynthesis of the endocannabinoid 2‐arachidonoylglycerol with potential anti‐obesity effects
Authors: Bisogno Tiziana , Mahadevan Anu , Coccurello Roberto , Chang Jae Won , Allarà Marco , Chen Yugang , Giacovazzo Giacomo , Lichtman Aron , Cravatt Benjamin , Moles Anna , Di Marzo Vincenzo
Published: October 2012

Background and Purpose

The development of potent and selective inhibitors of the biosynthesis of the endocannabinoid 2‐arachidonoylglycerol (2‐AG) via DAG lipases (DAGL) α and β is just starting to be considered as a novel and promising source of pharmaceuticals for the treatment of disorders that might benefit from a reduction in endocannabinoid tone, such as hyperphagia in obese subjects.

Experimental Approach

Three new fluorophosphonate compounds O‐7458, O‐7459 and O‐7460 were synthesized and characterized in various enzymatic assays. The effects of O‐7460 on high‐fat diet intake were tested in mice.

Key Results

Of the new compounds, O‐7460 exhibited the highest potency (IC50 = 690 nM) against the human recombinant DAGLα, and selectivity (IC50 > 10 μM) towards COS‐7 cell and human monoacylglycerol lipase (MAGL), and rat brain fatty acid amide hydrolase. Competitive activity‐based protein profiling confirmed that O‐7460 inhibits mouse brain MAGL only at concentrations ≥10 μM, and showed that this compound has only one major ‘off‐target’, that is, the serine hydrolase KIAA1363. O‐7460 did not exhibit measurable affinity for human recombinant CB1 or CB2 cannabinoid receptors (Ki > 10 μM). In mouse neuroblastoma N18TG2 cells stimulated with ionomycin, O‐7460 (10 μM) reduced 2‐AG levels. When administered to mice, O‐7460 dose‐dependently (0–12 mg·kg−1, i.p.) inhibited the intake of a high‐fat diet over a 14 h observation period, and, subsequently, slightly but significantly reduced body weight.

Conclusions and Implications

O‐7460 might be considered a useful pharmacological tool to investigate further the role played by 2‐AG both in vitro and in vivo under physiological as well as pathological conditions.

Linked Articles

This article is part of a themed section on Cannabinoids. To view the other articles in this section visit http://dx.doi.org/10.1111/bph.2013.169.issue‐4 & http://dx.doi.org/10.1111/bph.2012.167.issue‐8
Moxifloxacin modifies corneal fibroblast‐to‐myofibroblast differentiation
Authors: Chen TC , Chang SW , Wang TY
Published: October 2012

Background and Purpose

Fibroblast‐to‐myofibroblast differentiation is associated with scarring, an important issue in corneal surgery. Moxifloxacin (MOX), commonly applied to prevent post‐operative infection, would benefit more if it modifies fibroblast‐to‐myofibroblast differentiation other than antimicrobial activity. Our purpose was to explore whether MOX has anti‐fibrotic effect in human corneal fibroblasts (HCFs).

Experimental Approach

HCFs were incubated in MOX‐containing medium concurrently with TGF‐β1 (co‐treatment), before (pretreatment) or after (post‐treatment) adding TGF‐β1. HCF contractility was evaluated with a type I collagen gel contraction assay. Expression of α‐smooth muscle actin (α‐SMA), Smad2, phospho‐Smad2‐Ser467, Smad4 and Smad7 was determined by immunoblotting. Formation of α‐SMA‐positive filaments and distribution of active Smad2 were observed under confocal microscopy. Expression of TGF‐β receptor types I (TGFBR1) and II (TGFBR2) was assessed with flow cytometry.

Key Results

MOX did not affect gel contractility or α‐SMA filament formation in HCFs without TGF‐β1 stimulation. MOX did, however, retard HCF‐containing gel contractility and α‐SMA filament formation following TGF‐β1 stimulation in the pretreatment and co‐treatment groups but not in the post‐treatment group. MOX blocked the expression of Smad2, phospho‐Smad2‐Ser467 and TGFBR1 under TGF‐β1 incubation. Additionally, MOX enhanced Smad7 expression in TGF‐β1‐incubated HCFs, but did not interfere with TGF‐β‐triggered Smad2 nuclear translocation or Smad4 expression.

Conclusions and Implications

MOX inhibited TGF‐β‐induced fibroblast‐to‐myofibroblast differentiation via blocking TGFBR1 and enhancing Smad7 expression. MOX should be used before or during surgery to achieve these effects. These results suggest a de novo mechanism by which MOX participates in corneal wound healing.
On the selectivity of neuronal NOS inhibitors
Authors: Pigott B , Bartus K , Garthwaite J
Published: October 2012

Background and Purpose

Isoform‐selective inhibitors of NOS enzymes are desirable as research tools and for potential therapeutic purposes. Vinyl‐l‐N‐5‐(1‐imino‐3‐butenyl)‐l‐ornithine (l‐VNIO) and Nω‐propyl‐l‐arginine (NPA) purportedly have good selectivity for neuronal over endothelial NOS under cell‐free conditions, as does N‐[(3‐aminomethyl)benzyl]acetamidine (1400W), which is primarily an inducible NOS inhibitor. Although used in numerous investigations in vitro and in vivo, there have been surprisingly few tests of the potency and selectivity of these compounds in cells. This study addresses this deficiency and evaluates the activity of new and potentially better pyrrolidine‐based compounds.

Experimental Approach

The inhibitors were evaluated by measuring their effect on NMDA‐evoked cGMP accumulation in rodent hippocampal slices, a response dependent on neuronal NOS, and ACh‐evoked cGMP synthesis in aortic rings of the same animals, an endothelial NOS‐dependent phenomenon.

Key Results

l‐VNIO, NPA and 1400W inhibited responses in both tissues but all showed less than fivefold higher potency in the hippocampus than in the aorta, implying useless selectivity for neuronal over endothelial NOS at the tissue level. In addition, the inhibitors had a 25‐fold lower potency in the hippocampus than reported previously, the IC50 values being approximately 1 μM for l‐VNIO and NPA, and 150 μM for 1400W. Pyrrolidine‐based inhibitors were similarly weak and nonselective.

Conclusion and Implications

The results suggest that l‐VNIO, NPA and 1400W, as well as the newer pyrrolidine‐type inhibitors, cannot be used as neuronal NOS inhibitors in cells without stringent verification. The identification of inhibitors with useable selectivity in cells and tissues remains an important goal.
5‐HT3 receptor antagonists ameliorate 5‐fluorouracil‐induced intestinal mucositis by suppression of apoptosis in murine intestinal crypt cells
Authors: Yasuda M , Kato S , Yamanaka N , Iimori M , Matsumoto K , Utsumi D , Kitahara Y , Amagase K , Horie S , Takeuchi K
Published: October 2012

Background and Purpose

Chemotherapeutic agents, including 5‐fluorouracil (5‐FU), frequently cause intestinal mucositis resulting in severe diarrhoea and morphological mucosal damage. 5‐HT3 receptor antagonists are clinically effective in the treatment of nausea and emesis during cancer chemotherapy. Therefore we here have examined the effects of 5‐HT3 receptor antagonists on 5‐FU‐induced intestinal mucositis in mice.

Experimental Approach

Intestinal mucositis was induced in male C57BL/6 mice by daily administration of 5‐FU (50 mg·kg−1) for 5 days. Effects of 5‐HT3 receptor antagonists, ramosetron (0.01–0.1 mg·kg−1) and ondansetron (5 mg·kg−1), on the accompanying histology, cytokine production and apoptosis were assessed.

Key Results

Continuous administration of 5‐FU to mice caused severe intestinal mucositis, which was histologically characterized by the shortening of villi and destruction of intestinal crypts, accompanied by body weight loss and diarrhoea. Daily ramosetron administration dose‐dependently reduced the severity of intestinal mucositis, body weight loss and diarrhoea. Similar beneficial effects were observed with ondansetron. The number of apoptotic, caspase‐3‐ and caspase‐8‐activated cells increased 24 h after the first 5‐FU administration, and these responses were reduced by ramosetron. The up‐regulation of TNF‐α, IL‐1β and IL‐6 following 5‐FU treatment was also attenuated by ramosetron.

Conclusions and Implications

5‐HT3 receptor antagonists ameliorated 5‐FU‐induced intestinal mucositis in mice, and this action could result from suppression of apoptotic responses in the intestinal crypt cells via inhibition of cytokine expression. Thus, 5‐HT3 receptor antagonists may be useful for preventing not only nausea and emesis but also intestinal mucositis during 5‐FU chemotherapy.
Editorial commentary: Progress with extending payment by results (PbR) into CAMHS
Authors: York Ann
Published: October 2012

Payment by Results (PbR) is a healthcare payment system in England only, already in place for elective secondary care, which has started in Adult Mental Health and is being developed for CAMHS. The approach taken for Mental Health PbR is to allocate service users to groups which are similar in resource usage, called clusters. A choice of care packages and a mechanism for reviews linked with outcome measures all aim to facilitate innovative, efficient and effective management of mental health needs linked to a transparent payment system.
Overweight and obesity are not associated with dental caries among 12‐year‐old South Brazilian schoolchildren
Authors: Alves Luana Severo , Susin Cristiano , Damé‐Teixeira Nailê , Maltz Marisa
Published: October 2012

Objectives

To assess the association between weight status and dental caries among 12‐year‐old Brazilian schoolchildren.

Methods

This cross‐sectional study was carried out in Porto Alegre using a multistage probability sampling strategy to draw a representative sample of schoolchildren attending public and private schools. Data on demographics, socioeconomic status, oral hygiene habits, anthropometrics, and dental caries were collected. Overweight and obesity were defined according to WHO categories for BMI (body mass index)‐for‐age Z‐scores. Survey Poisson regression models were used to assess the association between weight status and dental caries. Estimates were adjusted for gender, socioeconomic status, and brushing frequency. Prevalence ratios (PR), rate ratios (RR) and 95% confidence intervals (95% CI) were reported.

Results

One thousand five hundred and twenty‐eight of 1837 eligible schoolchildren were examined. Prevalence of overweight and obesity were 22.15% (95% CI = 20.59–23.72) and 13.61% (95% CI = 11.44–15.78), respectively. Caries experience was observed in 55.23% (95% CI = 45.26–65.19) of children. Schoolchildren presented, on average, 1.39 (95% CI = 1.07–1.71) decayed, missing or filled teeth. No significant differences in caries experience or extent were observed among BMI groups. After adjusting for important cofactors, weight status was not associated with caries prevalence (overweight, PR = 0.99; 95% CI = 0.89–1.10; obese, PR = 1.00; 95% CI = 0.87–1.16) or caries extent (overweight, RR = 0.91; 95% CI = 0.74–1.12; obese, RR = 0.86; 95% CI = 0.72–1.04).

Conclusions

Our findings indicate that overweight and obese adolescents should not be regarded as at higher risk of dental caries in this population.
Is it safe to withdraw steroids within seven days of renal transplantation?
Authors: Zhang Xin , Huang Hejing , Han Shu , Fu Shangxi , Wang Liming
Published: October 2012

Background

The safety of very early steroid withdrawal (VESW) in renal transplant recipients remains unclear.

Methods

Literature searches for all randomized controlled trials comparing VESW with steroid maintenance regimens were performed using MEDLINE, EMBASE, and the Cochrane Library. Quality assessment was performed in each trial. Meta‐analyses were performed to demonstrate the pooled effects of relative risk (RR) and weighted mean difference with 95% confidence intervals (CI).

Results

A total of 3520 participants from 15 RCTs were included. VESW regimen increased the incidence of acute rejection (AR) over controls (RR = 1.46, CI = 1.20–1.79, p = 0.04). Subsequent analysis demonstrated that such difference lost significance in patients receiving tacrolimus (p = 0.16), but remained significant in patients with cyclosporin (p < 0.00001). The increased AR episodes were predominantly mild. VESW was associated with an increased incidence of delayed graft function (DGF) when steroids were withdrawn within three d post‐transplantation. Cardiovascular risk factors, including incidence of new onset diabetes and total cholesterol, were significantly reduced under VESW regimen.

Conclusions

It is safe and practical to withdraw steroids very early after renal transplantation. However, a three‐ to seven‐d course of steroids may decrease the risk for DGF relative to steroid withdrawal in <3 d. Antibody induction is effective in preventing early AR.
Attitude to organ donation among healthcare workers in Nigeria
Authors: Esezobor Christopher I. , Disu Elizabeth , Oseni Saheed B. A.
Published: October 2012

Introduction

As transplantation services are scaled up in Nigeria so will the need for organ donation. Crucial to the success of organ donation is the attitude of healthcare workers (HCW); this was determined in the present study.

Methods

HCW participating in three workshops were requested to complete a pretested questionnaire structured to elicit their attitude to organ donation. Predictors of willingness to donate were also determined.

Results

Of the 205 questionnaires distributed, 182 (88.8%) were returned; 10 were excluded for incomplete responses. The mean age of the respondents was 39.9 (8.9) yr. The majority were females (76.7%), Christians (87.8%), and worked in tertiary hospitals (77.3%). Medical doctors made up 55% of the respondents. Of the 172 respondents, 102 (59.3%) reported willingness to donate an organ. The majority of Muslims respondents willing to donate would prefer living donation. Being a medical doctor (odds ratio of 2.64 [1.17–5.94]) was the strongest predictor of willingness to donate an organ. The most common reasons for unwillingness to donate were “fear of complications” (44.9%) and “mistrust of the health sector” (20.6%).

Conclusion

The majority of the HCW are favorable to organ donation. Being a medical doctor is highly predictive of willingness to donate an organ.
Effect of Propranolol as Antiadhesive Therapy in Sickle Cell Disease
Authors: De Castro Laura M. , Zennadi Rahima , Jonassaint Jude C. , Batchvarova Milena , Telen Marilyn J.
Published: October 2012

Sickle red blood cells (SSRBCs) adhere to both endothelial cells (ECs) and the extracellular matrix. Epinephrine elevates cyclic adenosine monophosphate in SSRBCs and increases adhesion of SSRBCs to ECs in a β‐adrenergic receptor and protein kinase A‐dependent manner. Studies in vitro as well as in vivo have suggested that adrenergic stimuli like epinephrine may contribute to vaso‐occlusion associated with physiologic stress. We conducted both animal studies and a Phase I dose‐escalation study in sickle cell disease (SCD) patients to investigate whether systemically administered propranolol inhibits SSRBC adhesion and to document the safety of propranolol in SCD. Systemically administered propranolol prevented SSRBC adhesion and associated vaso‐occlusion in a mouse model. In patients receiving a single oral dose of 10, 20, or 40 mg propranolol, SSRBC adhesion to ECs was studied before and after propranolol, with and without stimulation with epinephrine. Propranolol administration significantly reduced epinephrine‐stimulated SSRBC adhesion in a dose dependent manner (p = 0.03), with maximum inhibition achieved at 40 mg. Adverse events were not severe, did not show dose dependence, and were likely unrelated to drug. No significant heart rate changes occurred. These results imply that β‐blockers may have a role as antiadhesive therapy for SCD. Clin Trans Sci 2012; Volume 5: 437–444
Basal cell carcinoma of the skin: whole genome screening by comparative genome hybridization revisited
Authors: Pesz Karolina A. , Bieniek Andrzej , Makowska Izabela , Sąsiadek Maria M.
Published: October 2012

Basal cell carcinoma (BCC) of the skin is considered to be the most common malignancy in people of European ancestry. It is often not clinically aggressive and has been regarded as genetically stable. However, histopathologic subtypes of BCC differ in their ability to invade surrounding tissues and recur. The aim of this work was to present a comprehensive study of chromosomal imbalances of cutaneous BCC and to correlate the findings with their histopathologic and clinical features. In all, 101 tumor samples were classified according to the current microscopic classification of BCC and then analyzed by comparative genomic hybridization (CGH). Over 60% of BCC were found to carry chromosomal imbalances – partial or whole chromosome gains and losses. Different subtypes of BCC presented common chromosomal alterations. No single chromosomal imbalance was found to be characteristic of a particular subtype of BCC, although the frequency of some chromosomal changes differed from one group to the other. The significance of chromosome 2 gains as a phenomenon that does not coexist with the losses in 9q is discussed.
Perceived stress and incidence of Type 2 diabetes: a 35‐year follow‐up study of middle‐aged Swedish men
Authors: Novak M. , Björck L. , Giang K. W. , Heden‐Ståhl C. , Wilhelmsen L. , Rosengren A.
Published: October 2012

Aim

To explore incident cases of diagnosed diabetes over 35 years of follow‐up in relation to self‐perceived stress at baseline.

Methods

This was a population‐based random sample of 7251 men derived from the Primary Prevention Trial Study, aged 47–56 years at baseline and without prior history of diabetes, coronary heart disease and stroke. Incident diabetes was identified from hospital discharge and death registries as principal or secondary diagnosis. Cox proportional hazards regression was used to evaluate the potential association between stress and diabetes.

Results

During a 35‐year follow‐up, a total of 899 men were identified with diabetes. The crude incidence was 5.2 per 1000 persons‐years. At baseline, 15.5% men reported permanent stress related to conditions at work or home. After adjusting for age and competing risk of death, the estimated 35‐year conditional probability of diabetes in men with permanent stress was 42.6%, compared with 31.0% for those with periodic stress and 31.2% with no stress. In age‐adjusted Cox regression analysis, men with permanent stress had a higher risk of diabetes [hazard ratio 1.52 (95% CI 1.26–1.82)] compared with men with no (referent) or periodic stress [hazard ratio 1.09 (95% CI 0.94–1.27)]. The association between stress and diabetes was slightly attenuated but remained significant after adjustment for age, socio‐economic status, physical inactivity, BMI, systolic blood pressure and use of anti‐hypertensive medication [hazard ratio 1.45 (95% CI 1.20–1.75)]. When examining principal diagnosis of diabetes cases separately from secondary diagnoses cases, the excess risk of diabetes associated with permanent stress remained significant both in age (only) and multivariable adjusted models.

Conclusion

Self‐perceived permanent stress is an important long‐term predictor of diagnosed diabetes, independently of socio‐economic status, BMI and other conventional Type 2 diabetes risk factors.
Effects of multiple matings on reproductive fitness of male and female Diaeretiella rapae
Authors: Kant R. , Trewick S.A. , Sandanayaka W.R.M. , Godfrey A.J.R. , Minor M.A.
Published: October 2012

Mating frequency and the amount of sperm transferred during mating have important consequences on progeny sex ratio and fitness of haplodiploid insects. Production of female offspring may be limited by the availability of sperm for fertilizing eggs. This study examined multiple mating and its effect on fitness of the cabbage aphid parasitoid Diaeretiella rapae McIntosh (Hymenoptera: Aphidiidae). Female D. rapae mated once, whereas males mated with on average more than three females in a single day. The minimum time lag between two consecutive matings by a male was 3 min, and the maximum number of matings a male achieved in a day was eight. Sperm depletion occurred as a consequence of multiple mating in D. rapae. The number of daughters produced by females that mated with multiple‐mated males was negatively correlated with the number of matings achieved by these males. Similarly, the proportion of female progeny decreased in females that mated with males that had already mated three times. Although the proportion of female progeny resulting from multiple mating decreased, the decrease was quicker when the mating occurred on the same day than when the matings occurred once per day over several days. Mating success of males initially increased after the first mating, but then males became ‘exhausted’ in later matings; their mating success decreased with the number of prior matings. The fertility of females was affected by mating with multiple‐mated males. The study suggests that male mating history affects the fitness of male and female D. rapae.
A Web‐based tool for personalized prediction of long‐term disease course in patients with multiple sclerosis
Authors: Galea I. , Lederer C. , Neuhaus A. , Muraro P. A. , Scalfari A. , Koch‐Henriksen N. , Heesen C. , Koepke S. , Stellmann P. , Albrecht H. , Winkelmann A. , Weber F. , Bahn E. , Hauser M. , Edan G. , Ebers G. , Daumer M.
Published: October 2012

Background and purpose

The Evidence‐Based Decision Support Tool in Multiple Sclerosis (EBDiMS) is the first Web‐based prognostic calculator in multiple sclerosis (MS) capable of delivering individualized estimates of disease progression. It has recently been extended to provide long‐term predictions based on the data from a large natural history cohort.

Methods

We compared the predictive accuracy and consistency of EBDiMS with that of 17 neurologists highly specialized in MS.

Results

We show that whilst the predictive accuracy was similar, neurologists showed a significant intra‐rater and inter‐rater variability.

Conclusions

Because EBDiMS was consistent, it is of superior utility in a specialist setting. Further field testing of EBDiMS in non‐specialist settings, and investigation of its usefulness for counselling patients in treatment decisions, is warranted.
A diverse set of family 48 bacterial glycoside hydrolase cellulases created by structure‐guided recombination
Authors: Smith Matthew A. , Rentmeister Andrea , Snow Christopher D. , Wu Timothy , Farrow Mary F. , Mingardon Florence , Arnold Frances H.
Published: October 2012

Sequence diversity within a family of functional enzymes provides a platform for elucidating structure–function relationships and for protein engineering to improve properties important for applications. Access to nature's vast sequence diversity is often limited by the fact that only a few enzymes have been characterized in a given family. Here, we recombined the catalytic domains of three glycoside hydrolase family 48 bacterial cellulases (Cel48; EC 3.2.1.176) – Clostridium cellulolyticum CelF, Clostridium stercorarium CelY, and Clostridium thermocellum CelS – to create a diverse library of Cel48 enzymes with an average of 106 mutations from the closest native enzyme. Within this set, we found large variations in properties such as the functional temperature range, stability, and specific activity on crystalline cellulose. We showed that functional status and stability were predictable from simple linear models of the sequence–property data: recombined protein fragments contributed additively to these properties in a given chimera. Using this, we correctly predicted sequences that were as stable as any of the native Cel48 enzymes described to date. The characterization of 60 active Cel48 chimeras expands the number of characterized Cel48 enzymes from 13 to 73. Our work illustrates the role that structure‐guided recombination can play in helping to identify sequence–function relationships within a family of enzymes by supplementing natural diversity with synthetic diversity.
Expression of LY6D is induced at the surface of MCF10A cells by X‐ray irradiation
Authors: Kurosawa Maiko , Jeyasekharan Anand D. , Surmann Eva‐Maria , Hashimoto Noboru , Venkatraman Vignesh , Kurosawa Gene , Furukawa Koichi , Venkitaraman Ashok R. , Kurosawa Yoshikazu
Published: October 2012

In order to identify membrane proteins whose expression is induced by X‐ray irradiation, we developed an antibody (Ab)‐directed strategy using a phage Ab library. X‐Ray‐irradiated cells were screened with a phage Ab library in the presence of a large excess of polyclonal Abs prepared against membrane proteins that are commonly present at the surface of both X‐ray‐irradiated and nonirradiated cells. After isolation of Ab that bound only to X‐ray‐irradiated cells, the antigen was identified using MS. Using this approach, we found that expression of LY6D is induced in MCF10A cells by X‐ray irradiation. The induction of LY6D expression is triggered through a pathway regulated by ATM, CHK2 and p53. This method is a new Ab‐directed proteomic strategy for analysis of membrane proteins, and is applicable to various biological phenomena in situations in which both target molecule‐expressing cells and nonexpressing cells are available.
Evaluation of skin cancer chemoprevention potential of sunscreen agents using the Epstein–Barr virus early antigen activation in vitro assay
Authors: Kapadia G. J. , S. Rao G. , Takayasu J. , Takasaki M. , Iida A. , Suzuki N. , Konoshima T. , Tokuda H.
Published: October 2012

Synopsis

In our continuing search for novel cancer chemopreventive compounds of natural and synthetic origin, we have evaluated 14 commonly used ultraviolet (UV) sunscreen agents (designated UV‐1 to UV‐14) for their skin cancer chemoprevention potential. They belong to 8 different chemical categories: aminobenzoate (UV‐5, UV‐7, UV‐8 and UV‐14), benzophenone (UV‐1, UV‐2, UV‐3 and UV‐13), benzotriazole (UV‐10), benzyloxyphenol (UV‐9), cinnamate (UV‐6), quinolone (UV‐4), salicylate (UV‐11) and xanthone (UV‐12). In the in vitro assay employed, the sunscreens were assessed by their inhibition of the Epstein–Barr virus early antigen (EBV‐EA) activation induced by the tumour promoter 12‐O‐tetradecanoylphorbol‐13‐acetate (TPA) in human lymphoblastoid Raji cells. All sunscreens tested were found to exhibit anti‐tumour promoting activity: listed in decreasing order, moderate (UV‐11, UV‐2, UV‐7, UV‐12, UV‐3, UV‐9 and UV‐14) to weak (UV‐1, UV‐6, UV‐8, UV‐16, UV‐5, UV‐4 and UV‐10) with octyl salicylate (UV‐11) as the most potent and drometrizole (UV‐10) as the least potent among the compounds evaluated. A plausible relationship between the antioxidant property of sunscreens and their ability to promote anti‐tumour activity was noted. The results call for a comprehensive analysis of skin cancer chemoprevention potential of currently used UV sunscreen agents around the globe to identify those with the best clinical profile.
Biodegradable polymers as encapsulation materials for cosmetics and personal care markets
Authors: Ammala Anne
Published: October 2012

Synopsis

The topical and transdermal delivery of active cosmetic ingredients requires safe and non‐toxic means of reaching the target sites without causing any irritation. Preservation of the active ingredients is also essential during formulation, storage and application of the final product. As many biologically active substances are not stable and sensitive to temperature, pH, light and oxidation, they require encapsulation to protect against unwanted degradation and also to target specific and controlled release of the active substance. The use of biodegradable polymers as encapsulation materials offers several advantages over other carrier materials. Encapsulation of active ingredients using biodegradable polymeric carriers can facilitate increased efficacy and bioavailability and they are also removed from the body via normal metabolic pathways. This article reviews current research on biodegradable polymers as carrier or encapsulation materials for cosmetic and personal care applications. Some of the challenges and limitations are also discussed. Examples of biodegradable polymers reviewed include polysaccharides, poly α‐esters, polyalkylcyanoacrylates and polyamidoamine dendrimers.
Peak provoked craving: an alternative to smoking cue‐reactivity
Authors: Sayette Michael A. , Tiffany Stephen T.
Published: October 2012

Smoking cue‐exposure research has provided a powerful tool for examining cravings in the laboratory. A key attraction of this method is that tightly controlled experimental procedures can model craving experiences that are presumed to relate to addiction. Despite its appeal, key assumptions underlying the clinical relevance of smoking cue‐reactivity studies have been questioned recently. For both conceptual and methodological reasons it may be difficult to tease apart cue‐based and abstinence‐based cravings. Moreover, conventional cue‐reactivity procedures typically generate levels of craving with only minimal clinical relevance. We argue here that sometimes it is unfeasible—and in some instances conceptually misguided—to disentangle abstinence‐based and cued components of cigarette cravings. In light of the challenges associated with cue‐reactivity research, we offer an alternative approach to smoking cue‐exposure experimental research focusing on peak provoked craving (PPC) states. The PPC approach uses nicotine‐deprived smokers and focuses on urges during smoking cue‐exposure without subtracting out urge ratings during control cue or baseline assessments. This design relies on two factors found in many cue‐exposure studies—nicotine deprivation and exposure to explicit smoking cues—which, when combined, can create powerful craving states. The PPC approach retains key aspects of the cue‐exposure method, and in many circumstances may be a viable design for studies examining robust laboratory‐induced cravings.
The Botrytis cinerea cerato‐platanin BcSpl1 is a potent inducer of systemic acquired resistance (SAR) in tobacco and generates a wave of salicylic acid expanding from the site of application
Authors: Frías Marcos , Brito Nélida , González Celedonio
Published: October 2012

Systemic acquired resistance (SAR) is a potent plant defence system that, in response to a first contact with a plant pathogen, prepares the whole plant for subsequent attacks, so that it becomes more resistant to the same and to other pathogens. BcSpl1, a cerato‐platanin family protein abundantly secreted by Botrytis cinerea, is required for full virulence and elicits the hypersensitive response in the host. Here, we report that BcSpl1 is also able to induce in tobacco systemic resistance to two plant pathogens, Pseudomonas syringae and B. cinerea, which correlates with the induction of two pathogenesis‐related genes, PR‐1a and PR‐5. Levels of salicylic acid were quantified in situ on BcSpl1 infiltration, and a wave of salicylic acid departing from the point of infiltration and running through the leaf was observed, as well as the appearance of this plant hormone in the neighbouring leaves as early as 3 days after infiltration.
Continuous glucose monitoring by intravenous microdialysis: influence of membrane length and dialysis flow rate
Authors: ROOYACKERS O. , BLIXT C. , MATTSSON P. , WERNERMAN J.
Published: October 2012

Background

The benefit of tight glucose control in the intensive care unit is controversial. Part of the debate is around the frequency of glucose measurements, and therefore, a continuous glucose monitoring system is needed. Previously, we have shown that intravenous microdialysis has the potential for this purpose but that the accuracy must be improved. The aim of this study was to investigate the effects of the microdialysis membrane length and the perfusion rate on improving the accuracy.

Methods

Two volunteer studies were performed, one comparing intravenous microdialysis catheters with different lengths (10 and 20 mm) and one comparing different perfusion rates (0.5, 1 and 2 μl/min) with plasma glucose reference levels. Median values of seven samples taken over 70‐min periods were compared using Bland–Altman plots.

Results

When microdialysis membranes of 10 and 20 mm perfused at a rate of 1 μl/min were used, the differences with measured plasma glucose levels were 30% ± 21% and 14% ± 13%. In comparison, plasma glucose measured in two different veins gave a difference of 3% ± 3%. In the second study, the differences between measured plasma glucose and that estimated with a microdialysis membrane of 30 mm perfused at 0.5, 1 and 2 μl/min were 8% ± 7%, 25% ± 19% and 39% ± 28%. Bland–Altman analyses gave the best line of equality (−0.11 mM) and the lowest limits of agreement (1.13 and −1.35 mM) when using the 30‐mm membrane perfused with 0.5 μl/min.

Conclusion

The agreement of the intravenous microdialysis with plasma glucose levels improved significantly when increasing the microdialysis membrane length, and thereby the membrane area, and decreasing the perfusion rate.
Hyperbaric articaine with or without fentanyl in spinal anaesthesia: patient and observer blinded comparison
Authors: KAIRALUOMA P. , BACHMANN M. , KALLIO H. , ROSENBERG P. , PERE P.
Published: October 2012

Background

The rapid and short‐acting local anaesthetic articaine is a feasible spinal anaesthetic for day‐case open inguinal herniorrhaphy (OIH). We hypothesised that similarly to other spinal local anaesthetics, the addition of fentanyl may prolong articaine spinal analgesia without prolonging motor block.

Methods

We performed a randomised, controlled study in 100 adult patients undergoing OIH. Spinal anaesthesia was induced by injecting hyperbaric articaine 72 mg with (Group A + F) or without (Group A) fentanyl 10 μg with the patient in lateral decubitus position. The distribution of sensory block was tested using pinprick and controlled by tilting the operating table 10 up or down. Motor block testing was based on the patient's ability to flex knees and ankles. Rescue analgesic was intravenous (i.v.) fentanyl. Pain scores were registered, and i.v. paracetamol 1 g was given as the first post‐operative analgesic.

Results

There were no differences (A + F vs. A) in the maximum median extension of the sensory block (T5 vs. T5), mean duration of sensory block ≥ T10 (76 min vs. 73 min), or total duration of sensory (146 min vs. 146 min) or motor block (99 min vs. 107 min). Fewer patients in Group A + F needed fentanyl (5 vs. 14, P < 0.05) perioperatively or paracetamol (3 vs. 18, P < 0.001) post‐operatively.

Conclusion

Fentanyl 10 μg added to spinal hyperbaric articaine improved analgesia and reduced analgesic consumption during and after OIH. Fentanyl did not prolong motor block or delay recovery.
Platelet‐derived growth factor‐BB increases expression of connexin 43 in an extracellular‐regulated protein kinase‐dependent manner in bladder smooth muscle cells
Authors: Shen Wenhao , Li Longkun , Song Bo , Li Weibing , Zhou Zhansong , Guo Ruiwei
Published: October 2012

Objectives

To investigate whether platelet‐derived growth factor‐BB induces the upregulation of connexin 43 in bladder smooth muscle cells and to examine the involved signaling pathway.

Methods

Bladder smooth muscle cells were exposed to platelet‐derived growth factor‐BB in the presence or absence of p38 mitogen‐activated protein kinase, c‐jun amino‐terminal kinase or extracellular‐regulated protein kinase inhibitors. Transfection of bladder smooth muscle cells with specific small interference ribonucleic acid against platelet‐derived growth factor receptor‐β gene expression was also carried out to investigate whether platelet‐derived growth factor receptor‐β was involved in the signaling pathway. Expression of messenger ribonucleic acid and protein for connexin 43 was measured by real time polymerase chain reaction and western blot.

Results

The addition of platelet‐derived growth factor‐BB in cultured bladder smooth muscle cells caused the significant upregulation of connexin 43, and the activation of extracellular‐regulated protein kinase, c‐jun amino‐terminal kinase and p38 mitogen‐activated protein kinase compared with the control group. This action of platelet‐derived growth factor‐BB could be abolished by the pretreatment of bladder smooth muscle cells with the extracellular‐regulated protein kinase inhibitor PD98059, whereas p38 mitogen‐activated protein kinase and c‐jun amino‐terminal kinase inhibitors did not have any effect on this. Platelet‐derived growth factor‐BB could induce the activation of platelet‐derived growth factor receptor‐β. Transfection of bladder smooth muscle cells with small interference ribonucleic acid specific for platelet‐derived growth factor receptor‐β gene resulted in the potent suppression of gene expression and inhibition of extracellular‐regulated protein kinase activation, as well as upregulation of connexin 43 induced by platelet‐derived growth factor‐BB.

Conclusions

Platelet‐derived growth factor‐BB upregulates connexin 43 expression through the activation of extracellular‐regulated protein kinase and platelet‐derived growth factor receptor‐β signaling pathways. This finding suggests that this signaling pathway might provide a potential target to manipulate detrusor overactivity.
Nodal metastasis microRNA expression correlates with the primary tumour in MTC
Authors: Gundara Justin S. , Zhao Jing Ting , Gill Anthony J. , Clifton‐Bligh Roderick , Robinson Bruce G. , Delbridge Leigh , Sidhu Stan B.
Published: October 2012

Introduction

Lymph node metastases represent a diagnostic and management challenge in patients with disseminated medullary thyroid carcinoma (MTC). Our understanding of microRNA (miRNA) profiles of metastatic disease also remains limited and may unveil novel therapeutic strategies for these patients.

Methods

MTC patients with a history of total thyroidectomy and lymph node dissection were identified from within the prospective Sydney University Endocrine Surgical Unit database. Patients with available formalin‐fixed paraffin‐embedded tumour tissue were included and clinicopathological data were collated. Total RNA was extracted and quantitave polymerase chain reaction (qPCR) analysis performed on the primary tumour and a corresponding lymph node metastasis for expression of miRNAs of proven significance in MTC (miR‐9*, miR‐183 and miR‐375).

Results

Tissue was available for analysis in seven patients. The median age at diagnosis was 55 years (range: 22–67). Median tumour size was 18 mm (range: 6–55) and over a median follow‐up period of 34 months (range: 1–210), five further operations were undertaken for residual disease. One patient died of metastatic disease. Pairwise correlations of qPCR expression levels between primary tumours and corresponding lymph node metastases revealed significant correlations for miR‐9* (P < 0.001), miR‐183 (P = 0.001) and miR‐375 (P = 0.004).

Conclusion

miRNA expression patterns in nodal metastases significantly reflect those of the primary tumour in MTC. This further validates previously reported miRNA profile analyses and reiterates the potential significance of miR‐9*, ‐183 and ‐375 in the pathophysiology of MTC. The possibility of lymph node biopsy miRNA analysis driven clinical decision making may now also be a possibility where conventional techniques are unhelpful.
Aortocaval fistula: current management strategies
Authors: Brightwell Robert E. , Pegna Victoria , Boyne Nicholas
Published: October 2012

Background

There has been a trend towards favouring endovascular repair for much acute aortic pathology. We undertook a review of the literature to determine if an endovascular approach could complement the traditional treatment of aortocaval fistula (ACF), a rare complication of abdominal aortic aneurysm.

Methods

A literature search was undertaken on PubMed using appropriate search terms. Case series and reviews reporting presentation, diagnosis and operative management (open and endovascular techniques) of ACF were selected and discussed.

Results

Open surgical treatment of ACF has an associated morbidity and mortality – mainly from excessive blood loss. Open repair mortality rates are reported around 30%, but some centres report far lower rates based on preoperative diagnosis of the ACF. These rates appear to be reduced when using endovascular repair in selected cases, with success rates of up to 96%. Reiteration of the importance of diagnosis of ACF preoperatively was the common denominator with both open and endovascular repair.

Conclusions

Endovascular exclusion appears to be an efficacious means of treating ACF and averting the significant blood loss commonly encountered in conventional repair of these lesions. However, some reviews have suggested equal success with open repair. There is limited available published literature on ACF management and outcome, and likely reporting bias attached to both open and endovascular results that are published. With a randomized controlled trial unlikely to occur, a prospective registry may provide better outcome data.
An Investigation of the Relationship between Use of International Accounting Standards and Source of Company Finance in Germany
Authors: Tarca Ann , Morris Richard D. , Moy Melissa
Published: October 2012

This study examines the relationship between use of international accounting standards and companies’ source of finance. We investigate the proposition contained in Nobes’ (1998) model that postulates outsider companies (those with a higher level of public finance) in weak equity–outsider markets (capital markets where public equity finance is not the dominant source of finance) are more likely to change their type of accounting system from one focused on information for creditors and tax authorities to one that meets the needs of external financiers. We found strong support for Nobes’ model. Using 408 German listed companies at 1999, we observed that companies with more outsider finance (the proportion of shares held by outsiders and the presence of public debt) were more likely to use international standards (U.S. GAAP or IAS). The results indicate the importance of controlling for source of finance at the company rather than country level in cross‐country studies investigating the benefits of adoption of international standards.
The Language Growth of Spanish‐Speaking English Language Learners
Authors: Rojas Raúl , Iglesias Aquiles
Published: October 2012

Although the research literature regarding language growth trajectories is burgeoning, the shape and direction of English Language Learners' (ELLs) language growth trajectories are largely not known. This study used growth curve modeling to determine the shape of ELLs' language growth trajectories across 12,248 oral narrative language samples (6,516 Spanish; 5,732 English) produced by 1,723 ELLs during the first 3 years of formal schooling (M age at first observation = 5 years 7 months). Results indicated distinct trajectories of language growth over time for each language differentially impacted by summer vacation and gender, significant intra‐ and interindividual differences in initial status and growth rates across both languages, and language‐specific relations between language growth and initial status. Implications of ELLs' language growth are discussed.
How Do Children Acquire Early Grammar and Build Multiword Utterances? A Corpus Study of French Children Aged 2 to 4
Authors: Le Normand M. T. , Moreno‐Torres I. , Parisse C. , Dellatolas G.
Published: October 2012

In the last 50 years, researchers have debated over the lexical or grammatical nature of children's early multiword utterances. Due to methodological limitations, the issue remains controversial. This corpus study explores the effect of grammatical, lexical, and pragmatic categories on mean length of utterances (MLU). A total of 312 speech samples from high‐low socioeconomic status (SES) French‐speaking children aged 2–4 years were annotated with a part‐of‐speech‐tagger. Multiple regression analyses show that grammatical categories, particularly the most frequent subcategories, were the best predictors of MLU both across age and SES groups. These findings support the view that early language learning is guided by grammatical rather than by lexical words. This corpus research design can be used for future cross‐linguistic and cross‐pathology studies.
Social protection and preventing illness in developing countries: Establishing the health effects of pensions and health insurance
Authors: Lloyd‐Sherlock Peter , Minicuci Nadia , Beard John , Chatterji Somnath
Published: October 2012

This article assesses the effectiveness of pension provision and health insurance in preventing ill health among older people in developing countries. It argues that, until recently, social protection agendas devoted insufficient attention to health risk prevention, instead focusing on the reduction of income poverty through cash transfers. The article shows that there is little reliable evidence to indicate that providing older people with pension benefits enhances their health status and that these effects should not be taken for granted by policy‐makers. The article then focuses on the effect of inclusion in health insurance schemes on health outcomes for older people, with specific reference to outcomes related to hypertension. Drawing on newly‐available data from the World Health Organization for Ghana, Mexico and South Africa, it shows that older people with health insurance are marginally more likely to be aware of health conditions such as hypertension and more likely to have them under control. Nevertheless, the great majority of hypertensive older people, insured or uninsured, are not effectively treated. The chief barriers to treatment are shown to be mainly related to awareness and service provision, rather than financial ones. Consequently, the capacity of pensions or health insurance to enhance health outcomes for older people in such countries, including in rural areas, is heavily contingent upon health education, health screening and adequate health service provision. These interventions should be viewed as an integral element of mainstream social protection strategies, rather than adjuncts to them. Yet, in practice, social protection and health promotion continue to be treated as almost entirely separate spheres, thus presenting substantial institutional barriers to developing combined interventions.
Imperial Origins of European Integration and the Case of Eurafrica: A Reply to Gary Marks’‘Europe and Its Empires’*
Authors: HANSEN PEO , JONSSON STEFAN
Published: October 2012

This article offers a critique of Gary Marks’ recent article in JCMS, entitled ‘Europe and Its Empires: From Rome to the European Union’. Although it sympathizes with Marks’ invocation of empire as a key theoretical concept and historical category in the study of European integration, it fundamentally disagrees with his ‘continentalist’ operationalization. Marks chooses to discuss the nexus of empire and European integration exclusively with reference to historical processes of imperial expansion and community formation occurring on the western European land mass. Since this methodology leaves out Europe's maritime colonial empires, it cannot account for the mutually conditioning relations between the intra‐ and extra‐European imperial processes. Consequently, Marks also fails to register colonialism's decisive bearing on post‐war European integration, and thus the fact that the scale of the original EEC was not delimited by the European land mass, but corresponded to the geopolitical constellation that at the time was called Eurafrica.
Negotiating the European External Action Service (EEAS): Analyzing the External Effects of Internal (Dis)Agreement*
Authors: MURDOCH ZUZANA
Published: October 2012

Analyses of the rising capacity for co‐ordination within the Secretariats‐General of the European Commission and Council have concentrated on their effectswithinthese respective institutions. This article, in contrast, argues that the presence/absence of co‐ordination capacities developedwithinan institution may have an important bearing also on the relationsbetweeninstitutions (for example, in inter‐institutional negotiations). The empirical analysis traces the negotiation process leading up to the creation of the European External Action Service (EEAS), and finds substantial support for the theoretical argument.