bluuebunny/crossref_metadata_2025 huggingface dataset:
Effects of Gluten‐Free Diet on Quality of Life and Depression in Children With Celiac Disease
Authors: Simsek Seref , Baysoy Gokhan , Gencoglan Salih , Uluca Unal
Published: March 2015

Objectives:

The aim of this study was to investigate the level of depression and quality of life in children with celiac disease (CD). In addition, it aimed to examine the relations of depression level and life quality with adherence to a gluten‐free diet (GFD).

Methods:

Twenty‐five children with CD and 25 healthy controls were included. The Depression Scale for Children and the General Purpose Health‐Related Quality of Life Scale for Children were performed on patients before and after receiving recommendations to follow a GFD.

Results:

No significant differences were found in the depression scores between the patients and the control subjects (P > 0.05). In contrast, total scores and scores of the emotional well‐being subscale of the measure of Quality of Life Scale for Children were significantly lower in patients with CD compared with the control group (P < 0.05). No significant improvements were observed in depression or life quality scores of the total subsample of celiac patients, all of whom received a recommendation to follow a GFD (P > 0.05). Significant decrease was observed in the depression scores, however, of celiac patients who were able to actually adhere to the GFD compared with nonadherent patients.

Conclusions:

CD negatively affected quality of life in children. Adherence to GFD was associated with reduction in depression symptoms. Improving the adherence of celiac patients to a GFD may have a favorable effect on their depression symptoms.
The Causes of Their Death Appear (Unto Our Shame Perpetual): Why Root Cause Analysis Is Not the Best Model for Error Investigation in Mental Health Services
Authors: Vrklevski Lila Petar , McKechnie Leanne , O'Connor Nick
Published: March 2015

Objectives

Root cause analysis (RCA) is the model of accident investigation mandated by the New South Wales Ministry of Health in Australia to review all serious incidents. Anecdotal evidence suggests that the RCA model is not suitable for reviewing adverse events in mental health services such as suicides and homicides. The aims of the research were to evaluate the impact of RCA on improving patient outcomes in a regional mental health service in New South Wales, Australia, and to discover whether the RCA model is the most appropriate model in mental health.

Methods

The literature on RCA was reviewed. The effectiveness of implementation of RCA recommendations was evaluated using quantitative and qualitative data.

Results

Suicides and homicides, which constitute 90% of serious critical incidents in mental health, do not always lend themselves well to identification of a root cause. There is evidence for low clinician engagement in the recommendations that arise from RCAs and a poor level of evidence that implementation of RCA recommendations results in safer patient care. Most troubling is the finding that RCAs frequently make recommendations that repeat existing policy or previous recommendations.

Conclusions

Although the RCA model offers a formal and systematic approach to the review of serious critical incidents in mental health, it is not the model of best fit. Only 65% of recommendations made through RCA reviews are implemented within 12 months.
A large-scale circuit mechanism for hierarchical dynamical processing in the primate cortex
Authors: Chaudhuri Rishidev , Knoblauch Kenneth , Gariel Marie-Alice , Kennedy Henry , Wang Xiao-Jing
Published: March 2015

We developed a large-scale dynamical model of the macaque neocortex based on recent quantitative connectivity data. A hierarchy of timescales naturally emerges from this system: sensory areas show brief, transient responses to input (appropriate for sensory processing), whereas association areas integrate inputs over time and exhibit persistent activity (suitable for decision-making and working memory). The model displays multiple temporal hierarchies, as evidenced by contrasting responses to visual and somatosensory stimulation. Moreover, slower prefrontal and temporal areas have a disproportionate impact on global brain dynamics. These findings establish for the first time a circuit mechanism for “temporal receptive windows” that are progressively enlarged along the cortical hierarchy, extend the concept of working memory from local to large circuits, and suggest a re-interpretation of functional connectivity measures.

Conflict of Interest

The authors declare no competing financial interests.

Acknowledgements

We thank Nikola Markov and John Murray for discussions. This work was supported by ONR grant N00014-13-1-0297 and NIH grant R01MH062349 (X.-J.W.) and by ANR-11-BSV4-501 and LABEX CORTEX (ANR-11-LABX-0042) of Université de Lyon, program “Investissements d’Avenir” (ANR-11-IDEX-0007) operated by the French National Research Agency (H.K.). The connectivity data is available atwww.core-nets.org.
Beyond size – morphological predictors of bite force in a diverse insectivorous bat assemblage from Malaysia
Authors: Senawi Juliana , Schmieder Daniela , Siemers Bjorn , Kingston Tigga
Published: March 2015

Bite force is used to investigate feeding performance in a variety of vertebrates. In all taxa studied, bite force is strongly correlated with body and head size. Studies of bite force in bats have largely centred on neotropical species with a particular focus on species that maximize dietary differences. Little is known about the bite force of bats from the Old World tropics, nor of variation in bite force within diverse assemblages of obligate insectivores. Moreover, factors other than size are poorly known but may be important in driving interspecific differences in bite force, and thereby diet.

Here, we examine the correlation between morphological variation and bite force of 35 species of insectivorous bats from a single palaeotropical assemblage. We confirmed the overall relationship between size and bite force across species, but found that bite force is predicted more strongly by head length than body mass or forearm length.

From the combined action of jaw muscles and muscle‐bone mechanisms, bats generate a mechanical advantage that creates pressure during biting. We calculated the size‐independent mechanical advantage for each of five mandible lever systems (three delineated by the temporalis muscle and two delineated by the masseter muscle) operating through three function points (molar, canine and incisor). Size‐independent mechanical advantage of the suprazygomatic portion of the temporalis muscle at the molar function point was the only significant predictor of size‐independent maximum bite force across all species.

Within families, the size‐independent mechanical advantage of the superficial portion of the masseter muscle plays a significant role in predicting size‐independent maximum bite force in both the Rhinolophidae and Vespertilionidae. For the family Hipposideridae, however, size‐independent mechanical advantage showed no role in predicting size‐independent maximum bite force, suggesting that size really matters in predicting the maximum bite force capacity for this family.
The Effects of Monetary Policy Shocks in the USA: A Forecast‐Augmented VAR Approach
Authors: Bhuiyan Rokon
Published: March 2015

This paper formulates a forward‐looking monetary policy function for the USA in a structural vector autoregression (VAR) model, by using forecasts of key macroeconomic variables, in addition to the ex post realised variables used in a standard VAR. Since this forecast‐augmented VAR (FOAVAR) uses both forecasted and realised variables, and the standard VAR uses only realised variables, the standard VAR is nested in the FOAVAR. I find that the Fed responds to forecasted macroeconomic variables more significantly than realised variables. I also find that the monetary policy shock in the FOAVAR generates impulse responses of variables that are consistent with the predictions of economic theories, while the policy shock in the standard VAR causes a price puzzle: an increase in the price level due to a contractionary policy shock. These results suggest that a monetary policy function identified in a standard VAR, by using only realised macroeconomic variables, may incorrectly represent the Fed's policy function.
Diffusion in the Face of Failure: The Evolution of a Management Innovation
Authors: Scarbrough Harry , Robertson Maxine , Swan Jacky
Published: March 2015

Recent work has questioned the institutional model of management innovation by highlighting interactions between the field‐level actors engaged in diffusing innovations and implementation of the innovation at organization level. Focusing on the adaptation of management innovations to their context, rather than their creation, we review this work and use it to analyse the global diffusion of resource planning (RP), counter posing this case with the widely studied example of total quality management. Both of these innovations experienced a high level of failure when implemented by organizations. Total quality management's diffusion was characterized by a ‘boom and bust’ cycle. RP, however, has continued to spread globally in the form of its variants: MRP, MRPII and ERP. Our analysis seeks to account for the long‐run diffusion of RP through a processual model which highlights the interplay between RP's discursive framing at field level, the affordances of the innovation itself and its adaptation within organizations. This demonstrates how objectifying RP in software not only helped to spread the innovation but also allowed field‐level actors to differentiate its development as a successful innovation from the many failures experienced by organizations attempting to adapt it.
Party elites and the search for credibility: Plaid Cymru and the SNP as new parties of government
Authors: McAngus Craig
Published: March 2015

Stateless Nationalist Regionalist Parties (SNRPs) are widely considered as mainstream political actors, and their ideological and strategic development in this regard has been well documented by scholars. However, little attention has been paid to how party elites view such processes. Adopting a comparative case study approach, this article looks at the case of Plaid Cymru and the Scottish National Party (SNP), both of whom entered government for the ﬁrst time in 2007. Drawing on original and extensive elite interview data, the article examines how elites in both parties attempted to use the transition to government to portray their respective parties as mainstream and credible. The article ﬁnds that this aspiration is driven largely by a desire to change historically embedded stereotypes, but also, in the case of the SNP, to further the party’s primary goal of Scottish independence. In the case of Plaid Cymru, having to become a junior coalition partner meant that the party felt obliged to take up stereotypical portfolios which undermined, in part, the purpose of governmental participation for some elites.
A Belated Debate
Authors: Allen Nicholas
Published: March 2015

The three televised leaders’ debates dominated the 2010 general election campaign. The House of Lords Communications Committee report on Broadcast General Election Debates is the product of a welcome but belated public inquiry into their organisation and conduct. The report is supportive of the view that ‘broadcast general election debates should take place during future campaigns’ and makes a number of cautious recommendations to the broadcasters. At the time of writing it was unclear whether the format proposed by the broadcasters for 2015 would be an improvement on that for 2010—or even if there would be any debates at all.
Back to the Future? Warnings from History for a Future UK Constitutional Convention
Authors: Evans Adam
Published: March 2015

Amid the fallout from the Scottish independence referendum, a UK constitutional convention has been proposed as a mechanism to take stock not only of the referendum, but also of the past fifteen years of devolution. However, despite longstanding conceptions of British constitutional development, a constitutional convention would not herald a brave new world for the UK's constitution. As the article highlights, in the past hundred years there have been two attempts to treat the territorial constitution in the round: the Speaker's Conference on Devolution, 1919–1920 and the Royal Commission on the Constitution, 1969–1973. This article examines both of these forums, arguing that they provide clear warnings for a future UK constitutional convention, in particular the threat of internal division that any such forum risks facing. A danger that this article highlights is heightened by the associated difficulty of reaching agreement across the UK's ‘state of unions’.
The Coalition and the Politics of the English Question
Authors: Hayton Richard
Published: March 2015

For much of the 2010–15 Parliament the English Question was not a conspicuous feature of political debate in the UK. However, the issue of English votes for English laws (EvfEl) was thrust to centre stage by Prime Minister David Cameron in the aftermath of the Scottish independence referendum, when he announced that fulfilment of the promise of further devolution to Scotland must be accompanied by an answer to the West Lothian Question at Westminster. This article analyses these events and explores their possible consequences. It argues that a reform of parliamentary procedures along the lines outlined in the report of the McKay Commission looks increasingly likely, but that this will not mark a resolution of the broader English Question, and the future of the Union remains in doubt.
Journalism, Intelligence and the New York Times: Cyrus L. Sulzberger, Harrison E. Salisbury and the CIA
Authors: Jones Matthew
Published: March 2015

This article examines the tensions brought to the relationship between two of the major figures of post‐war American journalism, Cyrus L. Sulzberger and Harrison E. Salisbury, during the late 1970s by the accusation that Sulzberger had been a long‐standing ‘asset’ of the CIA. The relentless efforts of Salisbury to pursue the story during the research for his 1980 book Without Fear or Favor, which dealt with the recent history of the New York Times, brought his previous friendship with Sulzberger to a breaking point, but also produced the revelation that Salisbury himself had once been regarded by the CIA as a willing and cooperative source of information on the communist bloc. This personal story serves to bring out the wider themes of the ambiguous relationship between journalism and intelligence and the connections between the CIA and the media that began to be exposed during the 1970s.
The Housewife, the Vigilante and the Cigarette‐Smoking Man: TheCIAand Television, 1975–2001
Authors: McCrisken Trevor
Published: March 2015

Reeling from the revelations about its operations in the 1970s, theCIAset up anOffice ofPublicAffairs to improve its public image. Among its activities was greater engagement with television producers, but it largely failed to lead to moreUSdrama series portraying theCIAin a better light. This article, however, analyses those fewTVdramas that did characterize theCIAin the 1980s and 1990s –Scarecrow andMrsKing,TheEqualizerandTheX‐Files. Each series gave a critique of theCIAand its practices while offering alternative pathways to redeeming the organization so that it could better serveUSsecurity and domestic safety. They are examples of how television dramas can ask questions, engage with critical issues in contemporary society, and push the boundaries of what we expect to see in our televisual entertainment. They may not have offered very much insight into what theCIAwas actually doing globally, but their storylines did confront the public image of theCIA, question its ethos and its methods, and offer some alternative viewpoints on how theAgency might develop its role and approach. Each series attempted to push beyond stereotypes of theCIAand its agents, upset the usual balance between gender roles and refused to give the kind of closed, unambiguous viewpoints that so manyUStelevision dramas offered their audiences during the period. They contributed significantly to the cultural representation of theCIAas theColdWar drew to a close.
Investigating Change in Adolescent Self‐Efficacy of Food Safety Through Educational Interventions
Authors: Beavers Amy S. , Murphy Lindsay , Richards Jennifer K.
Published: March 2015

A successfully targeted intervention can influence food safety knowledge, attitudes, and behaviors, as well as encourage participants to recognize their own responsibility for safe food handling. This acknowledgement of an individual's responsibility and capacity to address food safety can be understood as self‐efficacy of food safety (SEFS). This study investigated the impact of a specific educational intervention, Hands On: Real‐World Lessons for Middle School Classrooms, curriculum on SEFS in adolescents and was guided by two research questions: (1) to what extent can an existing food safety curriculum impact students’ SEFS, and (2) to what extent does a relationship exist between changes in self‐efficacy and changes in food safety behavior, particularly when controlling for knowledge gains. A total sample of 424 students across 6 states participated in this study. Teachers were trained to implement the Hands On program in their classrooms and then students were administered a pre‐ and posttest to measure the impact of the program on knowledge, food safety‐related behaviors, and SEFS. The data indicated that there is a strong predictive relationship between SEFS and positive behavior change. Additionally, the Hands On program was effective at increasing students’ SEFS.
Project‐Based Learning Involving Sensory Panelists Improves Student Learning Outcomes
Authors: Lee Yee Ming
Published: March 2015

Project‐based, collaborative learning is an effective teaching method when compared to traditional cognitive learning. The purpose of this study was to assess student learning after the completion of a final meal project that involved a group of sensory panelists. A paper survey was conducted among 73 senior nutrition and dietetics students enrolling in Experimental Food Science, Spring 2013 and 2014. The survey comprised of qualitative and quantitative questions about students’ perceived learning outcomes. The project required students to prepare a 4‐course meal in 90 min, in groups of 4. Eighteen sensory panelists consisting of faculty and graduate students from the Nutrition, Dietetics, and Hospitality Management Department and administrative staff from the college evaluated the foods, asked students several food science‐related questions, and completed a survey about their involvement in the project. Students reported that this project reinforced class material (4.7 ± 0.6), and was enjoyable (4.6 ± 0.6) yet challenging (4.4 ± 0.7); numerous skills were developed, including team‐building (4.7 ± 0.5), food preparation (4.6 ± 0.5), and time management (4.4 ± 0.5). Students perceived that the involvement of sensory panelists was beneficial in terms of providing constructive feedback for improvement and motivating them to prepare high‐quality foods. It also prepared them for serving foods to individuals from different cultural backgrounds. However, some students found the experience stressful. For the sensory panelists, the project helped them to venture out of their areas of expertise. In conclusion, a meal project involving sensory panelists can result in positive learning outcomes.
Geographic Variation in Zygomaxillary Suture Morphology and its Use in Ancestry Estimation
Authors: Maddux Scott D. , Sporleder Alexandria N. , Burns Casey E.
Published: March 2015

Angled/curved zygomaxillary suture coding is widely employed in cranial assessments of ancestry. However, the efficacy of this method has not been extensively evaluated across diverse populations. In this study, zygomaxillary suture morphology was assessed on a total of 411 human crania from six populations (European, Native American, African, Asian, Arctic Circle, and Aboriginal Australian) using a novel 3D coordinate landmark method. Our results indicate a predominance of angled sutures among native peoples of the Arctic and North America (85–86%), a prevalence of curved sutures among Africans and Aboriginal Australians (77–81%), and essentially equal proportions of both configurations in Asians and Europeans (50–56%). Statistically, angled/curved coding generally discriminates poorly between groups, except when populations with antithetically high frequencies of the two configurations (e.g., African vs. Native American) are compared. Moreover, comparisons across previous studies reveal conflicting frequencies for many populations, further suggesting limited utility of this trait in ancestry estimation.
Free and Bound Volatile Chemicals in Mulberry (Morus atropurpurea Roxb.)
Authors: Chen Liang , Zhang Xiaoxu , Jin Qing , Yang Lili , Li Jingming , Chen Feng
Published: March 2015

Mulberry (Morus atropurpurea Roxb.) is a popular and desirable fruit that is widely cultivated in China. Despite its popularity, the free volatile chemicals and glycosidically bound volatiles (GBVs) of mulberry have been minimally studied. To this end, we have investigated these compounds in 4 mulberry cultivars via solid phase extraction (SPE) and headspace solid phase microextraction with gas chromatography–mass spectrometry (HS‐SPME‐GC‐MS). A total of 55 free volatile chemicals and 57 GBVs were identified and quantified. In 3 of the cultivars (“YFS,” “T10,” and “D10”), the GBVs were found in higher amounts than their free counterparts, corresponding to a ratio of 1.2 to 1.8. The characteristic aromas were determined by their odor activity values (OAVs) and by generating an aroma series (AS). A total of 20 volatile compounds had OAVs ≥ 1.0. In particular, ethyl butanoate, hexanal, (Z)‐3‐hexenal (E)‐2‐hexenal, (E)‐2‐nonenal, and eugenol had relatively high OAVs and were considered to be the key aromas contributing to the mulberry flavor. Consequently, mulberry was characterized by a variety of herbaceous scents having a background of sweet, spicy, fruity, and floral notes. The free volatiles exhibited strong herbaceous notes, whereas the GBVs were responsible for the sweet and spicy qualities of the fruit. Based on our results, 2 cultivars (“YFS” and “D10”) are proposed to be good candidates suitable for the further development of mulberry‐based food products due to their complex and desirable aromas.
Does increased adherence to medications change health care financial burdens for adults with diabetes?
Authors: Miller G. Edward , Sarpong Eric M. , Hill Steven C.
Published: March 2015

Background

The aim of the present study was to investigate increased out‐of‐pocket drug costs and financial burdens of achieving adherence to oral antidiabetic medications and medications for prevalent comorbidities.

Methods

Concurrent adherence to medications, out‐of‐pocket drug costs, and financial burdens were measured among non‐elderly adults with diabetes in the Medical Expenditure Panel Survey. “Financial burden” was defined as spending on health care exceeding 10% of family income. This study simulated the increased out‐of‐pocket drug costs and financial burdens that would result if non‐adherent adults in our sample had obtained sufficient medications to be adherent. For each adult, for all therapeutic classes in which they were non‐adherent, we calculated the additional days supplied required to become adherent, as well as out‐of‐pocket spending on these additional days supplied.

Results

Approximately one‐quarter adhered to all required medications. Among non‐adherent adults with employer‐sponsored insurance and public insurance, the mean annual out‐of‐pocket drug costs of achieving adherence were US$171 and US$68, respectively, which was generally affordable. However, 35.6% of the uninsured lived in families that spent 10% or more of their income on health care. Mean simulated additional out‐of‐pocket drug costs of achieving adherence were US$310 for the uninsured. These additional drug costs would increase those spending 10% or more of income to 39.6% of the uninsured.

Conclusions

Efforts to reduce the costs faced by the uninsured and insured will make adherence more affordable and, therefore, more attainable for some adults with diabetes.
How Much Abatement Will Australia's Emissions Reduction Fund Buy?*
Authors: Clarke Harry , Fraser Iain , Waschik Robert George
Published: March 2015

The economic implications for Australia for replacing its carbon tax policy with an Emissions Reduction Fund (ERF) scheme are examined. A computable general equilibrium model is used to show that the budget allocated for the ERF provides about 50 per cent of that required to meet Australia's greenhouse gas abatement commitments.
Does lower lifetime fluoridation exposure explain why people outside capital cities have poor clinical oral health?
Authors: Crocombe LA , Brennan DS , Slade GD
Published: March 2015

Background

Australians outside state capital cities have greater caries experience than their counterparts in capital cities. We hypothesized that differing water fluoridation exposure was associated with this disparity.

Methods

Data were the 2004–06 Australian National Survey of Adult Oral Health. Examiners measured participant decayed, missing and filled teeth and DMFT Index, and lifetime fluoridation exposure was quantified. Multivariable linear regression models estimated differences in caries experience between capital city residents and others, with and without adjustment for fluoridation exposure.

Results

There was greater mean lifetime fluoridation exposure in state capital cities (59.1%, 95% confidence interval = 56.9, 61.4) than outside capital cities (42.3, confidence interval = 36.9, 47.6). People located outside capital city areas had differing sociodemographic characteristics and dental visiting patterns, and a higher mean DMFT (capital cities = 12.9, non‐capital cities = 14.3, p = 0.02), than people from capital cities. After adjustment for sociodemographic characteristics and dental visits, DMFT of people living in capital cities was less than non‐capital city residents (regression coefficient = 0.8, p = 0.01). The disparity was no longer statistically significant (regression coefficient = 0.6, p = 0.09) after additional adjustment for fluoridation exposure.
Review article: spontaneous bacterial peritonitis – bacteriology, diagnosis, treatment, risk factors and prevention
Authors: Dever J. B. , Sheikh M. Y.
Published: March 2015

Background

Spontaneous bacterial peritonitis (SBP) is a severe and often fatal infection in patients with cirrhosis and ascites.

Aim

To review the known and changing bacteriology, risk factors, ascitic fluid interpretation, steps in performing paracentesis, treatment, prophylaxis and evolving perspectives related to SBP.

Methods

Information was obtained from reviewing medical literature accessible on PubMed Central. The search term ‘spontaneous bacterial peritonitis’ was cross‐referenced with ‘bacteria’, ‘risk factors’, ‘ascites’, ‘paracentesis’, ‘ascitic fluid analysis’, ‘diagnosis’, ‘treatment’, ‘antibiotics’, ‘prophylaxis’, ‘liver transplantation’ and ‘nutrition’.

Results

Gram‐positive cocci (GPC) such as Staphylococcus, Enterococcus as well as multi‐resistant bacteria have become common pathogens and have changed the conventional approach to treatment of SBP. Health care‐associated and nosocomial SBP infections should prompt greater vigilance and consideration for alternative antibiotic coverage. Acid suppressive and beta‐adrenergic antagonist therapies are strongly associated with SBP in at‐risk individuals.

Conclusions

Third‐generation, broad‐spectrum cephalosporins remain a good initial choice for SBP treatment. Levofloxacin is an acceptable alternative for patients not receiving long‐term flouroquinolone prophylaxis or for those with a penicillin allergy. For uncomplicated SBP, early oral switch therapy is reasonable. Alternative antibiotics such as pipercillin–tazobactam should be considered for patients with nosocomial SBP or for patients who fail to improve on traditional antibiotic regimens. Selective albumin supplementation remains an important adjunct in SBP treatment. Withholding acid suppressive medication deserves strong consideration, and discontinuing beta‐adrenergic antagonist therapy in patients with end‐stage liver disease and resistant ascites is standard care. Liver transplant evaluation should be undertaken for patients who develop SBP barring contraindications.
Effect of the route of administration on the mucosal and systemic immune responses to Lawsonia intracellularis vaccine in pigs
Authors: Nogueira MG , Collins AM , Dunlop RH , Emery D
Published: March 2015

In an on‐farm study, 40 weaned piglets aged 3 weeks were vaccinated with Lawsonia intracellularis vaccine orally, IM or IP while a fourth group remained unvaccinated. All vaccinated animals showed increased serum levels of L. intracellularis‐specific IgG antibodies, but significantly elevated concentrations of specific IgG, IgA and cytokines were generated in ileal mucosal secretions from the orally and IP vaccinated pigs when examined at 17 days after vaccination.
Mirabegron
Authors: Goulooze Sebastiaan C. , Cohen Adam F. , Rissmann Robert
Published: March 2015

Mirabegron is used for the treatment of symptoms associated with overactive bladder syndrome. It selectively stimulates the β3‐adrenoreceptor, which relaxes the detrusor muscle. This improves urine storage by distension of the bladder body.
Haematopoietic stem cell transplantation for refractory Langerhans cell histiocytosis: outcome by intensity of conditioning
Authors: Veys Paul A. , Nanduri Vasanta , Baker K. Scott , He Wensheng , Bandini Giuseppe , Biondi Andrea , Dalissier Arnaud , Davis Jeffrey H. , Eames Gretchen M. , Egeler R. Maarten , Filipovich Alexandra H. , Fischer Alain , Jürgens Herbert , Krance Robert , Lanino Edoardo , Leung Wing H. , Matthes Susanne , Michel Gérard , Orchard Paul J. , Pieczonka Anna , Ringdén Olle , Schlegel Paul G. , Sirvent Anne , Vettenranta Kim , Eapen Mary
Published: March 2015

Patients with Langerhans cell histiocytosis (LCH) refractory to conventional chemotherapy have a poor outcome. There are currently two promising treatment strategies for high‐risk patients: the first involves the combination of 2‐chlorodeoxyadenosine and cytarabine; the other approach is allogeneic haematopoietic stem cell transplantation (HSCT). Here we evaluated 87 patients with high‐risk LCH who were transplanted between 1990 and 2013. Prior to the year 2000, most patients underwent HSCT following myeloablative conditioning (MAC): only 5 of 20 patients (25%) survived with a high rate (55%) of transplant‐related mortality (TRM). After the year 2000 an increasing number of patients underwent HSCT with reduced intensity conditioning (RIC): 49/67 (73%) patients survived, however, the improved survival was not overtly achieved by the introduction of RIC regimens with similar 3‐year probability of survival after MAC (77%) and RIC transplantation (71%). There was no significant difference in TRM by conditioning regimen intensity but relapse rates were higher after RIC compared to MAC regimens (28% vs. 8%, P = 0·02), although most patients relapsing after RIC transplantation could be salvaged with further chemotherapy. HSCT may be a curative approach in 3 out of 4 patients with high risk LCH refractory to chemotherapy: the optimal choice of HSCT conditioning remains uncertain.
Identification and optimization of 2‐aminobenzimidazole derivatives as novel inhibitors of TRPC4 and TRPC5 channels
Authors: Zhu Yingmin , Lu Yungang , Qu Chunrong , Miller Melissa , Tian Jinbin , Thakur Dhananjay P , Zhu Jinmei , Deng Zixin , Hu Xianming , Wu Meng , McManus Owen B , Li Min , Hong Xuechuan , Zhu Michael X , Luo Huai‐Rong
Published: March 2015

Background and Purpose

Transient receptor potential canonical (TRPC) channels play important roles in a broad array of physiological functions and are involved in various diseases. However, due to a lack of potent subtype‐specific inhibitors the exact roles of TRPC channels in physiological and pathophysiological conditions have not been elucidated.

Experimental Approach

Using fluorescence membrane potential and Ca2+ assays and electrophysiological recordings, we characterized new 2‐aminobenzimidazole‐based small molecule inhibitors of TRPC4 and TRPC5 channels identified from cell‐based fluorescence high‐throughput screening.

Key Results

The original compound, M084, was a potent inhibitor of both TRPC4 and TRPC5, but was also a weak inhibitor of TRPC3. Structural modifications of the lead compound resulted in the identification of analogues with improved potency and selectivity for TRPC4 and TRPC5 channels. The aminobenzimidazole derivatives rapidly inhibited the TRPC4‐ and TRPC5‐mediated currents when applied from the extracellular side and this inhibition was independent of the mode of activation of these channels. The compounds effectively blocked the plateau potential mediated by TRPC4‐containing channels in mouse lateral septal neurons, but did not affect the activity of heterologously expressed TRPA1, TRPM8, TRPV1 or TRPV3 channels or that of the native voltage‐gated Na+, K+ and Ca2+ channels in dissociated neurons.

Conclusions and Implications

The TRPC4/C5‐selective inhibitors developed here represent novel and useful pharmaceutical tools for investigation of physiological and pathophysiological functions of TRPC4/C5 channels.
Interleukin-2 treatment reverses effects of cAMP-responsive element modulator α-over-expressing T cells in autoimmune-prone mice
Authors: Ohl K , Wiener A , Schippers A , Wagner N , Tenbrock K
Published: March 2015

Systemic autoimmune diseases, such as systemic lupus erythematosus (SLE), are often characterized by a failure of self-tolerance and result in an uncontrolled activation of B cells and effector T cells. Interleukin (IL)-2 critically maintains homeostasis of regulatory T cells (Treg) and effector T cells in the periphery. Previously, we identified the cAMP-responsive element modulator α (CREMα) as a major factor responsible for decreased IL-2 production in T cells from SLE patients. Additionally, using a transgenic mouse that specifically over-expresses CREMα in T cells (CD2CREMαtg), we provided in-vivo evidence that CREMα indeed suppresses IL-2 production. To analyse the effects of CREMα in an autoimmune prone mouse model we introduced a Fas mutation in the CD2CREMαtg mice (FVB/Fas–/–CD2CREMαtg). Overexpression of CREMα strongly accelerated the lymphadenopathy and splenomegaly in the FVB/Fas–/– mice. This was accompanied by a massive expansion of double-negative (DN) T cells, enhanced numbers of interferon (IFN)-γ-producing T cells and reduced percentages of Tregs. Treatment of FVB/Fas–/–CD2CREMαtg mice with IL-2 restored the percentage of Tregs and reversed increased IFN-γ production, but did not affect the number of DNTs. Our data indicate that CREMα contributes to the failure of tolerance in SLE by favouring effector T cells and decreasing regulatory T cells, partially mediated by repression of IL-2 in vivo.
Positive association between serum thymic stromal lymphopoietin and anti-citrullinated peptide antibodies in patients with rheumatoid arthritis
Authors: Koyama K , Ohba T , Haro H , Nakao A
Published: March 2015

Thymic stromal lymphopoietin (TSLP) has been suggested recently to play an important role in the pathophysiology of rheumatoid arthritis (RA). However, there is little information on serum TSLP concentrations in RA and its clinical significance. The present study investigated whether serum TSLP concentrations were affected in patients with RA. Using an enzyme-linked immunosorbent assay (ELISA), we measured TSLP concentrations in the serum obtained from 100 patients with RA, 60 patients with osteoarthritis (OA) and 34 healthy volunteers. We also investigated the correlation between serum TSLP concentrations and clinical parameters of disease activity in RA [disease activity score using 28 joint counts (DAS28)-C-reactive protein (CRP), DAS28-erythrocyte sedimentation rate (ESR), Clinical Disease Activity Index (CDAI]), patient's/-physician's Visual Analogue Scale (VAS), swollen joints count, tender joints count, CRP, ESR and matrix metalloproteinase-3 (MMP-3) concentrations]. In addition, we investigated the correlation between serum TSLP concentrations and anti-citrullinated peptide antibody (ACPA) and serum tumour necrosis factor (TNF)-α. Serum TSLP levels in patients with RA were significantly higher than those in patients with OA and in healthy volunteers. Interestingly, serum TSLP concentrations were correlated significantly with ACPA titres, but not with other clinical parameters. There was a significant increase in serum TSLP concentrations in patients with RA, which was correlated positively with serum ACPA titres. These findings suggest that in patients with RA, TSLP may play a role in ACPA production by B cells.
Severe micrognathia with 21 trisomy assessed prenatally by performing three‐dimensional computed tomography
Authors: Shigeta Naoya , Kanagawa Takeshi , Mimura Kazuya , Kimura Tadashi
Published: March 2015

Severe micrognathia can lead to death shortly after birth without a proper resuscitation. However, it is difficult to develop an effective resuscitation strategy without a prenatal diagnosis of the severity of micrognathia. In the present case, we used fetal three‐dimensional computed tomography (3D‐CT) to assess the severity of micrognathia. Its images clearly demonstrated bony framework of mandible and suggested that mandibular hypoplasia was too severe to allow for oral intubation. We therefore decided that the ex utero intrapartum treatment (EXIT) procedure would be more appropriate to establish the airway at birth. The prenatal 3D‐CT is useful to evaluate the mandibular anatomy in utero if the severity of the micrognathia is not confirmed by the ultrasound or magnetic resonance imaging (MRI).
Racial disparities in reaching the renal transplant waitlist: is geography as important as race?
Authors: Saunders Milda R. , Lee Haena , Alexander G. Caleb , Tak Hyo Jung , Thistlethwaite J. Richard , Ross Lainie Friedman
Published: March 2015

Background

In the United States, African Americans and whites differ in access to the deceased donor renal transplant waitlist. The extent to which racial disparities in waitlisting differ between United Network for Organ Sharing (UNOS) regions is understudied.

Methods

The US Renal Data System (USRDS) was linked with US census data to examine time from dialysis initiation to waitlisting for whites (n = 188 410) and African Americans (n = 144 335) using Cox proportional hazards across 11 UNOS regions, adjusting for potentially confounding individual, neighborhood, and state characteristics.

Results

Likelihood of waitlisting varies significantly by UNOS region, overall and by race. Additionally, African Americans face significantly lower likelihood of waitlisting compared to whites in all but two regions (1 and 6). Overall, 39% of African Americans with ESRD reside in Regions 3 and 4 – regions with a large racial disparity and where African Americans comprise a large proportion of the ESRD population. In these regions, the African American–white disparity is an important contributor to their overall regional disparity.

Conclusions

Race remains an important factor in time to transplant waitlist in the United States. Race contributes to overall regional disparities; however, the importance of race varies by UNOS region.
Understanding and treating painful diabetic neuropathy: time for a paradigm shift
Authors: Gandhi R. A. , Selvarajah D.
Published: March 2015

The pathogenesis of diabetic neuropathy (DN) continues to be unclear and as a result, progress in developing effective therapies has been disappointing. In particular, there is only limited understanding of why some patients suffer severe chronic pain, whilst others have painless symptoms. Assessment of the peripheral nerves frequently shows no differences between painful and painless DN. There is growing evidence that the nerve damage in DN is more generalized, including the central nervous system, and these central changes are key to the development and persistence of pain in DN. The advent of new radiological techniques provides us with non‐invasive modalities to study central pathophysiological processes in greater detail. These insights are increasingly leading to the recognition that painful DN is a complex and heterogeneous disorder, which requires a multimodal approach to treatment.
Physical activity as a determinant of fasting and 2‐h post‐challenge glucose: a prospective cohort analysis of the NAVIGATOR trial
Authors: Yates T. , Davies M. J. , Haffner S. M. , Schulte P. J. , Thomas L. , Huffman K. M. , Bales C. W. , Preiss D. , Califf R. M. , Holman R. R. , McMurray J. J. V. , Bethel M. A. , Tuomilehto J. , Kraus W. E.
Published: March 2015

Aim

To investigate whether previous physical activity levels are associated with blood glucose levels in individuals with impaired glucose tolerance in the context of an international pharmaceutical trial.

Methods

Data were analysed from the NAVIGATOR trial, which involved 9306 individuals with impaired glucose tolerance and high cardiovascular risk from 40 different countries, recruited in the period 2002–2004. Fasting glucose, 2‐h post‐challenge glucose and physical activity (pedometer) were assessed annually. A longitudinal regression analysis was used to determine whether physical activity levels 2 years (t‐2) and 1 year (t‐1) previously were associated with levels of glucose, after adjusting for previous glucose levels and other patient characteristics. Those participants with four consecutive annual measures of glucose and two consecutive measures of physical activity were included in the analysis.

Results

The analysis included 3964 individuals. Change in physical activity from t‐2 to t‐1 and activity levels at t‐2 were both associated with 2‐h glucose levels after adjustment for previous glucose levels and baseline characteristics; however, the associations were weak: a 100% increase in physical activity was associated with a 0.9% reduction in 2‐h glucose levels. In addition, previous physical activity only explained an additional 0.05% of the variance in 2‐h glucose over the variance explained by the history of 2‐h glucose alone (R2 = 0.3473 vs. 0.3468). There was no association with fasting glucose.

Conclusions

In the context of a large international clinical trial, previous physical activity levels did not meaningfully influence glucose levels in those with a high risk of chronic disease, after taking into account participants' previous trajectory of glucose control.
Artificial Pancreas Project at Cambridge 2013
Authors: Hovorka R.
Published: March 2015

The development and clinical testing of closed‐loop systems (the artificial pancreas) is underpinned by advances in continuous glucose monitoring and benefits from concerted academic and industry collaborative efforts. This review describes the progress of the Artificial Pancreas Project at the University of Cambridge from 2006 to 2014. Initial studies under controlled laboratory conditions, designed to collect representative safety and performance data, were followed by short to medium free‐living unsupervised outpatient studies demonstrating the safety and efficacy of closed‐loop insulin delivery using a model predictive control algorithm. Accompanying investigations included assessment of the psychosocial impact and key factors affecting glucose control such as insulin kinetics and glucose absorption. Translation to other disease conditions such as critical illness and Type 2 diabetes took place. It is concluded that innovation of iteratively enhanced closed‐loop systems will provide tangible means to improve outcomes and quality of life in people with Type 1 diabetes and their families in the next decade.
Significant Reduction in Mitral Regurgitation Volume Is the Main Contributor for Increase in Systolic Forward Flow in Patients with Functional Mitral Regurgitation after Transcatheter Aortic Valve Replacement: Hemodynamic Analysis Using Echocardiography
Authors: Itabashi Yuji , Shibayama Kentaro , Mihara Hirotsugu , Utsunomiya Hiroto , Berdejo Javier , Arsanjani Reza , Siegel Robert , Chakravarty Tarun , Jilaihawi Hasan , Makkar Raj R. , Shiota Takahiro
Published: March 2015

Background

Reduction in mitral regurgitation (MR) after transcatheter aortic valve replacement (TAVR) has previously been reported. However, the hemodynamic effects of TAVR in patients with MR have not been previously evaluated.

Methods

We analyzed 571 patients who underwent TAVR from December 2010 to December 2013. We studied 20 patients with moderate or severe preprocedural functional mitral regurgitation (FMR) who also had a follow‐up transthoracic echocardiography (TTE) examination between 90 and 360 days (median 213 days) after TAVR (Significant FMR Group). We also studied age‐ and gender‐matched 20 patients with mild or lesser MR (Nonsignificant MR Group). Left ventricular functional measurements were assessed using echocardiography before and after TAVR. Left ventricular outflow tract stroke volume measurements using pulsed‐wave Doppler (SVLVOT) were calculated as a representative of systolic forward flow, and stroke volume by the Simpson's method (SVSimpson) was calculated as a parameter of degree of LV contraction.

Results

MR grade improved in 22 of 40 patients after TAVR. In both groups, BNP level decreased, left ventricular ejection fraction increased, and SVLVOT increased after TAVR. SVSimpson increased in the Nonsignificant MR Group and remained unchanged in the Significant FMR Group. Vena contracta width of MR (MRVC) decreased in the Significant FMR Group. Using multivariable analysis in the Significant FMR Group, the increase in SVLVOT significantly correlated with the decrease in MRVC (P < 0.05).

Conclusions

SVLVOT increased significantly after TAVR in patients with FMR. In these patients, increase in SVLVOT after TAVR was associated with decrease in severity of MR.
Origin of termite eusociality: trophallaxis integrates the social, nutritional, and microbial environments
Authors: NALEPA CHRISTINE A.
Published: March 2015

1. Numerous cladistic analyses have converged: termites are a monophyletic clade embedded within the paraphyletic cockroaches, and sister group to the biparental, wood‐feeding cockroach Cryptocercus. The latter is, therefore, an appropriate model for testing assumptions regarding early termite evolution.

2. The ground plan of the termite ancestor is reviewed based on shared characters of ecology, life history, and behaviour in Cryptocercus and incipient termite colonies, and includes two levels of dependence: a reliance of all individuals on gut microbiota, and dependence of early instars on parental care. Both these conditions co‐evolved with parent‐to‐offspring proctodeal trophallaxis.

3. The termite ancestor lived in a single log serving as food and nest. This ‘one‐piece’ nesting ecology prioritises nitrogen conservation and strongly influences interacting social, nutritional, and microbial environments. Each of these environments individually and in combination profoundly affect cockroach development.

4. Proctodeal trophallaxis integrates the social, nutritional, and microbial environments. A change in trophallactic behaviour, from parental to alloparental, can, therefore, shift developmental trajectories, ultimately adding a third level of dependence. The death of gut protists during the host molting period and consequent interdependence of family members shifted the hierarchical level at which selection acted; fixation of eusociality quickly followed.

5. The basic nesting ecology did not change when termites evolved eusociality, the change occurred in the allocation and use of existing resources within the social group, driven by nitrogen scarcity, mediated by trophallaxis, and made possible by a strongly lineage‐specific set of life history characteristics.