bluuebunny/crossref_metadata_2025 huggingface dataset:
Common Polymorphisms in the GSK3β Gene May Contribute to the Pathogenesis of Alzheimer Disease
Authors: Lin Qiao , Cao Yun-Peng , Gao Jie
Published: October 2014

Objective:

Although it is well known that GSK3β participates in the proliferation and survival of various tumor cells, its role in diseases of the central nervous system has been sparsely documented. In the past few years, studies regarding the relationship between GSK3β rs334558 T>C and rs6438552 C>T polymorphisms and Alzheimer disease (AD) risk have yielded contradictory results. As such, this meta-analysis seeks to satisfy the need to further investigate this relationship.

Methods:

In this research, published studies regarding the association of GSK3β rs6438552 and rs334558 mutation with AD risk was systematically assessed. Studies were retrieved from MEDLINE, Science Citation Index, the Cochrane Library, PubMed, Embase, CINAHL, Current Contents Index, Chinese Biomedical, Chinese Journal Full-Text, and Weipu Journal. Pooled odds ratios and 95% confidence intervals were calculated for allele contrast and homozygous, heterozygous, dominant, and recessive genetic model comparisons.

Results:

It was found that GSK3β rs334558 T>C and rs6438552 C>T polymorphisms were correlated with susceptibility to AD under 4 genetic models (all P < .05). In country-stratified subgroups, the results showed increased risk of developing AD in rs334558 T>C polymorphism among Chinese and Spain populations in majority groups. GSK3β rs6438552 C>T polymorphism was correlated with increased the risk of developing AD only in Australian populations.

Conclusion:

Our findings suggest that there exists a significant association between GSK3β rs334558 T>C polymorphism and increased susceptibility of AD. Moreover, future updated studies with stratified case–control population are warranted for validation studies.
Attitudes, Beliefs, and Practices of Integrative Medicine Among Nurses in the Netherlands
Authors: van Vliet Marja , Jong Mats , Busch Martine , Meijer Judith E. M. , von Rosenstiel Inès A. , Jong Miek C.
Published: October 2014

Purpose: This study assessed the attitude, beliefs, and practices of integrative medicine (IM) among nurses in the Netherlands. Design: Subscribers of a Dutch nursing journal were asked to fill in an anonymous, structured, online survey related to the topic under study. Results: A total of 355 people responded, of which 37% were familiar with the concept of IM in advance. On completion of the survey, the majority (83%) considered IM as a (very) important innovation in health care. Familiarity (odds ratio = 3.20; 95% confidence interval [1.48, 6.94]) and organization (nursing home compared to hospital (odds ratio = 5.98; 95% confidence interval [1.36, 26.23]) were characteristics associated with a positive attitude toward IM. Between 23% and 46% of respondents encountered obstacles regarding implementation of IM. The main obstacles were lack of support (69% to 78%), means (57% to 85%), and time (63% to 70%). Conclusions: Dutch nurses seem to have relatively positive attitudes and beliefs regarding IM. The outcome of this survey may contribute an increased awareness of the key role that nurses can play in the development and implementation of IM.
National Culture and Prosocial Behaviors
Authors: Luria Gil , Cnaan Ram A. , Boehm Amnon
Published: October 2014

Numerous studies have attempted to explain prosocial behaviors. Most of these studies focus on individual and contextual factors. Although existing data on the national level have demonstrated significant differences between countries in the frequency of prosocial behaviors, the reasons for these differences have rarely been explored. We hypothesize that Hofstede’s national culture perspective can explain this variance. We applied five societal culture structures to explaining cross-national variations: individualism (IND)–collectivism, power distance (PD), uncertainty avoidance (UA), masculinity, and future orientation (FO). Analysis of data from 66 countries supported our hypotheses: IND correlated positively and PD correlated negatively with prosocial behaviors. Contrary to our hypothesis, UA and FO correlated negatively with prosocial behaviors. Furthermore, PD and UA interact with IND in prediction of prosocial behaviors. We further explored the effect of the cultural dimensions on specific prosocial behaviors separately and found which of them are related to the cultural dimensions.
Adaptive active fault-tolerant control of generic hypersonic flight vehicles
Authors: Ji Yuehui , Zhou Hailiang , Zong Qun
Published: October 2014

A theoretical framework of active fault-tolerant control is exploited for a hypersonic flight vehicle longitudinal dynamical system in cruise phase subject to actuator loss-of-effectiveness fault. First, an active fault detection scheme is proposed by designing a nonlinear fault detection observer for the faulty hypersonic flight vehicle model. A finite-time convergence fault-tolerant controller is proposed on the basis of combined back-stepping and sliding mode technology. Moreover, the adaptive law is developed to estimate the bound information of actuator efficiency factor. The fault-free controller is accomplished which guarantees the globally asymptotic output tracking and boundedness of the closed-loop system. Finally, numerical simulations in Simulation and Verification Platform are presented to illustrate that the proposed fault-tolerant control strategy is effective in providing satisfactory tracking performance and rejecting actuator faults in a climbing maneuver case.
Curcumin as a protector for normal cells during bortezomib therapy
Authors: Kumar RR , Malhotra A
Published: October 2014

This study evaluated the protective potential of curcumin on the possible side effects of bortezomib (Bt) therapy on normal cells in mice. The mice were segregated into three groups ( n = 10) that included normal control, Bt-treated, and Bt + curcumin-treated groups. The Bt treatment resulted in significant decrease in the enzyme activity of erythrocyte δ-aminolevulinic acid dehydratase (ALAD). Also a significant decrease in the hemoglobin (Hb) was also noticed. On the other hand, curcumin co-treatment improvised enzyme activity of erythrocyte ALAD as well as Hb values. The study, therefore, concludes that curcumin co-treatment with Bt has a potential to take care of possible side effects of Bt therapy on normal cells.
Vancomycin-Resistant Enterococcal Bacteremia Pharmacotherapy
Authors: Patel Ruchi , Gallagher Jason C.
Published: October 2014

Objective: To review the literature on the pharmacotherapy of bloodstream infections (BSI) caused by vancomycin-resistant enterococci (VRE). Data Sources: A MEDLINE literature search was performed for the period 1946 to May 2014 using the search terms Enterococcus, enterococci, vancomycin-resistant, VRE, bacteremia, and bloodstream infection. References were also identified from selected review articles. Study Selection and Data Extraction: English-language case series, cohort studies, and meta-analyses assessing the options in the pharmacotherapy of VRE BSIs in adult patients were evaluated. Data Synthesis: Studies were identified that utilized linezolid, quinupristin/dalfopristin (Q/D), and daptomycin. In all, 8 comparative retrospective cohort studies, 2 meta-analyses of daptomycin and linezolid, and 3 retrospective comparisons of linezolid and Q/D were included for review. Mortality associated with VRE BSIs was high across studies, and the ability to determine differences in outcomes between agents was confounded by the complex nature of the patients included. Two meta-analyses comparing daptomycin with linezolid for VRE BSIs found modest advantages for linezolid, but these conclusions may be hampered by heterogeneity within the included studies. Conclusions: VRE BSIs remain a difficult-to-treat clinical situation. Differences in toxicity between the agents used to treat it are clear, but therapeutic differences are more difficult to discern. Meta-analyses suggest that a moderate advantage for linezolid over daptomycin may exist, but problems with the nature of studies that they included make definitive conclusions difficult.
Transnational Ethnic Kin and Civil War Outcomes
Authors: Gurses Mehmet
Published: October 2014

The literature on the transnational dimension of civil wars points to transnational ethnic kin as an important catalyst that initiates and sustains civil wars. Ethnic ties that transcend national boundaries, these studies argue, intensify the conflict by providing sanctuaries as well as human and material resources to the rebels. In this study, I argue that the same transborder ethnic ties make it more difficult for the government to achieve a decisive victory and contribute to outcomes more favorable to rebels. These networks can help create a more balanced relationship between an ethnic group and a previously antagonistic state by increasing the political, economic, and military costs of repression for the government. An analysis of ethnic civil wars starting and ending between 1950 and 2006 demonstrates that civil wars fought by ethnically mobilized rebel groups are more likely to be negotiated and settled in favor of rebels who have ethnic kin in a neighboring country.
Fault diagnosis of rolling element bearing using more robust spectral kurtosis and intrinsic time-scale decomposition
Authors: Bo Lin , Peng Chang
Published: October 2014

Spectral kurtosis (SK) has been proved to be a powerful tool to help extract impulse-like fault characteristics from original non-stationary vibration signals buried in strong masking noise. However, the SK coefficient based on the fourth sample moments suffers from a non-robustness problem, which may affect the accuracy of the SK-based kurtogram. Therefore, robust spectral kurtosis coefficients are defined based on quantiles in order to eliminate the influence of the outliers in original signals. Robust kurtograms are firstly utilized to analyze the fault signals. Subsequently, intrinsic time-scale decomposition followed by envelope demodulation is introduced to decompose the signal filtered by the kurtogram for fault detection. Compared with the conventional kurtogram and empirical mode decomposition, the results demonstrate that the improved method is able to facilitate the ability enhancement of the fault diagnosis of rolling element bearings.
Discrimination on the basis of a criminal record in South Africa
Authors: Mujuzi Jamil Ddamulira , Tsweledi Leruri Benjamin
Published: October 2014

Section 9(3) of the South African constitution prohibits unfair direct or indirect discrimination on grounds, including ‘race, gender, sex, pregnancy, marital status, ethnic or social origin, colour, sexual orientation, age, disability, religion, conscience, belief, culture, language and birth’. The Constitutional Court has interpreted section 9(3) to include analogous grounds such as marital status, citizenship and HIV status. There are many pieces of legislation or regulations in South Africa that prohibit employers from employing people with criminal records – irrespective of the lack of a nexus between the criminal record and the job in question. Invoking the test developed by the Constitutional Court on what criteria that should be met for an analogous ground, we argue that denying a person a job simply because of his criminal record amounts to unfair discrimination. We also discuss the issue of whether such discrimination could be justified on the basis of section 36 of the constitution.
Experiences of parenting a child with medical complexity in need of acute hospital care
Authors: Hagvall Monica , Ehnfors Margareta , Anderzén-Carlsson Agneta
Published: October 2014

Parents of children with medical complexity have described being responsible for providing advanced care for the child. When the child is acutely ill, they must rely on the health-care services during short or long periods of hospitalization. The purpose of this study was to describe parental experiences of caring for their child with medical complexity during hospitalization for acute deterioration, specifically focussing on parental needs and their experiences of the attitudes of staff. Data were gathered through individual interviews and analyzed using qualitative content analysis. The care period can be interpreted as a balancing act between acting as a caregiver and being in need of care. The parents needed skilled staff who could relieve them of medical responsibility, but they wanted to be involved in the care and in the decisions taken. They needed support, including relief, in order to meet their own needs and to be able to take care of their children. It was important that the child was treated with respect in order for the parent to trust the staff. An approach where staff view parents and children as a single unit, as recipients of care, would probably make the situation easier for these parents and children.
Rehabilitation of individuals on long-term sick leave due to sustained stress-related symptoms: A comparative follow-up study
Authors: Willert Morten Vejs , Wieclaw Joanna , Thulstrup Ane Marie
Published: October 2014

Aims: Nature-assisted therapy for mental health problems receives increased attention. However, quantitative evaluations are rare. This study evaluates the effects of an all-outdoors vocational rehabilitation program for individuals on long-term sick leave due to sustained stress-related symptoms. Methods: In a comparative pre–post intervention design the intervention group contained 48 participants from Mariendal Gardens (MG), while 45 participants at Stress- & Jobmanagement (SJ) formed the comparison group. At MG all activities took place outdoors, while activities at SJ were mainly indoors. Questionnaires were completed at baseline, 3- and 6-month follow-up. Outcomes included Perceived Stress Scale (PSS-10) and measures of sleep, mindfulness, self-efficacy, daily functioning, and work ability. Data were analyzed using mixed model repeated measures analysis of variance. Results: At baseline the MG-group PSS-10 mean score was 25.15 points (SD=7.20), while the SJ-group mean score was 23.91 (SD=7.48). At 3-months the MG within-group score dropped 4.61 [2.71; 6.52] points ( p<0.01), corresponding to at standardized mean difference (Cohen’s d) of d=0.64 [0.38; 0.91], while the SJ within-group score dropped 4.16 [1.73; 6.59] points ( p<0.01), corresponding to d=0.56 [0.23; 0.88]. The between-group mean difference was not significant ( p=0.77). Similarly, results for sleep, mindfulness, self-efficacy, daily functioning, and work ability demonstrated significant within-group effects and minimal between-group differences. Conclusions: Both interventions demonstrated small to large pre–post effect sizes. Negligible differences were observed between the effects of the two interventions, indicating no added effect of the all-outdoors setting. Results should be interpreted with caution as unequal lost to follow-up rates threatens the comparability of changes in the two groups.
The Effect of Supermajority Vote Requirements for Tax Increase in California: A Synthetic Control Method Approach
Authors: Lee Soomi
Published: October 2014

My article examines whether supermajority vote requirements (SMVR) to raise taxes in California's constitution suppresses state tax burdens. SMVR is a politically popular but contentious measure that 16 states have adopted and many other states have attempted to adopt. The rationale behind the rule is to contain the growth of government by making it costly to form a winning coalition to raise taxes. Nonetheless, the current empirical literature is mixed at best and suffers from causal inference. I take a different approach from extant literature and estimate the causal effect of SMVR on tax burdens in California by using synthetic control methods. The results show that, from 1979 to 2008, SMVR reduced the state nonproperty tax burden by an average of $1.44 per $100 of personal income, which is equivalent to 21% of the total tax burden for each year. The effect of SMVR was immediate after its adoption, but has abated over time.
Aortic Root Wrapped Procedure for Treating Aortic Root Sinus Aneurysm
Authors: Li Wenbin , Li Lu , Xu Xiufang , An Zhuoyi , Chao Quansheng , Zhou Zifan , Hua Guangbin , Zhou Haibo , Liu Anxin , Wan Zhihong
Published: October 2014

Background. To develop a relatively simple and effective and low-risk operation, aortic root wrapped procedure, to treat aortic root aneurysm or ectasia. Methods. From June 2008 to September 2010, 15 patients were accepted for aortic root wrapped angioplasty procedure, Marfan’s syndrome with aortic root ectasia in 2 cases, and aortic sinus aneurysm with middle to severe aortic valve stenosis and/or regurgitation in 13 cases. The diameter of aortic valve annulus was 25.43 ± 2.34 mm (range = 22-32 mm) and the diameter of aortic sinus was 50.45 ± 7.32 mm (range = 45-60 mm). All patients underwent aortic root wrapped angioplasty procedures with artificial blood vessel combined with aortic valve plasty or replacement with tissue valve prosthesis. Results. Fifteen patients survived well, and the perioperative mortality was 0%. Cardiopulmonary bypass time was 82.31 ± 16.34 minutes (range = 55-128 minutes). Predischarge echocardiography check result showed trace aortic regurgitation in 3 cases and normal aortic valve function in 12 cases. Compared with preoperative echocardiography results, the aortic annulus diameter (22.63 ± 1.25 mm [range = 21-25 mm]) decreased significantly ( P < .01) and the aortic sinus diameter (36.86 ± 7.41 mm [range = 30-41 mm]) decreased significantly ( P < .001). Follow-up results: All 15 patients survived well, and heart function (New York Heart Association classification) of the patients are all class I. The late mortality was 0%. Conclusion. Aortic root wrapped procedures combined with aortic valve plastic or replacement operation is an alternative surgical procedure in patients with aortic sinus aneurysm and aortic valve disease.
Considering the Impact of Acculturation on Lifestyle Interventions for Latinos
Authors: Moreno Jennette P. , Johnston Craig A.
Published: October 2014

Individuals of Latino descent are one of the fastest growing groups in the United States. They also experience multiple health disparities. To effectively treat individuals from these cultures, several issues should be considered. Assessing the degree of an individual’s acculturation and tailoring interventions to be more compatible with a patient’s cultural values are important steps to be taken.
Health Care providers and Teen Driving Safety
Authors: Dellinger Ann M. , West Bethany A.
Published: October 2014

Traffic crashes are the leading cause of death among teens. Health care providers have an opportunity to address what works to keep teens safe on the road during the patient visit. An online survey was conducted of 1088 health care providers who saw patients at or near driving age. The survey assessed which road safety topics were discussed and which types of educational products were used most often. Family and general practice physicians represented 44.3% of the sample, followed by pediatricians (22.5%), nurse practitioners (17.6%), and internists (15.5%). Nearly all respondents (92.9%) reported addressing one or more driving safety factors (seat belt use, nighttime driving, fatigue, teen passengers, alcohol/drug use, speeding/reckless driving, and cell phone use/texting) with adolescent patients and/or their parents. Seat belt use was reported more often (83.7%) than other topics. The use of parent–teen driving agreements, a known effective intervention, was reported by less than 10% of respondents. Since health care providers expressed interest in receiving written resource materials, distribution of parent–teen driving agreements to health care providers might encourage greater uptake and use of this effective intervention.
Dumpster diving in the trash bin of history
Authors: Waterstone Marv
Published: October 2014

While there is much to like in Simon Springer’s article, in this commentary I would like to re-examine several concepts that Springer consigns (much too prematurely, in my view) to the dustbin. Two of these he identifies quite explicitly—vanguardism and revolution; a third by implication—important dimensions of the state.
‘Carrying on the way we are is becoming shambolic’ – An interview study with prostate cancer specialists about their usual practice of follow-up
Authors: Bulger Jenna K , Hiscock Julia , Neal Richard D , Stanciu Andrei , Makin Matthew , Wilkinson Clare
Published: October 2014

Aim:

This study aims to clarify what practice for the follow-up of prostate cancer is occurring at present and to explain the reasons behind any variation.

Background:

Prostate cancer has been increasing in incidence in the UK for several years. It has been suggested that men with prostate cancer could be better managed, and that some aspects of care are duplicated by primary and secondary care professionals.

Methods:

This study aimed to interview the prostate cancer specialists identified as working within the district general hospitals of a large health board. The interviews used a qualitative semi-structured approach. Analysis was performed using The Framework method.

Findings:

Current practice for the follow-up of prostate cancer is variable both within and between hospitals. Patients are followed up in secondary care for longer than National Institute for Health and Care Excellence (NICE) recommends due to a lack of trust of general practitioners’ management. This inevitably impacts upon waiting lists, and many patients’ appointments are long overdue. A remote prostate-specific antigen (PSA) surveillance system may be beneficial. It is generally thought that change to the usual practice of follow-up of prostate cancer patients is required.
Community-Oriented Primary Care (COPC) and the Affordable Care Act
Authors: Gofin Jaime , Gofin Rosa , Stimpson Jim P.
Published: October 2014

Community-oriented primary care (COPC) is a model of health care delivery that tightly integrates primary care and public health. This model of care, applied around the globe, could be more widely adopted in the United States as clinical delivery systems respond to the growing demand for population health management, which has been driven largely by various provisions of the Affordable Care Act (ACA). For that purpose, there is need for changes in capacitating health professionals and changes in organizational structures that will address the needs and health priorities of the population, considering individual care management in the context of population health for a defined population. This article presents how the Affordable Care Act is an appropriate framework for COPC to succeed and the way forward to develop COPC through practical alternatives for the delivery of primary care within a population context.
Antipsychotic Prescriptions for Children Aged 5 Years or Younger
Authors: Lòpez-De Fede Ana , Vyavaharkar Medha , Bellinger Jessica D.
Published: October 2014

The use of antipsychotics in very young children is of concern given the lack of empirical evidence in their efficacy and long-term impact on children’s health. This study examined the prescription of antipsychotics among children aged ≤5 years enrolled in a state Medicaid program. Secondary data analysis was conducted using the Medicaid administrative data of a southeastern state. Using SAS 9.3, descriptive statistics were performed to examine socio-demographic characteristics, psychiatric diagnoses, off-label use, receipt of medications from multiple psychotropic drug classes, and receipt of non-pharmacologic psychiatric services among children aged ≤5 years who received antipsychotic prescriptions in calendar year (CY) 2011. A total of 112 children in the target age group received antipsychotics in CY 2011, the most common prescription being risperidone. The most common listed psychiatric diagnosis was attention deficit hyperactivity disorder. Two in five children received antipsychotics for off-label use. Three in four children also received medications from at least one other psychotropic drug class. More than half did not receive adjunct psychiatric services. State-level policies offering specific guidance and recommendations for antipsychotic use among very young children are urgently needed. Future research is warranted to examine long-term impact of such practices on children’s growth and development.
Microstructures and mechanical property of AlCoNiCrFe alloy annealed in high magnetic field
Authors: Zhang W. Q. , Lou C. S. , Wu X. C. , Fu H. M. , Zhang H. F.
Published: October 2014

A rapidly solidified high entropy alloy AlCoNiCrFe was annealed at different temperatures with high magnetic field applied up to 4 T. Both precipitation and coarsening of the precipitates were promoted during annealing in a high magnetic field, and nanosized arrayed particles as well as boundary oriented secondary phases were formed with effects of magnetic field. The microstructural features were obtained owing to enhancement of atomic diffusion by applying high magnetic field. It was found that both hardness and yield strength were not strongly dependent on the magnetic field, but the ultimate compression strength is reduced as higher magnetic field is applied due to formation and coarsening of the precipitates on grain boundaries.
The N-terminal SH2 domain of Syk is required for (hem)ITAM, but not integrin, signaling in mouse platelets
Authors: Hughes Craig E. , Finney Brenda A. , Koentgen Frank , Lowe Kate L. , Watson Steve P.
Published: October 2014

Key Points

Phosphotyrosine-binding capacity of the Syk N-SH2 domain is essential for GPVI and CLEC-2, but not αIIbβ3, activation of mouse platelets. Phosphorylation of Syk on Y519/20, but not of Y346, requires a functional Syk N-terminal SH2 domain.
CD1c+ blood dendritic cells have Langerhans cell potential
Authors: Milne Paul , Bigley Venetia , Gunawan Merry , Haniffa Muzlifah , Collin Matthew
Published: October 2014

Key Points

CD1c+ DCs differentiate into Langerhans cells in response to GM-CSF, TGFβ, and BMP7. CD14+ monocytes express low langerin but do not make Langerhans cells under the same conditions.
Subarachnoid hemorrhage induces an early and reversible cardiac injury associated with catecholamine release: one-week follow-up study
Authors: Salem Reda , Vallée Fabrice , Dépret François , Callebert Jacques , Maurice Jean Pierre Saint , Marty Philippe , Matéo Joaquim , Madadaki Catherine , Houdart Emmanuel , Bresson Damien , Froelich Sebastien , Stapf Christian , Payen Didier , Mebazaa Alexandre
Published: October 2014

Introduction

The occurrence of cardiac dysfunction is common after subarachnoid hemorrhage (SAH) and was hypothesized to be related to the release of endogenous catecholamines. The aim of this prospective study was to evaluate the relationship between endogenous catecholamine and cardiac dysfunction at the onset and during the first week after SAH.

Methods

Forty consecutive patients admitted for acute SAH without known heart disease were included. Catecholamine plasma concentrations and transthoracic echocardiography (TTE) were documented on admission, on day 1 (D1), and day 7 (D7).

Results

At baseline, 24 patients had a World Federation of Neurosurgical Societies score (WFNS) of one or two; the remaining 16 had a WFNS between three and five. Twenty patients showed signs of cardiac dysfunction on admission, including six with left ventricle (LV) systolodiastolic dysfunction and 14 with pure LV diastolic dysfunction. On admission, norepinephrine, epinephrine, dopamine, B-type Natriuretic Peptide (BNP) and Troponin Ic (cTnI) plasmatic levels were higher in patients with the higher WFNS score and in patients with altered cardiac function (all P <0.05). Among patients with cardiac injury, heart function was restored within one week in 13 patients, while seven showed persistent LV diastolic dysfunction (P = 0.002). Plasma BNP, cTnI, and catecholamine levels exerted a decrease towards normal values between D1 and D7.

Conclusion

Our findings show that cardiac dysfunction seen early after SAH was associated with both a rapid and sustained endogenous catecholamine release and WFNS score. SAH-induced cardiac dysfunction was regressive over the first week and paralleled the normalization of catecholamine concentration.
Efficacy and safety of pateclizumab (anti-lymphotoxin-α) compared to adalimumab in rheumatoid arthritis: a head-to-head phase 2 randomized controlled study (The ALTARA Study)
Authors: Kennedy William P , Simon J Abraham , Offutt Carolyn , Horn Priscilla , Herman Ann , Townsend Michael J , Tang Meina T , Grogan Jane L , Hsieh Frank , Davis John C
Published: October 2014

Introduction

Tumor necrosis factor (TNF) and, possibly, lymphotoxin alpha (LTα) signaling contribute to inflammation and rheumatoid arthritis (RA) pathogenesis. Pateclizumab (anti-lymphotoxin- alpha; MLTA3698A) is a humanized monoclonal antibody that blocks and depletes anti-LTα. This phase 2, randomized, head-to-head, active- and placebo-controlled trial examined the safety and efficacy of pateclizumab compared to adalimumab in RA patients with an inadequate response to disease-modifying antirheumatic drugs (DMARD-IR).

Methods

Patients (n = 214) with active RA (-6 swollen and tender joints, C-reactive protein -10 mg/L) on oral DMARDs were randomized (2:2:1) to receive pateclizumab 360 mg, adalimumab 40 mg, or placebo subcutaneously every 2 weeks. The primary endpoint, 4-variable, 28-joint disease activity score erythrocyte sedimentation rate (DAS28(4)-ESR) response, was evaluated at 12 weeks using an analysis of covariance (ANCOVA) model with adjustments for concomitant DMARD use and geographic region. Secondary efficacy endpoints included American College of Rheumatology (ACR) 20, ACR50, and ACR70 responses at Day 85. Pharmacokinetics, pharmacodynamics, and immunogenicity of pateclizumab were assessed.

Results

Pateclizumab reduced the DAS28(4)-ESR response (-1.89) at 12 weeks, however, this did not reach statistical significance compared to placebo (-1.54), while adalimumab (-2.52) differed significantly from both placebo and pateclizumab. Pateclizumab 12-week ACR20, ACR50 and ACR70 response rates (64%, 33%, and 14%) suggested clinical activity but were not statistically significant compared to placebo rates (46%, 24%, and 8%, respectively). CXCL13 serum levels decreased significantly following pateclizumab and adalimumab administration, demonstrating pharmacological target engagement by both drugs. Overall, adverse events (AEs) were comparable among all cohorts. Infections were the most common AE, occurring with comparable frequency in all groups. Serious AEs occurred in 0% of pateclizumab, 5.9% of adalimumab, and 2.3% of placebo patients, with serious infection in 2.3% of adalimumab patients and none in pateclizumab and placebo patients.

Conclusions

Pateclizumab had a good safety profile in patients inadequately responsive to DMARDs, but no statistically significant improvement in RA signs and symptoms after 12 weeks of treatment. Adalimumab demonstrated efficacy and safety comparable to published results in this head-to-head comparison in DMARD-IR RA patients.

Trial registration

ClinicalTrials.gov NCT01225393NCT01225393, Registered 18 October 2010.
Nociceptive neurons detect cytokines in arthritis
Authors: Schaible Hans-Georg
Published: October 2014

Proinflammatory cytokines are major mediators in the pathogenesis of diseases of joints such as rheumatoid arthritis and osteoarthritis. This review emphasizes that proinflammatory cytokines such as tumor necrosis factor-alpha, interleukin-1beta, interleukin-6 and interleukin-17 are also mediators of pain by directly acting on the nociceptive system. Proportions of nociceptive sensory neurons express receptors for these cytokines, and the application of cytokines rapidly changes the excitability, ion currents and second messenger systems of these neurons. By inducing persistent sensitization of nociceptive sensory neurons (C- and a proportion of Aδ-fibers) for mechanical stimuli in the joint (a process called peripheral sensitization), these cytokines significantly contribute to the persistent hyperalgesia typical for many disease states of the joint. In addition, the disease-associated release of cytokines in the spinal cord supports the generation of central sensitization. The therapeutic neutralization of proinflammatory cytokines thus not only reduces the process of inflammation but may directly reduce hyperalgesia and pain by reversing the neuronal effects of cytokines. It is emerging that different cytokines have different actions on neurons. The neutralization of tumor necrosis factor-alpha reduces both mechanical and thermal hyperalgesia of the joint. The neutralization of interleukin-1beta attenuates thermal hyperalgesia whereas the neutralization of interleukin-6 and interleukin-17 mainly reduces mechanical hyperalgesia. These different effects are partly explained by influencing different target molecules in sensory neurons. For example, in cultured sensory neurons tumor necrosis factor-alpha and interleukin-1beta upregulate the TRPV1 ion channel, which is involved in the transduction of heat stimuli, consistent with an effect of these cytokines in thermal hyperalgesia. By contrast, interleukin-17 upregulates the TRPV4 ion channel, which has a role in the transduction of mechanical stimuli. Thus, the analgesic potential of neutralizing cytokines seems to depend on which cytokine is mainly involved in the particular pain state.
Image-guided radiotherapy of the prostate using daily CBCT: the feasibility and likely benefit of implementing a margin reduction
Authors: Maund I F , Benson R J , Fairfoul J , Cook J , Huddart R , Poynter A
Published: October 2014

Objective:

To investigate whether planning target volume (PTV) margins may be safely reduced in radiotherapy of localized prostate cancer incorporating daily online tube potential-cone beam CT (CBCT) image guidance and the anticipated benefit in predicted rectal toxicity.

Methods:

The prostate-only clinical target volume (CTV2) and rectum were delineated on 1 pre-treatment CBCT each week in 18 randomly selected patients. By transposing these contours onto the original plan, dose–volume histograms (DVHs) for CTV2 and the rectum were each calculated and combined, for each patient, to produce a single mean DVH representative of the dose delivered over the treatment course. Plans were reoptimized using reduced CTV2 to PTV2 margins and the consequent radiobiological impact modelled by the tumour control probability (TCP) and normal tissue complication probability (NTCP) of the rectum.

Results:

All CBCT images were deemed of sufficient quality to identify the CTV and rectum. No loss of TCP was observed when plans using the standard 5-mm CTV2 to PTV2 margin of the centre were reoptimized with a 4- or 3-mm margin. Margin reduction was associated with a significant decrease in rectal NTCP (5–4 mm; p < 0.05 and 5–3 mm; p < 0.01).

Conclusion:

Using daily online image guidance with CBCT, a reduction in CTV2 to PTV2 margins to 3 mm is achievable without compromising tumour control. The consequent sparing of surrounding normal tissues is associated with reduced anticipated rectal toxicity.

Advances in knowledge:

Margin reduction is feasible and potentially beneficial. Centres with image-guided radiotherapy capability should consider assessing whether margin reduction is possible within their institutes.
Siblings' Mediated Learning Strategies in Families With and Without Children With Intellectual Disabilities
Authors: Tzuriel David , Hanuka-Levy Dikla
Published: October 2014

Dyads of siblings in which the younger sibling had an intellectual disability (ID, n  =  25) were videotaped interacting. The ID group was compared with typically developing sibling dyads matched on mental age (n  =  25) and chronological age (n  =  25). We observed the mediation strategies, activation, and antimediation behaviors of older siblings and younger siblings' responsiveness to mediation. Mediation strategies were analyzed by the Observation of Mediation Interaction scale. The ID group scored highest on mediation strategies and lowest on activation and antimediation behaviors. Younger siblings' responsiveness to mediation was highest among the ID group. Mediation for Intentionality and Reciprocity and Meaning were positively associated with the verbal responsiveness of the younger siblings. Activation and antimediation behaviors were negatively associated with the verbal responsiveness.
Debate: Lessons Learnt from 10 Years and USD 50 million of Grant Making to End Human Trafficking
Authors: Newcomb Randy
Published: October 2014

On 26 September 2013, Humanity United, with our partners Legatum Foundation and Walk Free, announced the creation of the USD 100 million Freedom Fund to combat human trafficking around the world. This fund is the first of its kind, organised by three private foundations and borne in part from Humanity United’s experience as a donor over the past decade, during which time we provided more than USD 50 million to fund anti-trafficking efforts globally.During this time, we also worked closely with the donor community as well as organisations and activists working on the frontlines of the struggle to end human trafficking.  Over this period, four themes have emerged that help us better understand how to more effectively work and provide grants to combat human trafficking.
Effect of Se application on photosynthesis, osmolytes and water relations in two durum wheat (Triticum durum L.) genotypes under drought stress
Authors: HAJIBOLAND Roghieh , SADEGHZADEH Noushin , SADEGHZADEH Behzad
Published: October 2014

Effect of Se (as Na2SeO4 at final concentration of 10 µg l-1) was studied in two durum wheat (Triticum durum L.) genotypes in perlite under drought conditions. Se treatment increased slightly biomass of both genotypes under drought but not under control conditions. Photosynthetic rate was depressed by drought while increased by Se treatments in both genotypes up to 2.3 fold. However, transpirational water loss was also enhanced in Se-treated plants under both well-watered and drought conditions. Se application resulted in higher concentrations of soluble proteins and free α-amino acids under drought conditions, but not proline. Our results indicated that Se application improves some physiological parameters such as photosynthesis, accumulation of osmolyes and water use efficiency but did not change significantly plants biomass or water relation parameters.
Efficacy, safety, and tolerability of IVIG-SN in patients with primary immunodeficiency
Authors: Stein Mark R. , Wasserman Richard L. , Moy James , Lumry William , Grunebaum Eyal , Nemet Agnes , Roifman Chaim M. , Sussman Gordon
Published: October 2014

Background: IVIG-SN is a modern intravenous immunoglobulin with multiple pathogen elimination steps. This clinical trial in patients with primary immunodeficiency (PID) was designed to evaluate the safety, efficacy, and tolerability of this product in adults and children.

Methods: Forty-four patients with PID were treated with IVIG-SN for 12 months. IgG trough levels and pharmacokinetics of IVIG-SN were evaluated as well as efficacy and safety according to standard FDA guidelines.

Results: Overall, a total of 572 IVIG-SN infusions were administered according to either a 21- or a 28-day schedule. IgG trough levels during the treatment period ranged from 823.00 to 902.77 mg/dL, respectively, and half-life in serum of the administered IgG was 43.45 ± 30.25 days. There were no deaths and no adverse events leading to withdrawal from the study. Of all infusions administered, only 137 (24%) were temporally associated with an adverse event (AE). The upper bound for the 95% CI for the frequency of infusions temporally associated with an AE was 29.2%. Drug-related AEs were predominantly mild, and there were no acute serious bacterial infections during the study. Efficacy was also demonstrated by low rates of missed work, school, or daycare days (mean 2.6 days); unscheduled visits to physicians (mean 1.7); and therapeutic antibiotic use (mean 15 days).

Conclusion: IVIG-SN is effective in preventing infections and is safe and well tolerated.

Statement of novelty: This efficacy and toxicity trial was conducted using a new IVIG preparation.
Genetic or Pharmacological Reduction of PERK Enhances Cortical-Dependent Taste Learning
Authors: Ounallah-Saad Hadile , Sharma Vijendra , Edry Efrat , Rosenblum Kobi
Published: October 2014

Protein translation initiation is controlled by levels of eIF2α phosphorylation (p-eIF2α) on Ser51. In addition, increased p-eIF2α levels impair long-term synaptic plasticity and memory consolidation, whereas decreased levels enhance them. Levels of p-eIF2α are determined by four kinases, of which protein kinase RNA-activated (PKR), PKR-like endoplastic reticulum kinase (PERK), and general control nonderepressible 2 are extensively expressed in the mammalian mature brain. Following identification of PERK as the major kinase to determine basal levels of p-eIF2α in primary neuronal cultures, we tested its function as a physiological constraint of memory consolidation in the cortex, the brain structure suggested to store, at least in part, long-term memories in the mammalian brain. To that aim, insular cortex (IC)-dependent positive and negative forms of taste learning were used. Genetic reduction of PERK expression was accomplished by local microinfusion of a lentivirus harboring PERK Short hairpin RNA, and pharmacological inhibition was achieved by local microinfusion of a PERK-specific inhibitor (GSK2606414) to the rat IC. Both genetic reduction of PERK expression and pharmacological inhibition of its activity reduced p-eIF2α levels and enhanced novel taste learning and conditioned taste aversion, but not memory retrieval. Moreover, enhanced extinction was observed together with enhanced associative memory, suggesting increased cortical-dependent behavioral plasticity. The results suggest that, by phosphorylating eIF2α, PERK functions in the cortex as a physiological constraint of memory consolidation, and its downregulation serves as cognitive enhancement.
Apnea-Induced Rapid Eye Movement Sleep Disruption Impairs Human Spatial Navigational Memory
Authors: Varga Andrew W. , Kishi Akifumi , Mantua Janna , Lim Jason , Koushyk Viachaslau , Leibert David P. , Osorio Ricardo S. , Rapoport David M. , Ayappa Indu
Published: October 2014

Hippocampal electrophysiology and behavioral evidence support a role for sleep in spatial navigational memory, but the role of particular sleep stages is less clear. Although rodent models suggest the importance of rapid eye movement (REM) sleep in spatial navigational memory, a similar role for REM sleep has never been examined in humans. We recruited subjects with severe obstructive sleep apnea (OSA) who were well treated and adherent with continuous positive airway pressure (CPAP). Restricting CPAP withdrawal to REM through real-time monitoring of the polysomnogram provides a novel way of addressing the role of REM sleep in spatial navigational memory with a physiologically relevant stimulus. Individuals spent two different nights in the laboratory, during which subjects performed timed trials before and after sleep on one of two unique 3D spatial mazes. One night of sleep was normally consolidated with use of therapeutic CPAP throughout, whereas on the other night, CPAP was reduced only in REM sleep, allowing REM OSA to recur. REM disruption via this method caused REM sleep reduction and significantly fragmented any remaining REM sleep without affecting total sleep time, sleep efficiency, or slow-wave sleep. We observed improvements in maze performance after a night of normal sleep that were significantly attenuated after a night of REM disruption without changes in psychomotor vigilance. Furthermore, the improvement in maze completion time significantly positively correlated with the mean REM run duration across both sleep conditions. In conclusion, we demonstrate a novel role for REM sleep in human memory formation and highlight a significant cognitive consequence of OSA.
Difference in the Gain in the Phototransduction Cascade Between Rods and Cones in Carp
Authors: Kawakami Naoto , Kawamura Satoru
Published: October 2014

In the vertebrate retina, there are two types of photoreceptors, rods and cones. Rods are highly light-sensitive and cones are less light-sensitive. One of the possible mechanisms accounting for the lower light-sensitivity in cones would be lower signal amplification, i.e., lower gain in the phototransduction cascade in cones. In this study, we compared the difference in the gain between rods and cones electrophysiologically in carp. The initial rising phases of the light responses were analyzed to determine an index of the gain,G, a parameter that can be used to compare the gain among cells of varying outer segment volumes.G(in fL · sec−2) was 91.2 ± 14.8 (n= 5) in carp rods and 25.3 ± 3.2 (n= 4) in carp red cones, so that the gain in carp red cones is ∼1/4 of that in carp rods.Gwas also determined in bullfrog rods and was 81.0 ± 17.2 (n= 3) which was very similar to that in carp rods. The difference in the gain between rods and cones in carp determined in this study (∼1/4 in cones compared with rods) is consistent with that we recently determined biochemically (∼1/5 in cones compared with rods). Together with the result obtained in bullfrog rods in this study and the results obtained by others, we concluded that the gain in the cascade is several-fold lower in cones than in rods in carp and probably in other animal species also.
Association Mapping of Disease Resistance Traits in Rainbow Trout Using Restriction Site Associated DNA Sequencing
Authors: Campbell Nathan R , LaPatra Scott E , Overturf Ken , Towner Richard , Narum Shawn R
Published: October 2014

Recent advances in genotyping-by-sequencing have enabled genome-wide association studies in nonmodel species including those in aquaculture programs. As with other aquaculture species, rainbow trout and steelhead (Oncorhynchus mykiss) are susceptible to disease and outbreaks can lead to significant losses. Fish culturists have therefore been pursuing strategies to prevent losses to common pathogens such as Flavobacterium psychrophilum (the etiological agent for bacterial cold water disease [CWD]) and infectious hematopoietic necrosis virus (IHNV) by adjusting feed formulations, vaccine development, and selective breeding. However, discovery of genetic markers linked to disease resistance offers the potential to use marker-assisted selection to increase resistance and reduce outbreaks. For this study we sampled juvenile fish from 40 families from 2-yr classes that either survived or died after controlled exposure to either CWD or IHNV. Restriction site−associated DNA sequencing produced 4661 polymorphic single-nucleotide polymorphism loci after strict filtering. Genotypes from individual survivors and mortalities were then used to test for association between disease resistance and genotype at each locus using the program TASSEL. After we accounted for kinship and stratification of the samples, tests revealed 12 single-nucleotide polymorphism markers that were highly associated with resistance to CWD and 19 markers associated with resistance to IHNV. These markers are candidates for further investigation and are expected to be useful for marker assisted selection in future broodstock selection for various aquaculture programs.