bluuebunny/crossref_metadata_2025 huggingface dataset:
Effect of distigmine combined with propiverine on bladder activity in rats with spinal cord injury
Authors: Sugaya Kimio , Nishijima Saori , Kadekawa Katsumi , Ashitomi Katsuhiro , Yamamoto Hideyuki
Published: January 2012

It is not uncommon for patients with spinal cord injury to have both detrusor overactivity during the storage phase and detrusor underactivity during the voiding phase. However, there has been no information about the efficacy of combined treatment with cholinesterase inhibitors and anti‐muscarinic agents for this condition. Therefore, the effect of co‐administration of distigmine bromide (a cholinesterase inhibitor) and propiverine hydrochloride (an anti‐muscarinic agent) on bladder activity was examined in rats with spinal cord injury. Rats were anesthetized with isoflurane and the lower thoracic spinal cord was transected. The bladder was emptied by abdominal compression twice a day for 14 days after surgery. A total of 4 weeks after surgery, the animals were anesthetized with urethane, and the effect of intravenous injection of distigmine (0.01–1 mg/kg) followed by propiverine (1 mg/kg) on continuous cystometry parameters was examined. After injection of distigmine (0.1 and 1 mg/kg), the maximum bladder contraction pressure was significantly increased, and the duration of bladder contraction and the interval between bladder contractions were significantly prolonged. The baseline bladder pressure was not changed by injection of distigmine. After the addition of propiverine, the interval between bladder contractions was significantly further prolonged without any change of the maximum contraction pressure, baseline pressure or duration of bladder contraction. The residual volume after voiding bladder contraction was less than 0.1 mL in all animals. In conclusion, co‐administration of distigmine with propiverine might improve both bladder underactivity during the voiding phase and bladder overactivity during the storage phase.
Pregnancy rate after vasectomy reversal in a contemporary series: influence of smoking, semen quality and post‐surgical use of assisted reproductive techniques
Authors: van Dongen Joyce , Tekle Fetene B. , van Roijen J. Herman
Published: January 2012

Study Type – Outcomes (cohort series)

Level of Evidence 2b

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

Microsurgical vasectomy reversal is an effective and cost‐effective method of reinstating fertility in a man who has previously had a vasectomy. The current literature indicates that the success rate (i.e. potency and pregnancy rates) are dependent primarily on the time elapsed since vasectomy and the age of the female partner.

Using a multivariate Cox regression model, evaluation of the influence of preoperative data (including smoking) and semen parameters indicates a significant influence of post‐surgical sperm motility only, on time to first pregnancy. The use of assisted reproductive techniques, when natural pregnancy failed, was successful in ≈50% of couples who attempted this procedure and accounted for an absolute increase in pregnancy rate of 14%.

OBJECTIVE

To determine the influence of smoking, postoperative semen characteristics and the use of an assisted reproductive technique (ART) on pregnancy rate in a contemporary series of men undergoing vasectomy reversal.

PATIENTS AND METHODS

Between January 2002 and January 2009, 186 vasectomy reversals were performed. Of the 171 patients who could be contacted for follow‐up, 162 attempted pregnancy and constitute the study group.

Semen analysis was performed 3 months after the procedure and at subsequent 3‐monthly intervals.

Patient characteristics and surgical information were obtained from a computerized database, and follow‐up data were collected by telephone interview.

A multivariate Cox regression model was used to discern possible prognosticators with respect to pregnancy outcome.

RESULTS

The overall patency rate was 91.4%, with a natural pregnancy rate of 44.4% and a subsequent 14.2% of patients conceiving using a ARTs resulting in a total pregnancy rate of 58.6%. Multiple pregnancies were obtained by 20.4% of couples.

Smoking of the male or female partner did not influence the probability of conception.

In a multivariate model that included, among other factors, time since vasectomy, female age and semen characteristics, only sperm motility was significantly related to natural pregnancy outcome.

The probability of obtaining a natural pregnancy within 2 years after surgery is 53% for men with sperm motility >20% (WHO a+b) compared to 19% for men with sperm motility <5% (P= 0.003).

CONCLUSIONS

A clear and significant association between sperm motility and the probability of conception was found, whereas smoking, female age and time since vasectomy appeared to have no influence on pregnancy outcome in this patient cohort.

The use of ARTs accounted for an absolute increase in pregnancy rate of 14.2%.
Impact of pathological tumour characteristics in patients with sarcomatoid renal cell carcinoma
Authors: Shuch Brian , Bratslavsky Gennady , Shih Joanna , Vourganti Srinivas , Finley David , Castor Brandon , Treat Eric , Linehan W. Marston , Pantuck Allan J. , Said Jonathan W. , Belldegrun Arie S.
Published: January 2012

Study Type – Prognosis (case series)

Level of Evidence 4

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

Sarcomatoid renal cell carcinoma can occur in the setting of all histological subtypes of kidney cancer. These tumours are very aggressive and many patients present with disseminated disease. Long‐term survival is poor and the durable responses to systemic therapy are infrequent.

Our large cohort analyses the influence of pathological tumour characteristics in determining prognosis for patients with sarcomatoid renal cell carcinoma undergoing surgical resection. This series helps define the prognostic influence of histological subtype, type of sarcomatoid morphology, the percentage necrosis and sarcomatoid features, and the presence of microvascular invasion.

OBJECTIVES

To examine the influence of pathological tumour characteristics on survival to aid prognostication and clinical trial design.

Patients with sarcomatoid renal cell carcinoma (sRCC) are known to have poor prognosis and response to systemic therapy.

PATIENTS AND METHODS

A single‐centre database was reviewed to identify all patients with sRCC.

Clinical variables and pathological information, including histology, necrosis, percentage of sarcomatoid features (PSF) and microvascular invasion (MVI), were recorded and correlated to outcome.

RESULTS

Analyses of 104 patients with sRCC found that the median (range) size of tumours was 9.5 cm (2.5–30), 65% of patients had areas of clear cell histology, and 69.2% had metastatic disease at presentation.

The PSF did not influence tumour size, stage, necrosis, MVI, nodes or metastasis.

A total of 85 patients (81.7%) died during the follow‐up period with a median (95% confidence interval [CI]) survival of 5.9 months (4.7–8.9).

In the overall cohort, Eastern Cooperative Group performance status (ECOGPS), tumour size and metastatic disease were independent predictors of poor survival. MVI, PSF and percentage necrosis were strongly associated with outcome but were not independent predictors of outcome.

A multivariate risk model was established that incorporated six covariates (tumour size, MVI, ECOGPS, PSF, necrosis, and metastatic disease) to produce a predictive tool.

CONCLUSIONS

Both patients with localized and metastatic sRCC have very poor survival outcomes.

Pathological features MVI, PSF and necrosis are important predictors of survival and could be used in a prognostic model while grade and histology do not influence prognosis.

A prognostic model, if validated, could aid in patient counselling and/or clinical trial design.
Recreational urethral sounding is associated with high risk sexual behaviour and sexually transmitted infections
Authors: Breyer Benjamin N. , Shindel Alan W.
Published: January 2012

Study Type – Symptom prevalence (case series)

Level of Evidence 4

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

Most of the medical literature regarding recreational urethral sounding pertains to foreign body retrieval. Very little is known about men who perform sounding and do not require medical attention.

Of >2000 men, who responded to a urinary and sexual wellness survey, 10% had a history of recreational urethral sounding. Compared with men who did not sound, men who did reported higher risk sexual behaviours such as multiple sexual partners, sex with strangers and reported more sexually transmitted infections. Men who seek medical attention for complications resulting from sounding should be counselled regarding the hazards of the practice. Realistic strategies for risk reduction should be discussed with men who engage in recreational sounding.

OBJECTIVE

To determine whether men who perform recreational sounding are at increased risk of engaging in unsafe sexual behaviours, developing sexually transmitted infections (STIs) and lower urinary tract symptoms (LUTS).

SUBJECTS AND METHODS

In a cross‐sectional, international, internet‐based survey of the sexual practices of >2000 men who have sex with men, subjects were asked if they had engaged in urethral sounding for sexual gratification.

We compared ethnodemographic and health‐related variables between the sounding and non‐sounding populations. The International Prostate Symptom Score and a modified validated version of the International Index of Erectile Function were used to quantify LUTS and erectile dysfunction (ED) in both populations.

RESULTS

There were 2122 respondents with complete data, 228 (10.7%) of whom had engaged in recreational sounding.

Men who had engaged in sounding were more likely to report certain high risk sexual behaviours (e.g. multiple sexual partners and sex with partners who were not well known) and had increased odds of reporting STIs.

Men who had engaged in sounding had a slight but statistically significant increase in LUTS but no significant difference in prevalence of ED.

CONCLUSIONS

Urethral sounding is a sexual practice that is associated with higher risk sexual behaviour and carries the potential for morbidity.

Research on means for risk reduction for men who choose to engage in recreational sounding requires further study.
Interpersonal Development, Stability, and Change in Early Adulthood
Authors: Wright Aidan G. C. , Pincus Aaron L. , Lenzenweger Mark F.
Published: January 2012

The goal of this research was to explore the development of the interpersonal system mapped by the interpersonal circumplex in early adulthood (ages 18–22). This study uses the Longitudinal Study of Personality Disorders sample (N = 250; 53% female). Participants completed the Revised Interpersonal Adjective Scales (Wiggins, Trapnell, & Phillips, 1988) in their freshman, sophomore, and senior years of college. Estimates of structural, rank‐order, mean, individual, and ipsative stability were calculated for the broad interpersonal dimensions of Dominance and Affiliation and also the lower order octant scales. Additionally, the interpersonal profile parameters of differentiation and prototypicality were calculated at each wave and explored longitudinally and also used as predictors of interpersonal stability. We found excellent structural and high rank‐order and ipsative stability in the interpersonal scales over this time period. Mean increases on the Affiliation axis, but not on the Dominace axis, were found to mask differential rates of change among the octant scales, along with significant individual variation in the rates of change. Interpersonal differentiation and prototypicality were related to higher stability in overall interpersonal style. Results point to evidence of both stability and nuanced change, illuminating some of the features of the structural variables that can be derived from interpersonal circumplex profiles.
Hierarchical Integration of Agency and Communion: A Study of Influential Moral Figures
Authors: Frimer Jeremy A. , Walker Lawrence J. , Lee Brenda H. , Riches Amanda , Dunlop William L.
Published: January 2012

The purpose of this research is to (a) identify which of recent history's influential figures did and which did not personify moral excellence, and (b) to examine the motives that drove these individuals along such divergent paths. In Study 1, 102 social scientists evaluated the moral qualities of influential figures from Time Magazine's lists. In Study 2, we selected the 15 top ranking of these figures to comprise a moral exemplar group and the bottom 15 to comprise a comparison group of similarly influential people. We measured the motivational aspects of their personality (agency and communion) by content‐analyzing extant speeches and interviews. Moral exemplars exhibited the hierarchical integration of agency and communion by treating agentic motives as a means to an end of communal motives. Comparison subjects, by contrast, personified unmitigated agency by treating motives of agency as both a means to an end and an end unto itself. These results imply that both the strength and structure of a person's motives account for moral behavior.
Envy Divides the Two Faces of Narcissism
Authors: Krizan Zlatan , Johar Omesh
Published: January 2012

In this article, we test psychodynamic assumptions about envy and narcissism by examining malicious envy in the context of narcissistic grandiosity and vulnerability. In Study 1, students (N = 192) and community adults (N = 161) completed trait measures of narcissism, envy, and schadenfreude. In Study 2 (N = 121), participants relived an episode of envy, and cognitive‐affective components of envy were examined in the context of both self‐ and informant reports of their envy and narcissism. In Study 3 (N = 69), narcissism was linked to reports of envy covertly induced in the laboratory. Vulnerable narcissism was strongly and consistently related to dispositional envy and schadenfreude (Studies 1–2), as well as to all cognitive‐affective components of envy (Study 2). Furthermore, it facilitated envy and schadenfreude toward a high‐status peer (Study 3). Grandiose narcissism was slightly negatively related to dispositional envy (Studies 1–2), and it did not predict informant reports of envy or cognitive‐affective components of the emotion (Study 2). Finally, it did not exacerbate envy, hostility, or resentment toward a high‐status peer (Study 3). The results suggest envy is a central emotion in the lives of those with narcissistic vulnerability and imply that envy should be reconsidered as a symptom accompanying grandiose features in the diagnosis of narcissistic personality disorder.
Systematic review of family and home‐based interventions targeting paediatric overweight and obesity
Authors: Knowlden A. P. , Sharma M.
Published: January 2012

The family and home environment is a highly influential psychosocial antecedent of paediatric obesity. The purpose of this investigation was to systematically analyze family and home‐based randomized control trials aimed at treating overweight and obesity in children ages 2–7 years. In gathering materials for this review, a search of Cumulative Index to Nursing and Allied Health, MEDLINE, Education Resources Information Center, Psychology and Behavioural Sciences Collection and CENTRAL databases was conducted for the time frame of January 2001 to August 2011. The data extraction spanned three phases resulting in a total of nine interventions that met the specified inclusion criteria. Among the identified studies, eight produced significant outcomes. The majority of the programmes incorporated educational sessions targeting parents as the primary modality for intervention delivery. Less than one‐quarter of the interventions included home visitations; however, all of the interventions included home‐based activities to reinforce behaviour modification. Only three of the interventions applied social and behavioural theory, and only two interventions employed process evaluation. Additional research is needed to gauge the efficacy of the home and family milieu for treating paediatric obesity.
The returns to promotion of healthy choices in Tasmania: are you in the dark about the power of mushrooms?
Authors: Alston Julian M. , Parks Joanna C.
Published: January 2012

The Australian Mushroom Growers Association (AMGA) has recently developed a revised marketing strategy to promote mushrooms using messages based on scientific findings about the nutrition and health consequences of regularly incorporating mushrooms into meals. This article evaluates impacts based on a test‐market experiment in Tasmania. We use a difference‐in‐differences econometric methodology to quantify the programme‐induced shifts in demand, and we use the resulting estimates in a supply and demand modelling framework to quantify the effects of promotion‐induced demand shifts on prices, quantities, and measures of economic well‐being. We estimate a conservative benefit–cost ratio for Tasmanian producers of 7.6:1 if they were to bear the entire cost and 11.4:1 if the programme were financed by a levy on production (or spawn). The aggregate benefit–cost ratio, including benefits to consumers is also 11.4:1.
Do Celebrity Politics and Celebrity Politicians Matter?
Authors: Street John
Published: January 2012

This article asks what it means to take celebrity politics seriously. It does so from three perspectives. It begins by looking at the case of New Labour and the role that celebrity politics played in party political communication and in government policy-making. It places both in the context of New Labour's cultural policy more broadly. This leads to a second perspective, in which the focus is upon how celebrity politics might be seen within social and political change more generally. A contrast is drawn between the ‘late modernity’ approach adopted by David Marsh and his colleagues, and the media-oriented approach adopted by Aeron Davis. Both approaches, it is suggested, invite a turn to empirical investigation, and the article's final section reviews existing research into celebrity politics, and argues for more emphasis on (a) cross-national comparison of forms of celebrity politics, and (b) audience perceptions of celebrity politicians, going beyond the current focus on large-scale surveys and experimentation.
Managing Distributed Innovation: Strategic Utilization of Open and User Innovation
Authors: Bogers Marcel , West Joel
Published: January 2012

Research from a variety of perspectives has argued that innovation no longer takes place within a single organization, but rather is distributed across multiple stakeholders in a value network. Here we contrast the vertically integrated innovation model to open innovation, user innovation, as well as other distributed processes (cumulative innovation, communities or social production, and co‐creation), while we also discuss open source software and crowdsourcing as applications of the perspectives. We consider differences in the nature of distributed innovation, as well as its origins and its effects. From this, we contrast the predictions of the perspectives on the sources, motivation and value appropriation of external innovation, and thereby provide a framework for the strategic management of distributed innovation.
Videogames, Persuasion and the War on Terror: Escaping or Embedding the Military—Entertainment Complex?
Authors: Robinson Nick
Published: January 2012

This article presents a call for political scientists to look seriously at videogames. Beginning with a demonstration of their growing importance, the article then sets out the existing game-related literature which demonstrates their persuasive potential. The importance of games for political studies is illustrated through an in-depth discussion of the link between videogames and the militarisation of politics and society: exploration of the role of the military—entertainment complex, felt in particular through the militarisation of the content of games, suggests that this complex is influencing the militarisation of society. Finally, the article explores some of the ways in which such militarisation is being challenged through the use of games for political activism, centred on protests within game spaces and the development of ‘critical’ games. While the article as a whole concludes that the forces that serve to legitimate the military—entertainment complex are considerably greater than those which challenge it, and that the potential of games for activism is at present relatively limited, this does not mean that they are not worthy of study. Games retain considerable scope for both learning (with games offering vital potential to embed real social critique in players) and as potential sources for political activism, which is only likely to grow in the future.
The Dynamic ‘Expectation–Conditional Maximization Either’ Algorithm
Authors: He Yunxiao , Liu Chuanhai
Published: January 2012

The ‘expectation–conditional maximization either’ (ECME) algorithm has proven to be an effective way of accelerating the expectation–maximization algorithm for many problems. Recognizing the limitation of using prefixed acceleration subspaces in the ECME algorithm, we propose a dynamic ECME (DECME) algorithm which allows the acceleration subspaces to be chosen dynamically. The simplest DECME implementation is what we call DECME-1, which uses the line that is determined by the two most recent estimates as the acceleration subspace. The investigation of DECME-1 leads to an efficient, simple, stable and widely applicable DECME implementation, which uses two-dimensional acceleration subspaces and is referred to as DECME-2. The fast convergence of DECME-2 is established by the theoretical result that, in a small neighbourhood of the maximum likelihood estimate, it is equivalent to a conjugate direction method. The remarkable accelerating effect of DECME-2 and its variant is also demonstrated with several numerical examples.
Longitudinal Penalized Functional Regression for Cognitive Outcomes on Neuronal Tract Measurements
Authors: Goldsmith Jeff , Crainiceanu Ciprian M. , Caffo Brian , Reich Daniel
Published: January 2012

We describe and analyse a longitudinal diffusion tensor imaging study relating changes in the microstructure of intracranial white matter tracts to cognitive disability in multiple-sclerosis patients. In this application the scalar outcome and the functional exposure are measured longitudinally. This data structure is new and raises challenges that cannot be addressed with current methods and software. To analyse the data, we introduce a penalized functional regression model and inferential tools designed specifically for these emerging types of data. Our proposed model extends the generalized linear mixed model by adding functional predictors; this method is computationally feasible and is applicable when the functional predictors are measured densely, sparsely or with error. On-line supplements compare two implementations, one likelihood based and the other Bayesian, and provide the software that is used in simulations; the likelihood-based implementation is included as the lpfr() function in the R package refund that is available in the Comprehensive R Archive Network.
Patient preferences for psoriasis treatments: impact of treatment experience
Authors: Schaarschmidt M.‐L. , Umar N. , Schmieder A. , Terris D.D. , Goebeler M. , Goerdt S. , Peitsch W.K.
Published: January 2012

Background  Patient preferences for psoriasis treatments can impact treatment satisfaction and adherence and may therefore influence clinical outcome.

Objective  To assess the impact of treatment experience (satisfaction with current treatment, number of prior visits, disease duration, number of preceding therapies and currently prescribed treatment modalities) on treatment preferences.

Methods  A computer‐based conjoint analysis experiment was conducted to analyse preferences of patients with moderate or severe psoriasis (n = 163) treated at a German University Medical Center for outcome (probability, magnitude and duration of benefit; probability, severity and reversibility of side effects) and process attributes (location, frequency, duration, delivery method, individual cost) of psoriasis treatments. Relative importance scores (RIS) were calculated for each attribute and compared using anova, post hoc test and multivariate regression analysis.

Results  Participants with longer disease duration attached significantly greater importance to duration of benefit (β = 0.206, P = 0.018), whereas participants on oral therapy were more concerned about magnitude of benefit by trend (β = 0.218, P = 0.058). Participants receiving injectables not only set higher value to probability of benefit (RIS = 32.80 vs. 21.89, P = 0.025) but also to treatment location (RIS = 44.74 vs. 23.03, P = 0.011), delivery method (RIS = 43.75 vs. 19.29, P = 0.019), treatment frequency (RIS = 31.24 vs. 16.89, P = 0.005) and duration (RIS = 32.54 vs. 16.57, P = 0.003) when compared with others. Treatment satisfaction was significantly higher in participants on infusions or injections compared with those on phototherapy and mere topical therapy.

Conclusions  Treatment preferences may change over time course and with treatment experience. Participants on injectables attach great importance to efficiency and convenience of therapies, and are highly satisfied with their treatment.
Efficacy of a Peer‐Guided Exercise Programme for Adolescents with Intellectual Disability
Authors: Stanish Heidi I. , Temple Viviene A.
Published: January 2012

Background  Peer support is strongly associated with physical activity of adolescents. This study examined the efficacy of a YMCA‐based, peer‐guided exercise training programme for increasing health‐related physical fitness among adolescents with intellectual disabilities.

Materials and Methods  Adolescents with intellectual disabilities and typically developing peer partners provided reciprocal support during 1‐h exercise sessions that included aerobic exercise, weight training and stretching activities. The programme was conducted 2 days/week for 15 weeks and pre‐ and post‐test fitness testing was conducted.

Results  Participants demonstrated significant improvements in curl‐ups, 6‐min walk and BMI. Exercise session attendance was high and participants typically completed all of the prescribed aerobic and stretching exercises, whereas weight training exercises were completed less consistently.

Conclusions  This peer‐guided model integrates social and instructional support for adolescents with intellectual disabilities and may encourage exercise participation in community settings.
Pioglitazone treatment increases COX‐2‐derived prostacyclin production and reduces oxidative stress in hypertensive rats: role in vascular function
Authors: Hernanz Raquel , Martín Ángela , Pérez‐Girón Jose V , Palacios Roberto , Briones Ana M , Miguel Marta , Salaices Mercedes , Alonso María J
Published: January 2012

BACKGROUND AND PURPOSE PPARγ agonists, glitazones, have cardioprotective and anti‐inflammatory actions associated with gene transcription interference. In this study, we determined whether chronic treatment of adult spontaneously hypertensive rats (SHR) with pioglitazone alters BP and vascular structure and function, and the possible mechanisms involved.

EXPERIMENTAL APPROACH Mesenteric resistance arteries from untreated or pioglitazone‐treated (2.5 mg·kg−1·day−1, 28 days) SHR and normotensive [Wistar Kyoto (WKY)] rats were used. Vascular structure was studied by pressure myography, vascular function by wire myography, protein expression by Western blot and immunohistochemistry, mRNA levels by RT‐PCR, prostanoid levels by commercial kits and reactive oxygen species (ROS) production by dihydroethidium‐emitted fluorescence.

KEY RESULTS In SHR, pioglitazone did not modify either BP or vascular structural and mechanical alterations or phenylephrine‐induced contraction, but it increased vascular COX‐2 levels, prostacyclin (PGI2) production and the inhibitory effects of NS 398, SQ 29,548 and tranylcypromine on phenylephrine responses. The contractile phase of the iloprost response, which was reduced by SQ 29,548, was greater in pioglitazone‐treated and pioglitazone‐untreated SHR than WKY. In addition, pioglitazone abolished the increased vascular ROS production, NOX‐1 levels and the inhibitory effect of apocynin and allopurinol on phenylephrine contraction, whereas it did not modify eNOS expression but restored the potentiating effect of N‐nitro‐L‐arginine methyl ester on phenylephrine responses.

CONCLUSIONS AND IMPLICATIONS Although pioglitazone did not reduce BP in SHR, it increased COX‐2‐derived PGI2 production, reduced oxidative stress, and increased NO bioavailability, which are all involved in vasoconstrictor responses in resistance arteries. These effects would contribute to the cardioprotective effect of glitazones reported in several pathologies.
Triptolide increases transcript and protein levels of survival motor neurons in human SMA fibroblasts and improves survival in SMA‐like mice
Authors: Hsu Ya‐Yun , Jong Yuh‐Jyh , Tsai Hsin‐Hung , Tseng Yu‐Ting , An Li‐Mei , Lo Yi‐Ching
Published: January 2012

BACKGROUND AND PURPOSE

Spinal muscular atrophy (SMA) is a progressive neuromuscular disease. Since disease severity is related to the amount of survival motor neuron (SMN) protein, up‐regulated functional SMN protein levels from the SMN2 gene are considered a major SMA drug‐discovery strategy. In this study, we investigated the possible effects of triptolide, a diterpene triepoxide purified from Tripterygium wilfordii Hook. F., as a new compound for increasing SMN protein.

EXPERIMENTAL APPROACH

The effects and mechanisms of triptolide on the production of SMA protein were determined by cell‐based assays using the motor neuronal cell line NSC34 and skin fibroblasts from SMA patients. Wild‐type (Smn+/+SMN2−/−, C57BL/6) and SMA‐like (Smn−/−SMN2) mice were injected with triptolide (0.01 or 0.1 mg·kg−1·day−1, i.p.) and their survival rate and level of change in SMN protein in neurons and muscle tissue measured.

KEY RESULTS

In NSC34 cells and human SMA fibroblasts, pM concentrations of triptolide significantly increased SMN protein expression and the levels of SMN complex component (Gemin2 and Gemin3). In human SMA fibroblasts, triptolide increased SMN‐containing nuclear gems and the ratio of full‐length transcripts (FL‐SMN2) to SMN2 transcripts lacking exon 7 (SMN2Δ7). Furthermore, in SMA‐like mice, triptolide significantly increased SMN protein levels in the brain, spinal cord and gastrocnemius muscle. Furthermore, triptolide treatment increased survival and reduced weight loss in SMA‐like mice.

CONCLUSION AND IMPLICATIONS

Triptolide enhanced SMN protein production by promoting SMN2 activation, exon 7 inclusion and increasing nuclear gems, and increased survival in SMA mice, which suggests triptolide might be a potential candidate for SMA therapy.
Randomized, Controlled Study of Telcagepant in Patients With Migraine and Coronary Artery Disease
Authors: Ho Tony W. , Ho Andrew P. , Chaitman Bernard R. , Johnson Constance , Mathew Ninan T. , Kost James , Fan Xiaoyin , Aurora Sheena K. , Brandes Jan L. , Fei Kaiyin , Beebe Louise , Lines Christopher , Krucoff Mitchell W.
Published: January 2012

Objective.— To evaluate the efficacy of telcagepant in patients with migraine and coronary artery disease.

Background.— Calcitonin gene‐related peptide receptor antagonists, such as telcagepant, may be useful for acute migraine treatment in patients with cardiovascular disease, a population for whom triptans are contraindicated.

Methods.— Randomized, double‐blind, two‐period (6 weeks per period) crossover study in patients with stable coronary artery disease and migraine. Patients were randomized 1:1 to either: (1) Period 1: telcagepant (280‐mg tablet/300‐mg capsule), Period 2: acetaminophen (1000‐mg); or (2) Period 1: placebo for attack 1 then acetaminophen for subsequent attacks, Period 2: telcagepant. Patients could treat up to 12 migraine attacks per period to assess the tolerability of telcagepant. The primary efficacy analysis evaluated telcagepant vs placebo on 2‐hour pain freedom during the first attack of Period 1.

Results.— One hundred and sixty‐five of the planned 400 patients were enrolled, and 114 took at least one dose of treatment. Telcagepant was not statistically different from placebo for 2‐hour pain freedom (25.0% vs 18.9%, odds ratio = 1.62 [95% confidence interval: 0.62, 4.25]). The median number of attacks treated per period was 3. No cardiovascular thrombotic adverse events occurred within 14 days of dosing.

Conclusion.— The study was underpowered due to enrollment difficulties and did not demonstrate a significant efficacy difference between telcagepant and placebo for the treatment of a migraine attack in patients with stable coronary artery disease. Telcagepant was generally well tolerated for acute intermittent migraine treatment in these patients.
The mechanism of action of retigabine (ezogabine), a first‐in‐class K+ channel opener for the treatment of epilepsy
Authors: Gunthorpe Martin J. , Large Charles H. , Sankar Raman
Published: January 2012

The pharmacologic profile of retigabine [RTG (international nonproprietary name); ezogabine, EZG (U.S. adopted name)], is different from all currently approved antiepileptic drugs (AEDs). Its primary mechanism of action (MoA) as a positive allosteric modulator of KCNQ2–5 (Kv7.2–7.5) ion channels defines RTG/EZG as the first neuronal potassium (K+) channel opener for the treatment of epilepsy. KCNQ2–5 channels are predominantly expressed in neurons and are important determinants of cellular excitability, as indicated by the occurrence of human genetic mutations in KCNQ channels that underlie inheritable disorders including, in the case of KCNQ2/3, the syndrome of benign familial neonatal convulsions. In vitro pharmacologic studies demonstrate that the most potent action of RTG/EZG is at KCNQ2–5 channels, particularly heteromeric KCNQ2/3. Furthermore, mutagenesis and modeling studies have pinpointed the RTG/EZG binding site to a hydrophobic pocket near the channel gate, indicating how RTG/EZG can stabilize the open form of KCNQ2–5 channels; the absence of this site in KCNQ1 also provides a clear explanation for the inbuilt selectivity RTG/EZG has for potassium channels other than the KCNQ cardiac channel. KCNQ channels are active at the normal cell resting membrane potential (RMP) and contribute a continual hyperpolarizing influence that stabilizes cellular excitability. The MoA of RTG/EZG increases the number of KCNQ channels that are open at rest and also primes the cell to retort with a larger, more rapid, and more prolonged response to membrane depolarization or increased neuronal excitability. In this way, RTG/EZG amplifies this natural inhibitory force in the brain, acting like a brake to prevent the high levels of neuronal action potential burst firing (epileptiform activity) that may accompany sustained depolarizations associated with the initiation and propagation of seizures. This action to restore physiologic levels of neuronal activity is thought to underlie the efficacy of RTG/EZG as an anticonvulsant in a broad spectrum of preclinical seizure models and in placebo‐controlled trials in patients with partial epilepsy. In this article, we consider the pharmacologic characteristics of RTG/EZG at the receptor, cellular, and network levels as a means of understanding the novel and efficacious MoA of this new AED as defined in both preclinical and clinical research.
Do mood instability symptoms in epilepsy represent formal bipolar disorder?
Authors: Lau Connie , Ettinger Alan B. , Hamberger Sandra , Fanning Kristina , Reed Michael L.
Published: January 2012

We aimed to assess rates of bipolar symptoms versus bipolar disorder in epilepsy, and the effect of bipolar symptoms on quality of life (QOL) in epilepsy. Bipolar, disability, and QOL instruments were administered to 99 tertiary epilepsy center patients. Patients who scored positive on the Mood Disorder Questionnaire (MDQ) also completed depression scales and a structured psychiatric interview. Results indicated MDQ+ patients (10.1%) had worse QOL and more work, social, and family life disruptions. Most MDQ+ patients did not have bipolar disorder. There was close overlap between depressive and bipolar symptomatology. Based on results of this study, bipolar symptom is not synonymous with bipolar disorder. Symptoms picked up by the MDQ may be epilepsy‐related depressive symptoms. Bipolar symptoms are associated with more disability, worse QOL, and may have treatment implications.
Efficacy and Safety of Deracoxib for Control of Postoperative Pain and Inflammation Associated with Soft Tissue Surgery in Dogs
Authors: Bienhoff Stephen E. , Smith Eric S. , Roycroft Linda M. , Roberts Elizabeth S.
Published: January 2012

Objective

To investigate the effectiveness and safety of deracoxib (Deramaxx®) administered at a dose of 1–2 mg/kg/day for 3 days for control of postoperative pain and inflammation associated with soft tissue surgery in dogs.

Study Design

Prospective, randomized, blinded, placebo‐controlled, multi‐center clinical study.

Animals

Dogs (n = 34).

Methods

Dogs undergoing soft tissue surgeries were randomly assigned to receive either deracoxib (n = 18) or placebo (n = 16) as a preoperative treatment and again once daily for 2 additional days after surgery unless removed from the study. Dogs were evaluated before surgery and again postsurgically at predetermined times using the Glasgow Composite Pain Scale (GCPS). All dogs were allowed to receive another pain medication (except nonsteroidal anti‐inflammatory drugs [NSAIDs] or corticosteroids) as postsurgical pain intervention if the dog scored ≥6 on the GCPS or was in obvious discomfort. Dogs receiving pain intervention were considered treatment failures and were removed from the study.

Results

Two of 16 dogs treated with deracoxib were rescued compared with 9 of 16 dogs receiving placebo (P = .0091). In addition, deracoxib treated dogs had numerically lower GCPS scores.

Conclusions

Results suggest perioperative administration of deracoxib to dogs at 1–2 mg/kg/day for 3 days significantly improves analgesia in the postoperative surgical period after soft tissue surgery. Placebo dogs not rescued after painful procedures highlight the need for refinement of current pain assessment tools.
A Time‐Series DDP for Functional Proteomics Profiles
Authors: Nieto‐Barajas Luis E. , Müller Peter , Ji Yuan , Lu Yiling , Mills Gordon B.
Published: January 2012

SummaryUsing a new type of array technology, the reverse phase protein array (RPPA), we measure time‐course protein expression for a set of selected markers that are known to coregulate biological functions in a pathway structure. To accommodate the complex dependent nature of the data, including temporal correlation and pathway dependence for the protein markers, we propose a mixed effects model with temporal and protein‐specific components. We develop a sequence of random probability measures (RPM) to account for the dependence in time of the protein expression measurements. Marginally, for each RPM we assume a Dirichlet process model. The dependence is introduced by defining multivariate beta distributions for the unnormalized weights of the stick‐breaking representation. We also acknowledge the pathway dependence among proteins via a conditionally autoregressive model. Applying our model to the RPPA data, we reveal a pathway‐dependent functional profile for the set of proteins as well as marginal expression profiles over time for individual markers.
Platelet‐derived growth factor receptor α‐positive cells in the tunica muscularis of human colon
Authors: Kurahashi Masaaki , Nakano Yasuko , Hennig Grant W. , Ward Sean M. , Sanders Kenton M.
Published: January 2012

An obstacle to understanding motor pathologies of the gastrointestinal (GI) tract is that the physiology of some of the cellular components of the gut wall is not understood. Morphologists identified fibroblast‐like cells in the tunica muscularis many years ago, but little is known about these interstitial cells because of inadequate techniques to identify these cells. Recent findings have shown that fibroblast‐like cells express platelet‐derived growth factor receptor α (PDGFRα) in mice and that antibodies for these receptors can be used to label the cells. We used immunohistochemical techniques to study the phenotype and intercellular relationships of fibroblast‐like cells in the human colon. Fibroblast‐like cells are labelled specifically with antibodies to PDGFRα and widely distributed through the tunica muscularis of human colon. These cells form discrete networks in the region of the myenteric plexus and within the circular and longitudinal muscle layers. Platelet‐derived growth factor receptor α+ cells are distinct from c‐Kit+ interstitial cells of Cajal and closely associated with varicose processes of neurons expressing substance P (excitatory motor neurons) or neuronal nitric oxide synthase (nNOS) (inhibitory motor neurons). Platelet‐derived growth factor receptor α+ cells express small conductance Ca2+‐activated K+ channels (SK3), which are likely to mediate purinergic neural regulation of colonic muscles. Our data suggest that PDGFRα+ cells may have an important role in transducing inputs from enteric motor neurons. This study identifies reagents and techniques that will allow investigation of this class of interstitial cells and help develop an understanding of the role of PDGFRα+ cells in the human GI tract in health and disease.
Investigating the effect of collective organizational commitment on unit‐level performance and absence
Authors: Conway Neil , Briner Rob B.
Published: January 2012

The relationship between individual‐level organizational commitment and employee's performance has been the subject of considerable empirical investigation over several decades. However, few studies have examined the effect of collective organizational commitment on unit or organizational‐level performance, even though available theory suggests commitment's effects may be stronger at the unit level. We present results of a study examining the effects of unit‐level organizational commitment on the speed and quality of performance, and employee absence, drawing on a sample of 893 service sector employees (representing a 90% response rate) from 39 office units in a UK public sector organization. Results show that unit‐level organizational commitment was statistically significantly associated with both unit‐level performance quality (i.e., reduced customer complaints per service transaction) and performance speed (i.e., customer average queuing time). Collective organizational commitment was not significantly associated with a unit‐level measure of the average time customers spent at service counters with the tellers, nor was it associated with unit‐level employee absence.

Practitioner Points

Bottom‐line impact of organizational commitment: unit‐level organizational commitment had substantial effects on unit‐level performance.

Managers must recognize that committed employees have a value beyond their immediate and individual performance as such individuals contribute to unit performance.

Unit‐level organizational commitment implies different managerial interventions.

Our research indicates the value to organizations of analysing survey data at the unit‐level: it is easier to ensure participant anonymity and confidentiality of responses and it provides information beyond individual level data.
Colloid volume loading does not mitigate decreases in central blood volume during simulated haemorrhage while heat stressed
Authors: Crandall C. G. , Wilson T. E. , Marving J. , Bundgaard‐Nielsen M. , Seifert T. , Klausen T. L. , Andersen F. , Secher N. H. , Hesse B.
Published: January 2012

Key points 

The capacity for humans to withstand a haemorrhagic challenge is reduced while heat stressed.

Identification of changes in central blood volume during simulated haemorrhage may help identify the mechanisms by which tolerance to haemorrhage is reduced during heat stress.

We found that the magnitude of reduction in central blood volume to a simulated hemorrhagic challenge is approximately three fold greater when individuals are heat stressed.

Volume loading did not change the relative magnitude of the reduction in central blood volume to that simulated haemorrhagic challenge.

These data show that greater reductions in central blood volume during a simulated haemorrhagic challenge while heat stressed may be a primary mechanism for impaired capacity to withstand that challenge in this thermal condition.
Denavit-Hartenberg Parameterization of Euler Angles
Authors: Shah S. V. , Saha S. K. , Dutt J. K.
Published: January 2012

Euler angles describe rotations of a rigid body in three-dimensional Cartesian space, as can be obtained by, say, a spherical joint. The rotation carried out by a spherical joint can also be expressed by using three intersecting revolute joints that can be described using the popular Denavit-Hartenberg (DH) parameters. However, the motions of these revolute joints do not necessarily correspond to any set of the Euler angles. This paper attempts to correlate the Euler angles and DH parameters by introducing a concept of DH parameterization of Euler angels. A systematic approach is presented in order to obtain the DH parameters for any Euler angles set. This gives rise to the concept of Euler-angle-joints (EAJs), which provide rotations equivalent to a particular set of Euler angles. Such EAJs can be conveniently used for the modeling of multibody systems having multiple-degrees-of-freedom joints.
Multiyear Prediction of Monthly Mean Atlantic Meridional Overturning Circulation at 26.5°N
Authors: Matei Daniela , Baehr Johanna , Jungclaus Johann H. , Haak Helmuth , Müller Wolfgang A. , Marotzke Jochem
Published: January 2012

Stable Flow

Whole-ocean deep circulation in the Atlantic, the Atlantic Meridional Overturning Circulation (AMOC), transports great quantities of heat from low latitudes to higher ones, which, for example, helps to warm Europe's climate.

Matei
et al.

(p.
76
) describe a modeling technique that allows AMOC strength to be predicted for up to 4 years in advance and suggests that AMOC should remain stable until at least 2014.
RNA Editing Underlies Temperature Adaptation in K
+
Channels from Polar Octopuses
Authors: Garrett Sandra , Rosenthal Joshua J. C.
Published: January 2012

Adapting to the Cold

The gating of potassium channels is temperature sensitive, suggesting that these channels must adapt to function efficiently in the extreme cold.
Garrett and Rosenthal
(p.
848
, published online 5 January; see the Perspective by

Ö
hman

) show that the coding sequences for delayed rectifier potassium channels from an Antarctic and a tropical octopus differed at only four positions and gave functionally identical channels when expressed in
Xenopus
oocytes. A variation in temperature responses instead came from extensive messenger RNA editing. In particular, an edit that recoded an isoleucine to a valine in the pore of the Antarctic octopus channel greatly accelerated gating kinetics.
Subparticle Ultrafast Spectrum Imaging in 4D Electron Microscopy
Authors: Yurtsever Aycan , van der Veen Renske M. , Zewail Ahmed H.
Published: January 2012

Plasmon Probe

When light of certain wavelengths strikes a metal surface, it sets the metal's electrons in motion along trajectories termed “plasmon modes.”

Yurtsever
et al.

(p.
59
; see the Perspective by

Batson

) constructed a type of electron microscope that can probe the electric fields associated with this process by measuring the energy of a separate pulse of electrons that is bounced off the surface immediately (less than trillionths of a second) after the light strikes. The spatial resolution was sufficient to map intensities in distinct regions of a single silver nanoparticle.