bluuebunny/crossref_metadata_2025 huggingface dataset:
Maintenance therapy with bacillus Calmette‐Guérin Connaught strain clearly prolongs recurrence‐free survival following transurethral resection of bladder tumour for non‐muscle‐invasive bladder cancer
Authors: Hinotsu Shiro , Akaza Hideyuki , Naito Seiji , Ozono Seiichiro , Sumiyoshi Yoshiteru , Noguchi Sumio , Yamaguchi Akito , Nagamori Satoshi , Terai Akito , Nasu Yasutomo , Kume Haruki , Tomita Yoshihiko , Tanaka Yoshinori , Samma Shoji , Uemura Hirotsugu , Koga Hirofumi , Tsushima Tomoyasu
Published: December 2010

Study Type – Therapy (RCT)

Level of Evidence 1b

OBJECTIVE

To confirm the recurrence‐preventing efficacy and safety of 18‐month bacillus Calmette‐Guérin (BCG) maintenance therapy for non‐muscle‐invasive bladder cancer.

PATIENTS AND METHODS

The enrolled patients had been diagnosed with recurrent or multiple non‐muscle‐invasive bladder cancer (stage Ta or T1) after complete transurethral resection of bladder tumours (TURBT).

The patients were randomized into three treatment groups: a maintenance group (BCG, 81 mg, intravesically instilled once weekly for 6 weeks as induction therapy, followed by three once‐weekly instillations at 3, 6, 12 and 18 months after initiation of the induction therapy), a non‐maintenance group (BCG, 81 mg, intravesically instilled once weekly for 6 weeks) and an epirubicin group (epirubicin, 40 mg, intravesically instilled nine times). The primary endpoint was recurrence‐free survival (RFS).

RESULTS

Efficacy analysis was performed for 115 of the full‐analysis‐set population of 116 eligible patients, including 41 maintenance group patients, 42 non‐maintenance group patients and 32 epirubicin group patients.

At the 2‐year median point of the overall actual follow‐up period, the final cumulative RFS rates in the maintenance, non‐maintenance and epirubicin groups were 84.6%, 65.4% and 27.7%, respectively.

The RFS following TURBT was significantly prolonged in the maintenance group compared with the non‐maintenance group (generalized Wilcoxon test, P= 0.0190).

CONCLUSION

BCG maintenance therapy significantly prolonged the post‐TURBT RFS compared with BCG induction therapy alone or epirubicin intravesical therapy.
Does the presence of muscularis propria on transurethral resection of bladder tumour specimens affect the rate of upstaging in cT1 bladder cancer?
Authors: Badalato Gina , Patel Trushar , Hruby Gregory , McKiernan James
Published: December 2010

Study Type – Therapy (case series)

Level of Evidence 4

What’s known on the subject? and What does the study add?

It is already known and accepted that the presence of mucularis propria (MP) on bladder biopsy is incremental to the clinical staging process for this disease entity. This study establishes that the lack of MP also portends a higher risk of pathologic upstaging at the time of radical cystectomy.

OBJECTIVE

To determine how the presence of MP on T1 biopsy specimens affects the outcome of patients undergoing RC as compared to when no MP is identified in the TURBT specimen.

PATIENTS AND METHODS

Patients were retrospectively identified from the Columbia University Urologic Oncology Database.

From January 1986 to October 2009, 114 patients diagnosed with cT1N0M0 bladder cancer who underwent RC within 4 months of their last biopsy were identified.

Patients were stratified based on the presence of MP on T1 biopsy, and upstaging was defined as any tumor T2 or greater, N+, or M+ at the time of radical cystectomy.

The rate of upstaging was assessed using univariate and multivariate regression models; Kaplan meier curves were also extrapolated for each cohort to compare disease specific and overall survival patterns.

RESULTS

Of the 114 patients evaluated in this study, 24 (20.2%) did not have MP on their T1 biopsy before RC. The rate of upstaging (>=pT2) stratified by the presence of MP on biopsy was 50% and 78%, respectively (p = 0.017).

On univariate analysis, lack of MP on biopsy was associated with an increased risk of upstaging (HR 3.52, p = 0.021, CI 1.2–10.3), however did not reach significance as an independent predictor (HR 2.9, p = 0.056, CI 0.97–8.9).

At a mean follow‐up of 33.5 months, there was no difference in disease specific (p = 0.41) and overall survival (p = 0.68) between groups.

CONCLUSIONS

The lack of MP on TURBT for high grade cT1N0M0 bladder cancer portends a high likelihood of upstaging at RC, although this risk did not translate into a detectable increased risk of disease specific mortality.
Magnetic resonance imaging does not improve the prediction of misclassification of prostate cancer patients eligible for active surveillance when the most stringent selection criteria are based on the saturation biopsy scheme
Authors: Ploussard Guillaume , Xylinas Evanguelos , Durand Xavier , Ouzaïd Idir , Allory Yves , Bouanane Mohamed , Abbou Claude‐Clément , Salomon Laurent , de la Taille Alexandre
Published: December 2010

Study Type – Diagnostic (case series)

Level of Evidence 4

OBJECTIVE

To investigate the role of magnetic resonance imaging (MRI) in selecting patients for active surveillance (AS).

PATIENTS AND METHODS

We identified prostate cancers patients who had undergone a 21‐core biopsy scheme and fulfilled the criteria as follows: prostate‐specific antigen (PSA) level ≤10 ng/mL, T1–T2a disease, a Gleason score ≤6, <3 positive cores and tumour length per core <3 mm.

We included 96 patients who underwent a radical prostatectomy (RP) and a prostate MRI before surgery.

The main end point of the study was the unfavourable disease features at RP, with or without the use of MRI as AS inclusion criterion.

RESULTS

Mean age and mean PSA were 62.4 years and 6.1 ng/mL, respectively. Prostate cancer was staged pT3 in 17.7% of cases.

The rate of unfavourable disease (pT3–4 and/or Gleason score ≥4 + 3) was 24.0%. A T3 disease on MRI was noted in 28 men (29.2%).

MRI was not a significant predictor of pT3 disease in RP specimens (P = 0.980), rate of unfavourable disease (P = 0.604), positive surgical margins (P = 0.750) or Gleason upgrading (P = 0.314).

In a logistic regression model, no preoperative parameter was an independent predictor of unfavourable disease in the RP specimen.

After a mean follow‐up of 29 months, the recurrence‐free survival (RFS) was statistically equivalent between men with T3 on MRI and those with T1–T2 disease (P = 0.853).

CONCLUSION

The results of the present study emphasize that, when the selection of patients for AS is based on an extended 21‐core biopsy scheme, and uses the most stringent inclusion criteria, MRI does not improve the prediction of high‐risk and/or non organ‐confined disease in a RP specimen.
Impact of personalized cardiovascular disease risk estimates on physical activity—a randomized controlled trial
Authors: Price H. C. , Griffin S. J. , Holman R. R.
Published: December 2010

Diabet. Med. 28, 363–372 (2011)

Aim  Informing a person of their individual risk of developing a disease in the future may be sufficient to provide the person with the impetus to adopt risk reducing behaviours. The aim of this study was to determine if a personalised 10‐year cardiovascular disease (CVD) risk estimate can increase physical activity and other risk reduction behaviours in adults at high risk of CVD.

Methods  Pilot 2 × 2 factorial randomised controlled trial conducted in Oxfordshire, UK including 194 adults at increased CVD risk (10‐year CVD risk ≥20%) recruited from four general practices. Main outcome measure at one month was physical activity measured by accelerometer.

Results  Median (IQR) age was 62.3 (54.9, 66.1) years, 67% were men and 19% had known diabetes. Mean (SD) total accelerometer counts per day was 297 × 10−3 (110 × 10−3) and activity of moderate or greater intensity was undertaken for 53 (22) minutes per day.

In the 185 (95%) participants attending follow‐up an increase in physical activity was not seen. There was a non‐significant 0.5% (p = 0.56) greater increase in accelerometer counts in those receiving personalised CVD risk estimates. No significant within or between group changes were seen at one month in estimated 10‐year CVD risk. A net 7% decrease in mean LDL cholesterol (p = 0.004) was seen in the intervention group despite similar increases in new prescriptions for lipid lowering therapies.

Conclusion  In adults at increased risk of CVD provision of personalised 10‐year CVD risk estimates did not appear to increase physical activity or estimated CVD risk over a one‐month period.
Reference values for the Chinese population of skin autofluorescence as a marker of advanced glycation end products accumulated in tissue
Authors: Yue X. , Hu H. , Koetsier M. , Graaff R. , Han C.
Published: December 2010

Diabet. Med. 28, 818–823 (2011)

Aim  Advanced glycation end products play an important role in the pathophysiology of several chronic and age‐related diseases, especially diabetes mellitus. Skin autofluorescence is a non‐invasive method for assessing levels of tissue advanced glycation end products. This study aims to establish the normal reference value of advanced glycation end products accumulated in tissue measured by the advanced glycation end product reader—skin autofluorescence—and discusses some factors influencing it.

Methods  The values of autofluorescence in healthy individuals in China were determined by the advanced glycation end product reader; age, gender, skin reflectance, smoking habits and alcohol consumption of the subjects were also recorded.

Results  The mean reference values of autofluorescence in healthy Chinese subjects are (95% confidence interval) 20–29 years: 1.54–1.62 arbitrary units; 30–39 years: 1.66–1.75; 40–49 years: 1.78–1.89; 50–59 years: 1.87–2.03; 60–69 years: 1.86–2.09; 70–79 years: 1.97–2.31. The value of autofluorescence is strongly related to age, but no significant difference between males and females were found (all P > 0.05). Autofluorescence was higher in smokers than in non‐smokers (P < 0.05). In persons with low skin reflectance (< 10%), skin autofluorescence was dependent on skin colour, but was still related to age.

Conclusions  The mean reference values of autofluorescence we established could be used for a Chinese population in a clinical setting and are agreement with those in a Caucasian population. Future developments are needed to make the advanced glycation end product reader reliable for lower skin reflections as well, independently of the skin colour.
Controversy in innovation outsourcing research: review, synthesis and future directions
Authors: Stanko Michael A. , Calantone Roger J.
Published: December 2010

There is a growing stream of research into the outsourcing of innovation activities within the innovation, management, marketing and economics disciplines. Understandably, this coincides with the practice becoming more commonplace in industry. Here, we attempt to synthesize research surrounding the question of whether to outsource or internalize innovation activities and the performance implications of this decision. Support for both transaction cost and resource‐based arguments is examined, with both theory bases showing substantial attention from both case‐based and empirical research. As innovation outsourcing research has progressed, several controversies have emerged in the literature and remain unresolved. For instance, case‐based research provides evidence that outsourcing innovation activities can lead to faster product development and cost savings; yet, empirical research shows that outsourcing may lead to higher costs and slower new product development. Further, the role of technological uncertainty may have two distinct and conflicting impacts on the outsourcing decision that are not yet well understood. Thus, we present an integrated, timely review of innovation outsourcing research and identify several areas that necessitate future research projects.
How do innovation intermediaries add value? Insight from new product development in fashion markets
Authors: Tran Yen , Hsuan Juliana , Mahnke Volker
Published: December 2010

Innovation intermediaries are increasingly being used in practice, but there is little concrete theoretical guidance on when and how they add value to client's new product development (NPD) processes. This paper develops propositions on innovation intermediaries value‐added based on a detailed case study of an innovation intermediary's relations to three major clients in the European apparel fashion industry. We identify key contingencies to an innovation intermediary's value added (e.g. NDP speed and complexity of involvement). We also suggest a framework that specifies when a combination of four types of specific intermediary capabilities (best‐cost capabilities, timing‐capabilities, market‐response capabilities, and product solution capabilities) increases value added in clients' NDP processes.
The limits of design and engineering outsourcing: performance integration and the unfulfilled promises of modularity
Authors: Zirpoli Francesco , Becker Markus C.
Published: December 2010

Outsourcing design and engineering tasks in product development is increasingly popular. However, firms that outsource design and engineering tasks often experience problems. So far, no satisfactory answer exists regarding the question to what extent design and engineering tasks can be outsourced before negative consequences occur. We address this gap. This paper identifies the limits of design and engineering outsourcing in product development, and the sources of these limits. To do so, it investigates the organizational challenges that a major European automotive manufacturer faced when it decided to adopt an extreme form of design and engineering outsourcing. Based on an in‐depth case study, we identify the sources of problems with outsourcing design and engineering tasks in product development, and shed light on the limits of design and engineering outsourcing in product development.
Inference for Lévy‐Driven Stochastic Volatility Models via Adaptive Sequential Monte Carlo
Authors: JASRA AJAY , STEPHENS DAVID A. , DOUCET ARNAUD , TSAGARIS THEODOROS
Published: December 2010

Abstract. We investigate simulation methodology for Bayesian inference in Lévy‐driven stochastic volatility (SV) models. Typically, Bayesian inference from such models is performed using Markov chain Monte Carlo (MCMC); this is often a challenging task. Sequential Monte Carlo (SMC) samplers are methods that can improve over MCMC; however, there are many user‐set parameters to specify. We develop a fully automated SMC algorithm, which substantially improves over the standard MCMC methods in the literature. To illustrate our methodology, we look at a model comprised of a Heston model with an independent, additive, variance gamma process in the returns equation. The driving gamma process can capture the stylized behaviour of many financial time series and a discretized version, fit in a Bayesian manner, has been found to be very useful for modelling equity data. We demonstrate that it is possible to draw exact inference, in the sense of no time‐discretization error, from the Bayesian SV model.
Endogenous Selection of Comparison Groups, Human Capital Formation, and Tax Policy
Authors: STARK ODED , HYLL WALTER , WANG YONG
Published: December 2010

We consider a setting in which the acquisition of human capital entails a change of location in social space that causes individuals to revise their comparison groups. Skill levels are viewed as occupational groups. Moving up the skill ladder by acquiring additional human capital, in itself rewarding, leads to a shift in the individual's inclination to compare himself with a different, and on average better‐paid, comparison group, in itself penalizing. We shed new light on the dynamics of human capital formation, and suggest novel policy interventions to encourage human capital formation in the aggregate and reduce inter‐group income inequality.
Financial Market Liquidity and the Financial Crisis: An Assessment Using UK Data*
Authors: Martin Christopher , Milas Costas
Published: December 2010

A steady increase in financial market liquidity followed by a rapid reduction played a central role in the financial crisis that began in 2007. We present empirical evidence that the marked rise in liquidity in 2001–07 was due to large and persistent current account deficits and loose monetary policy.
Acceleration of keratinocyte differentiation by transient receptor potential vanilloid (TRPV6) channel activation
Authors: Lehen’kyi V , Vandenberghe M , Belaubre F , Julié S , Castex‐Rizzi N , Skryma R , Prevarskaya N
Published: December 2010

Background  Numerous studies have demonstrated the beneficial effect of Avène Thermal Spring Water (TSW) in dermatological diseases but the molecular mechanisms remain unknown. The objective of the present study was to evaluate the effect of Avène TSW on the morphological and molecular features related to the more advanced status of differentiation of human keratinocytes.

Material and Methods Normal human keratinocytes (NHK) were differentiated in medium powder reconstituted with Avène TSW and assessed by RT‐PCR and immunohistochemistry. Calcium entry was measured by a Fura‐2 AM probe. TRPV6 channel were detected by immunohistochemistry, RT‐PCR and western blot.

Results  Treatment of NHK with Avène TSW led to an enhanced constitutive calcium entry that resulted in the increased expression of involucrin and cytokeratins 1 and 10. This enhanced constitutive calcium entry in Avène TSW‐treated keratinocytes was mediated by the TRPV6 calcium channel. Moreover, Avène TSW‐mediated calcium entry was due to the increase in TRPV6 expression as well as the channel abundance at the cell membrane.

Conclusions  An other mechanism of action of Avène TSW is described. Avène TSW treatment induced an enhanced constitutive calcium entry mediated by TRPV6 channel leading to the acceleration of human keratinocytes differentiation.
Pimecrolimus 1% cream for oral erosive lichen planus: a 6‐week randomized, double‐blind, vehicle‐controlled study with a 6‐week open‐label extension to assess efficacy and safety
Authors: McCaughey C. , Machan M. , Bennett R. , Zone J.J. , Hull C.M.
Published: December 2010

Objective  To assess the efficacy and safety of topical pimecrolimus 1% cream in the treatment of oral erosive lichen planus.

Design  A 6‐week randomized, double‐blind, vehicle‐controlled phase followed by a 6‐week open‐label phase.

Setting  Outpatients of the Department of Dermatology, University of Utah.

Patients  Twenty‐one patients with oral erosive lichen planus were randomized and treated with either pimecrolimus 1% cream or vehicle cream.

Intervention  Pimecrolimus 1% cream, or its vehicle, were applied twice daily for 6 weeks to each side of the mouth with a 2 × 2 inch gauze pad folded in half and placed directly on the erosive lesion.

Main Outcome Measures  Efficacy was based on clinical evaluation of Investigator’s Global Assessment (IGA) of the overall severity of the disease, erythema, measurement of the size of any target erosion in millimetres, and assessment of spontaneous pain. Blood levels of pimecrolimus were monitored in all subjects on day 0 and repeated on day 7.

Results  Pimecrolimus 1% cream was superior to vehicle cream in reducing mean IGA, pain, and erosion size. For the vehicle group that entered the open‐label phase, pimecrolimus 1% cream improved the mean IGA, pain, erosion size, and erythema. Pimecrolimus levels were detected in nine out of 10 of the pimecrolimus‐treated subjects. These levels were consistently low. The pimecrolimus cream was well‐tolerated. No clinically relevant, drug‐related adverse events were reported.

Conclusion  Pimecrolimus 1% cream was superior to vehicle in reducing pain, erythema, decreasing erosion size, and improving overall severity of disease when compared with vehicle treatment.
Approach and withdrawal actions modulate the startle reflex independent of affective valence and muscular effort
Authors: Thibodeau Ryan
Published: December 2010

The startle reflex is modulated during processing of pleasant and unpleasant affective cues. One explanation of this finding contends that approach and withdrawal motivational processes are key to explaining the effect. Undergraduates performed arm flexion and arm extension actions shown elsewhere to reliably elicit approach and withdrawal motives, respectively. Results showed that arm extension (a withdrawal action) was associated with the largest startles, followed by a neutral control action and arm flexion (an approach action). This pattern was not attributable to the subjective pleasantness or muscular effort associated with the actions. Results support motivational priming accounts of startle reflex modulation.
Abnormal exocytotic release of glutamate in a mouse model of amyotrophic lateral sclerosis
Authors: Milanese Marco , Zappettini Simona , Onofri Franco , Musazzi Laura , Tardito Daniela , Bonifacino Tiziana , Messa Mirko , Racagni Giorgio , Usai Cesare , Benfenati Fabio , Popoli Maurizio , Bonanno Giambattista
Published: December 2010

J. Neurochem. (2011) 116, 1028–1042.

Glutamate‐mediated excitotoxicity plays a major role in the degeneration of motor neurons in amyotrophic lateral sclerosis and reduced astrocytary glutamate transport, which in turn increases the synaptic availability of the amino acid neurotransmitter, was suggested as a cause. Alternatively, here we report our studies on the exocytotic release of glutamate as a possible source of excessive glutamate transmission. The basal glutamate efflux from spinal cord nerve terminals of mice‐expressing human soluble superoxide dismutase (SOD1) with the G93A mutation [SOD1/G93A(+)], a transgenic model of amyotrophic lateral sclerosis, was elevated when compared with transgenic mice expressing the wild‐type human SOD1 or to non‐transgenic controls. Exposure to 15 mM KCl or 0.3 μM ionomycin provoked Ca2+‐dependent glutamate release that was dramatically increased in late symptomatic and in pre‐symptomatic SOD1/G93A(+) mice. Increased Ca2+levels were detected in SOD1/G93A(+) mouse spinal cord nerve terminals, accompanied by increased activation of Ca2+/calmodulin‐dependent kinase II and increased phosphorylation of synapsin I. In line with these findings, release experiments suggested that the glutamate release augmentation involves the readily releasable pool of vesicles and a greater capability of these vesicles to fuse upon stimulation in SOD1/G93A(+) mice.
Motivation for lifestyle changes to improve health in people with impaired glucose tolerance
Authors: Hansen Elisabeth , Landstad Bodil J. , Hellzén Ove , Svebak Sven
Published: December 2010

Scand J Caring Sci; 2011; 25; 484–490
 
Motivation for lifestyle changes to improve health in people with impaired glucose tolerance

Aim:  To identify factors that could have motivational significance for lifestyle change to facilitate the reduction of Impaired Glucose Tolerance (IGT) and, consequently, the risk of having type 2 diabetes.

Methods:  Eighteen people living in a municipality in central Norway participated in the study. A large‐scale public health screening study had defined them as people with IGT. The participants took part in a semi‐structured interview that focused on four aspects of everyday lifestyle: (1) structure and rhythm, (2) physical health, (3) physical activity and (4) social relations.

Results:  The interviews showed that the participants in the study changed their priorities regarding daily living. Results indicated four domains of motivational factors that appeared as significant for lifestyle changes. The participants attributed great significance to their physical health and were strongly motivated to prevent disease development by improvement of everyday structure and rhythm, reduction of sickness risk, activity level and social relation. Research indicates, however, that lasting lifestyle changes take time and that health care support must be adapted to the individual in light of their social setting.

Conclusion:  Persons with IGT appear to benefit from lifestyle changes along four dimensions of motivational significance: Structure and rhythm, Sickness concerns, Activity levels, Social relations. This means that attention needs to be more carefully tailored the individual along these four dimensions than has been the case in traditional health care.
Feather ornaments are dynamic traits in the Great Tit Parus major
Authors: ADAMÍK PETER , VAŇÁKOVÁ MARKÉTA
Published: December 2010

In behavioural studies it has been common to quantify plumage colours or ornaments over a range of dates and link them to fitness characteristics without accounting for seasonal changes in these traits. Such changes are likely to be widespread among birds, yet we lack assessments of this variability within individuals. We studied both within‐ and between‐individual temporal changes in Great Tit Parus major ornaments, specifically the melanin‐based black breast stripe and the pigment‐free white cheek patch. During the non‐breeding season both ornaments varied. In juveniles and adult females, the area of the breast stripe first rose and then, from near the end of December, decreased. In adult males there was a linear decrease. In the cheek patch, the irregularity of the cheek borders showed either a linear (adults) or a non‐linear (juveniles) increase as the season progressed. In individuals repeatedly sampled during the same winter, the decrease in the size of the breast stripe was larger for males than females and there was an overall decrease in the regularity of the cheek borders. There was no relationship between the size of the breast stripe and the white cheek patch irregularities or the cheek patch area. These results imply that more attention should be paid to quantification, within individuals, of the components of expression of phenotypic traits. In addition, we suggest that further research should focus on explaining the causes and functions of ornament change.
Resistance of skin fibroblasts to peroxide and UV damage predicts hearing loss in aging mice
Authors: Miller Richard A. , Dolan David , Han Melissa , Kohler William , Schacht Jochen
Published: December 2010

Those mice whose skin‐derived primary fibroblast cell lines resist lethal injury induced by hydrogen peroxide or UV light show lower age‐related decline in hearing. Skin cell lines may provide an easily accessible surrogate index of intrinsic stress resistance that varies among individuals and influences the pace of neurosensory decline in aging mice.
Sexual media use and relational satisfaction in heterosexual couples
Authors: BRIDGES ANA J. , MOROKOFF PATRICIA J.
Published: December 2010

This study assessed how sexual media use by one or both members of a romantic dyad relates to relationship and sexual satisfaction. A total of 217 heterosexual couples completed an Internet survey that assessed sexual media use, relationship and sexual satisfaction, and demographic variables. Results revealed that a higher frequency of men's sexual media use related to negative satisfaction in men, while a higher frequency of women's sexual media use related to positive satisfaction in male partners. Reasons for sexual media use differed by gender: Men reported primarily using sexual media for masturbation, while women reported primarily using sexual media as part of lovemaking with their partners. Shared sexual media use was associated with higher relational satisfaction compared to solitary sexual media use.
Trapping and dissociation of propafenone derivatives in HERG channels
Authors: Windisch A , Timin EN , Schwarz T , Stork‐Riedler D , Erker T , Ecker GF , Hering S
Published: December 2010

BACKGROUND AND PURPOSEHumanether‐a‐go‐gorelated gene (HERG) channel inhibitors may be subdivided into compounds that are trapped in the closed channel conformation and others that dissociate at rest. The structural peculiarities promoting resting state dissociation from HERG channels are currently unknown. A small molecule‐like propafenone is efficiently trapped in the closed HERG channel conformation. The aim of this study was to identify structural moieties that would promote dissociation of propafenone derivatives.

EXPERIMENTAL APPROACHHumanether‐a‐go‐gorelated gene channels were heterologously expressed in Xenopus oocytes and potassium currents were recorded using the two‐microelectrode voltage clamp technique. Recovery from block by 10 propafenone derivatives with variable side chains, but a conserved putative pharmacophore, was analysed.

KEY RESULTSWe have identified structural determinants of propafenone derivatives that enable drug dissociation from the closed channel state. Propafenone and four derivatives with ‘short’ side chains were trapped in the closed channel. Five out of six bulky derivatives efficiently dissociated from the channel at rest. One propafenone derivative with a similar bulk but lacking an H‐bond acceptor in this region was trapped. Correlations were observed between molecular weight and onset of channel block as well as between pKaand recovery at rest.

CONCLUSION AND IMPLICATIONSThe data show that extending the size of a trapped HERG blocker‐like propafenone by adding a bulky side chain may impede channel closure and thereby facilitate drug dissociation at rest. The presence of an H‐bond acceptor in the bulky side chain is, however, essential.
Animal modelling of traumatic brain injury in preclinical drug development: where do we go from here?
Authors: Marklund Niklas , Hillered Lars
Published: December 2010

Traumatic brain injury (TBI) is the leading cause of death and disability in young adults. Survivors of TBI frequently suffer from long‐term personality changes and deficits in cognitive and motor performance, urgently calling for novel pharmacological treatment options. To date, all clinical trials evaluating neuroprotective compounds have failed in demonstrating clinical efficacy in cohorts of severely injured TBI patients. The purpose of the present review is to describe the utility of animal models of TBI for preclinical evaluation of pharmacological compounds. No single animal model can adequately mimic all aspects of human TBI owing to the heterogeneity of clinical TBI. To successfully develop compounds for clinical TBI, a thorough evaluation in several TBI models and injury severities is crucial. Additionally, brain pharmacokinetics and the time window must be carefully evaluated. Although the search for a single‐compound, ‘silver bullet’ therapy is ongoing, a combination of drugs targeting various aspects of neuroprotection, neuroinflammation and regeneration may be needed. In summary, finding drugs and prove clinical efficacy in TBI is a major challenge ahead for the research community and the drug industry. For a successful translation of basic science knowledge to the clinic to occur we believe that a further refinement of animal models and functional outcome methods is important. In the clinical setting, improved patient classification, more homogenous patient cohorts in clinical trials, standardized treatment strategies, improved central nervous system drug delivery systems and monitoring of target drug levels and drug effects is warranted.

LINKED ARTICLESThis article is part of a themed issue on Translational Neuropharmacology. To view the other articles in this issue visithttp://dx.doi.org/10.1111/bph.2011.164.issue‐4
Role of angiotensin II receptor subtype activation in cognitive function and ischaemic brain damage
Authors: Horiuchi Masatsugu , Mogi Masaki
Published: December 2010

Recent clinical studies have demonstrated that angiotensin II type 1 (AT1) receptor blockers (ARBs) reduce the onset of stroke, stroke severity and the incidence and progression of Alzheimer's disease and dementia. We can expect that ARBs exert these effects by both AT1receptor blockade and angiotensin II type 2 (AT2) receptor stimulation. Moreover, recent experimental results support the notion that AT2receptor stimulation with AT1receptor blockade could contribute to protection against ischaemic brain damage at least partly due to an increase in cerebral blood flow and decrease in oxidative stress, and prevent cognitive decline. Cellular therapy has been focused on as a new therapeutic approach to restore injured neurons. In this context, it has been reported that AT2receptor stimulation enhances neurite outgrowth and decreases neural damage, thereby enhancing neurogenesis. Moreover, additional beneficial effects of ARBs with an AT1receptor blocking action with a partial peroxisome proliferator‐activated receptor (PPAR)‐γ agonistic effect have been reported, and interaction of AT2receptor activation and PPAR‐γ might be involved in these ARBs' effects. This article reviews the effects of regulation of activation of angiotensin II receptor subtypes on ischaemic brain damage and cognitive function, focusing on the effects of AT2receptor stimulation.

LINKED ARTICLESThis article is one of a set of reviews submitted toBJPin connection with talks given at the September 2010 meeting of the International Society of Hypertension in Vancouver, Canada. To view the other articles in this collection visithttp://dx.doi.org/10.1111/j.1476‐5381.2011.01235.x,http://dx.doi.org/10.1111/j.1476‐5381.2011.01260.xandhttp://dx.doi.org/10.1111/j.1476‐5381.2011.01366.x
Ca2+entry following P2X receptor activation induces IP3receptor‐mediated Ca2+release in myocytes from small renal arteries
Authors: Povstyan Oleksandr V , Harhun Maksym I , Gordienko Dmitri V
Published: December 2010

BACKGROUND AND PURPOSEP2X receptors mediate sympathetic control and autoregulation of the renal circulation triggering contraction of renal vascular smooth muscle cells (RVSMCs) via an elevation of intracellular Ca2+concentration ([Ca2+]i). Although it is well‐appreciated that the myocyte Ca2+signalling system is composed of microdomains, little is known about the structure of the [Ca2+]iresponses induced by P2X receptor stimulation in vascular myocytes.

EXPERIMENTAL APPROACHESUsing confocal microscopy, perforated‐patch electrical recordings, immuno‐/organelle‐specific staining, flash photolysis and RT‐PCR analysis we explored, at the subcellular level, the Ca2+signalling system engaged in RVSMCs on stimulation of P2X receptors with the selective agonistαβ‐methylene ATP (αβ‐meATP).

KEY RESULTSRT‐PCR analysis of single RVSMCs showed the presence of genes encoding inositol 1,4,5‐trisphosphate receptor type 1(IP3R1) and ryanodine receptor type 2 (RyR2). The amplitude of the [Ca2+]itransients depended onαβ‐meATP concentration. Depolarization induced by 10 µmol·L−1αβ‐meATP triggered an abrupt Ca2+release from sub‐plasmalemmal (‘junctional’) sarcoplasmic reticulum enriched with IP3Rs but poor in RyRs. Depletion of calcium stores, block of voltage‐gated Ca2+channels (VGCCs) or IP3Rs suppressed the sub‐plasmalemmal [Ca2+]iupstroke significantly more than block of RyRs. The effect of calcium store depletion or IP3R inhibition on the sub‐plasmalemmal [Ca2+]iupstroke was attenuated following block of VGCCs.

CONCLUSIONS AND IMPLICATIONSDepolarization of RVSMCs following P2X receptor activation induces IP3R‐mediated Ca2+release from sub‐plasmalemmal (‘junctional’) sarcoplasmic reticulum, which is activated mainly by Ca2+influx through VGCCs. This mechanism provides convergence of signalling pathways engaged in electromechanical and pharmacomechanical coupling in renal vascular myocytes.
Geranylated flavanone tomentodiplacone B inhibits proliferation of human monocytic leukaemia (THP‐1) cells
Authors: Kollár Peter , Bárta Tomáš , Závalová Veronika , Šmejkal Karel , Hampl Aleš
Published: December 2010

BACKGROUND AND PURPOSE

Paulownia tomentosa is a rich source of geranylated flavanones, some of which we have previously shown to have cytotoxic activity. To identify members of this class of compounds with cytostatic effects, we assessed the effects of the geranylated flavanone tomentodiplacone B (TOM B) on cell cycle progression and cell cycle regulatory pathways of THP‐1 human monocytic leukaemia cells.

EXPERIMENTAL APPROACH

Cell viability was measured by dye exclusion and proliferation by WST‐1 assays; cell cycle was monitored by flow cytometry. Regulatory proteins were assessed by immunoprecipitation and kinase assays, and Western blotting.

KEY RESULTS

Tomentodiplacone B had no effect during the first 24 h of cell growth at concentrations between 1 and 2.5 µM, but inhibited cell growth in a dose‐dependent manner at concentrations of 5 µM or higher. Growth inhibition during the first 24 h of exposure to TOM B was not accompanied by cytotoxicity as cells were accumulated in G1 phase dose‐dependently. This G1 phase accumulation was associated with down‐regulation of cyclin‐dependent kinase 2 activity and also protein levels of cyclins E1 and A2. However, key stress‐related molecules (γ‐H2AX, p53 and p21) were not induced, suggesting that TOM B acts by directly inhibiting the cyclin‐dependent kinase 2 signalling pathway rather than initiating DNA damage or cellular stress.

CONCLUSIONS AND IMPLICATIONS

Our study provides the first evidence that TOM B directly inhibits proliferation of human monocytic leukaemia cells, and thus is a potential anticancer agent, preventing leukaemia cells from progressing from G1 phase into DNA synthesis.
New perspectives regarding β2‐adrenoceptor ligands in the treatment of asthma
Authors: Walker JKL , Penn RB , Hanania NA , Dickey BF , Bond RA
Published: December 2010

In the last two decades several significant changes have been proposed in the receptor theory that describes how ligands can interact with G protein‐coupled receptors (GPCRs). Here we briefly summarize the evolution of receptor theory and detail recent prominent advances. These include: (i) the existence of spontaneously active GPCRs that are capable of signalling even though they are unoccupied by any ligand; (ii) the discovery of ligands that can inactivate these spontaneously active receptors; (iii) the notion that a ligand may simultaneously activate more than one GPCR signalling pathway; and (iv) the notion that certain ligands may be able to preferentially direct receptor signalling to a specific pathway. Because the data supporting these receptor theory ideas are derived primarily from studies using artificial expression systems, the physiological relevance of these new paradigms remains in question. As a potential example of how these new perspectives in receptor theory relate to drug actions and clinical outcomes, we discuss their relevance to the recent controversy regarding the chronic use of β2‐adrenoceptor agonists in the treatment of asthma.

LINKED ARTICLESThis article is part of a themed issue on Respiratory Pharmacology. To view the other articles in this issue visithttp://dx.doi.org/10.1111/bph.2011.163.issue‐1
Minerals in Dialysis Therapy: An Introduction
Authors: Weisberg Lawrence S. , Zanger Ron
Published: December 2010

The 180 l of glomerular filtrate formed each day contain some 1100 g (2.5 pounds) of sodium chloride, of which only 5–10 g are excreted in the urine – 95% is reabsorbed by the tubules. Some 425 g (nearly a pound) of sodium bicarbonate and 145 g of glucose are filtered, and more than 99% of both are reabsorbed. Also filtered, only to be reabsorbed, are substantial quantities of potassium, calcium, magnesium, phosphate, sulfate, amino acids, vitamins, and many other substances valuable to the body.

It is no exaggeration to say that the composition of the blood is determined not by what the mouth takes in but by what the kidneys keep: they are the master chemists of our internal environment, which, so to speak, they manufacture in reverse by working it over completely some fifteen times a day…Our bones, muscles, glands, even our brains are called upon to do only one kind of physiological work, but our kidneys are called upon to perform an innumerable variety of operations. Bones can break, muscles can atrophy, glands can loaf, even the brain can go to sleep, without immediately endangering our survival; but should the kidneys fail to manufacture the proper kind of blood neither bone, muscle, gland nor brain could carry on (1).
Thrombectomy of Arteriovenous Dialysis Grafts with Early Failure: Is it Worthwhile?
Authors: Mudunuri Vijay , O’Neal Jeremy C. , Allon Michael
Published: December 2010

Arteriovenous dialysis grafts are prone to frequent thrombosis, which can be treated either percutaneously or surgically. To assess the outcomes of grafts treated for early thrombosis, we retrospectively queried a prospective, computerized database, and identified all grafts placed over a 5‐year period that required thrombectomy within 60 days of creation. Technical success was defined as the immediate restoration of graft patency. Primary patency was calculated from thrombectomy to the next intervention, and cumulative graft survival from thrombectomy to permanent graft failure. Of 709 grafts placed, 98 grafts (14%) clotted within 60 days of creation, including 63 (9%) within 30 days of graft creation, and 35 (5%) at 31–60 days after creation. Most (95%) of grafts clotting within 30 days of creation underwent surgical thrombectomy, whereas 71% of those clotting at 31–60 days underwent percutaneous thrombectomy. The immediate technical success was 82% and 80% in grafts undergoing thrombectomy at <30 vs. 31–60 days (p = 0.76). The median primary patency was 11 and 23 days (p = 0.46), and the median cumulative graft survival was 27 and 163 days, respectively (p = 0.29). In conclusion, thrombectomy within 60 days of graft creation is associated with poor primary and cumulative graft patency, and may not be worthwhile.
Safety of Low Volume Iodinated Contrast Administration for Arteriovenous Fistula Intervention in Chronic Kidney Disease Stage 4 or 5 Utilizing a Bicarbonate Prophylaxis Strategy
Authors: Eisenhart Elizabeth , Benson Scott , Lacombe Patricia , Himmelfarb Jonathan , Zimmerman Robert , Schimelman Brad , Parker Mark G.
Published: December 2010

Efforts to increase the number of functioning arteriovenous fistulas in chronic kidney disease (CKD) stages 4 and 5 have been impacted by concerns about the risk for contrast‐induced nephropathy during diagnostic and interventional procedures for poorly developed fistulas. We conducted a prospective observational study of low volume iodinated contrast administration for fistulography and angioplasty in a CKD stage 4 and stage 5 population pretreated with a sodium bicarbonate protocol. Acute kidney injury was assessed by change in serum creatinine and urinary neutrophil‐gelatinase associated lipocalcin (NGAL). Only 1/18 patients (5.5%) developed acute kidney injury as defined by change in serum creatinine 48 hours after contrast exposure. No patients demonstrated significant change in urinary NGAL at 3 or 48 hours after procedure, nor did any require acute initiation of dialysis. Fistulography alone, or with angioplasty, utilizing a low volume of iodinated contrast and sodium bicarbonate solution for prophylaxis, appears to be safe in the CKD stages 4 and 5 population.
PHYCOBILIN CONTENT OF THE CONCHOCELIS PHASE OF ALASKAN PORPHYRA (BANGIALES, RHODOPHYTA) SPECIES: RESPONSES TO ENVIRONMENTAL VARIABLES1
Authors: Lin Rulong , Stekoll Michael S.
Published: December 2010

Variations of pigment content in the microscopic conchocelis stage of four Alaskan Porphyra species were investigated in response to environmental variables. Conchocelis filaments were cultured under varying conditions of irradiance and nutrient concentrations for up to 60 d at 11°C and 30 psu salinity. Results indicate that conchocelis filaments contain relatively high concentrations of phycobilins under optimal culture conditions. Phycobilin pigment production was significantly affected by irradiance, nutrient concentration, and culture duration. For Porphyra abbottiae V. Krishnam., Porphyra sp., and Porphyra torta V. Krishnam., maximal phycoerythrin (63.2–95.1 mg · g dwt−1) and phycocyanin (28.8–64.8 mg · g dwt−1) content generally occurred at 10 μmol photons · m−2 · s−1, f/4–f/2 nutrient concentration after 10–20 d of culture. Whereas for Porphyra hiberna S. C. Lindstrom et K. M. Cole, the highest phycoerythrin (73.3 mg · g dwt−1) and phycocyanin (70.2 mg · g dwt−1) content occurred at 10 μmol photons · m−2 · s−1, f nutrient concentration after 60 d in culture. Under similar conditions, the different species showed significant differences in pigment content. P. abbottiae had higher phycoerythrin content than the other three species, and P. hiberna had the highest phycocyanin content. P. torta had the lowest phycobilin content.
DISTINGUISHING MULTIPLE LINEAGES OF PEDIASTRUM DUPLEX WITH MORPHOMETRICS AND A PROPOSAL FOR LACUNASTRUM GEN. NOV1
Authors: McManus Hilary A. , Lewis Louise A. , Schultz Eric T.
Published: December 2010

Accurately defining species boundaries in the green algae (Chlorophyta) is integral for studies of biodiversity and conservation, water‐quality assessments, and the use of particular species as paleoindicators. Recent molecular phylogenetic and SEM analyses of the family Hydrodictyaceae (Chlorophyta) resolved three phylogenetic lineages of isolates with the Pediastrum duplex Meyen 1829 phenotype. The present study employed analyses of cell shape and cell wall ultrastructure to determine if the three lineages possessing the P. duplex morphotype were distinguishable. Only one of the groups, containing isolates with the P. duplex var. gracillimum West et G. S. West phenotype, was shown to be morphologically distinct from the other two P. duplex groups. The erection of a new genus, Lacunastrum, is proposed to recognize this group as a separate taxon.
The relationship between alloimmunization and posttransfusion granulocyte survival: experience in a chronic granulomatous disease cohort
Authors: Heim K.F. , Fleisher T.A. , Stroncek D.F. , Holland S.M. , Gallin J.I. , Malech H.L. , Leitman S.F.
Published: December 2010

BACKGROUND: The efficacy of granulocyte transfusions in patients with HLA alloimmunization is uncertain. A flow cytometric assay using dihydrorhodamine 123 (DHR), a marker for cellular NADPH oxidase activity, was used to monitor the differential survival of transfused oxidase‐positive granulocytes in alloimmunized patients with chronic granulomatous disease (CGD).

STUDY DESIGN AND METHODS: Ten patients with CGD and serious infections were treated with daily granulocyte transfusions derived from steroid and granulocyte–colony‐stimulating factor–stimulated donors. The proportion of neutrophils with intact oxidase activity was quantitated by DHR fluorescence on samples drawn before and 1 hour after transfusion. The incidence of acute transfusion reactions was correlated with the results of DHR fluorescence and biweekly HLA serologic screening assays.

RESULTS: Eight of 10 patients experienced acute adverse reactions in association with granulocyte transfusions. Four had only chills and/or fever, and four experienced respiratory compromise; all eight exhibited HLA alloimmunization. Mean (±SD) oxidase‐positive cell recovery was 19.7 ± 17.4% (n = 15 transfusions) versus 0.95 ± 1.59% (n = 16) in the absence and presence of HLA allosensitization, respectively (p < 0.01). Greater than 1% in vivo recovery of DHR‐enhancing donor granulocytes was strongly correlated with lack of HLA alloimmunization.

CONCLUSION: The ability to detect DHR‐positive donor granulocytes by flow cytometry is strongly correlated with absence of HLA alloimmunization and lack of acute reactions to granulocyte transfusions in patients with CGD. If HLA antibodies are present and the survival of donor granulocytes is low by DHR analysis, transfusions should be discontinued, avoiding a therapy associated with high risk and unclear benefit.