bluuebunny/crossref_metadata_2025 huggingface dataset:
Tumor budding, a novel prognostic indicator for predicting stage progression in T1 bladder cancers
Authors: Fukumoto Keishiro , Kikuchi Eiji , Mikami Shuji , Ogihara Koichiro , Matsumoto Kazuhiro , Miyajima Akira , Oya Mototsugu
Published: June 2016

Tumor budding has been defined as an isolated single cancer cell or a cluster composed of fewer than five cancer cells scattered in the stroma. It is a strong predictor for lymph node metastasis in T1 colorectal cancer. We introduced this concept to T1 non‐muscle invasive bladder cancer and evaluated whether tumor budding could have a prognostic impact on the clinical outcome. We identified 121 consecutive patients with newly diagnosed T1 bladder cancer between 1994 and 2014 at Keio University Hospital. All slides were re‐reviewed by a dedicated uropathologist. Budding foci were counted under ×200 magnification. When the number of budding foci was 10 or more, tumor budding was defined as positive. The relationship between tumor budding and clinical outcomes was assessed using a multivariate analysis. The median follow‐up was 52 months. Tumor budding was positive in 21 patients (17.4%). Tumor budding was significantly associated with T1 substaging, tumor architecture and lymphovascular invasion. The 5‐year progression‐free survival rate in T1 bladder cancer patients with tumor budding was 53.8%, which was significantly lower than that in patients without tumor budding (88.4%, P = 0.001). A multivariate Cox regression analysis revealed that tumor budding was independently associated with stage progression (P = 0.002, hazard ratio = 4.90). In a subgroup of patients treated with bacillus Calmette‐Guérin instillation (n = 88), tumor budding was also independently associated with stage progression (P = 0.003, hazard ratio = 5.65). Tumor budding may be a novel indicator for predicting stage progression in T1 bladder cancer, and would likely be easily introduced in clinical practice.
Response to chemotherapy improves hepatic reserve for patients with hepatocellular carcinoma and Child–Pugh B cirrhosis
Authors: Terashima Takeshi , Yamashita Tatsuya , Arai Kuniaki , Kawaguchi Kazunori , Kitamura Kazuya , Yamashita Taro , Sakai Yoshio , Mizukoshi Eishiro , Honda Masao , Kaneko Shuichi
Published: June 2016

There is no established treatment for patients with advanced hepatocellular carcinoma (HCC) with Child–Pugh class B cirrhosis. The aim of the present study was to assess the efficacy of hepatic arterial infusion chemotherapy (HAIC) according to Child–Pugh score (CPS) and to evaluate the correlation of a patient's response to HAIC with hepatic reserve and outcome. We retrospectively reviewed the medical records of 377 patients treated with HAIC between March 2003 and February 2015. Subjects included 179 with Child–Pugh class B. Median overall survival was 12.1 months for patients with CPS = 7 (n = 75) and 11.9 months for patients with CPS = 8 (n = 58), which were significantly longer compared with those of patients with CPS = 9 (n = 46, 6.3 months). The objective response rates of patients with CPS = 7, 8 and 9 were 26.7%, 27.6% and 6.5%, respectively. The CPS of responders improved significantly after HAIC, whereas those of nonresponders did not. A multivariate analysis demonstrated that improved CPS, responses to HAIC and absence of extrahepatic lesions were independent favorable prognostic factors. Patients with CPS = 7 or 8 tolerated HAIC, but nine (19.6%) of patients with CPS = 9 were unable to complete one course. HAIC is effective and safe for patients with a CPS = 7 or 8 and improved hepatic reserve of responders significantly.
Synthesis, structure–activity relationship studies and biological evaluation of novel 2,5‐disubstituted indole derivatives as anticancer agents
Authors: Hu Hongyu , Wu Jun , Ao Mingtao , Wang Huiru , Zhou Tongtong , Xue Yuhua , Qiu Yingkun , Fang Meijuan , Wu Zhen
Published: June 2016

Three novel series of 2,5‐disubstituted indole derivatives were synthesized and evaluated in vitro for their antiproliferative activity against human cancer cells and HIV‐1 inhibition activity used as a readout of cellular activity. Most compounds were found to have potent anticancer activity. In particular, 2c and 3b which showed effectively to repress HIV‐1 transcription had a pan antiproliferative activity in cervical cancer cells (HeLa), breast cancer cells (MCF‐7), liver cancer cells (HepG2), and lung cancer cells (H460 and A549). While 3b exhibited high sensitivity to A549 cells with the IC50 value 0.48 ± 0.15 μm, 2c showed high selectivity toward HepG2 cells with the IC50 value 13.21 ± 0.30 μm. With respect to the cellular mechanism of action, HepG2 cells treated with 2c and A549 cells treated with 3b for 24 h were studied by annexin V/PI staining and Western blot analysis, and results revealed that 2c and 3b may induce cancer cells apoptosis through inhibiting the phosphorylation at Ser2 of RNAPII CTD which can be phosphorylated by cyclin‐dependent kinase 9. These studies indicated that 2c and 3b may develop as potent lead compounds in the therapy of cancer. However, determining their roles in preventing HIV‐1 still requires further intensive study.
Young Children Detect and Avoid Logically Inconsistent Sources: The Importance of Communicative Context and Executive Function
Authors: Doebel Sabine , Rowell Shaina F. , Koenig Melissa A.
Published: June 2016

The reported research tested the hypothesis that young children detect logical inconsistency in communicative contexts that support the evaluation of speakers’ epistemic reliability. In two experiments (N = 194), 3‐ to 5‐year‐olds were presented with two speakers who expressed logically consistent or inconsistent claims. Three‐year‐olds failed to detect inconsistencies (Experiment 1), 4‐year‐olds detected inconsistencies when expressed by human speakers but not when read from books, and 5‐year‐olds detected inconsistencies in both contexts (Experiment 2). In both experiments, children demonstrated skepticism toward testimony from previously inconsistent sources. Executive function and working memory each predicted inconsistency detection. These findings indicate logical inconsistency understanding emerges in early childhood, is supported by social and domain general cognitive skills, and plays a role in adaptive learning from testimony.
Extensive surgery and lymphadenectomy do not improve survival in primary melanoma of the anorectum: results from analysis of a large database (SEER)
Authors: Ciarrocchi A. , Pietroletti R. , Carlei F. , Amicucci G.
Published: June 2016

Aim

Primary anorectal melanoma is a rare disease with a dismal prognosis due to early distant metastasis. The prognostic value of positive loco‐regional lymph nodes and the impact of lymphadenectomy on overall survival are unclear. We have investigated this by analysis of data obtained from a national representative database, controlling for potential confounders.

Methods

Data were retrieved from the Surveillance, Epidemiology and End Results (SEER) database. Multiple imputation analysis was performed to deal with missing data. Cox regression models were formulated using different prognostic factors including site of origin, gender, size, race, rate of lymph node metastasis (ratio between positive lymph node count and total lymph nodes harvested), extent of lymphadenectomy (none, level I etc.), age, type of surgery, stage of disease and administration of radiotherapy.

Results

Our population was composed of 208 patients who underwent surgery between 1998 and 2012. Rate of lymph node metastasis (P = 0.027; hazard ratio 1.873, 95% CI 1.076–3.261) and race (P = 0.019; hazard ratio 2.291, 95% CI 1.148–4.575) were found to be independent predictors of survival.

Conclusion

Based on the data retrieved from the SEER database, metastasis to loco‐regional lymph nodes is an important prognostic factor, but lymphadenectomy does not improve survival.
External validation of a prognostic model of preoperative risk factors for failure of restorative proctocolectomy
Authors: Sahami S. , Bartels S. A. L. , D'Hoore A. , Young Fadok T. , Tanis P. J. , de Buck van Overstraeten A. , Wolthuis A. M. , Buskens C. J. , Bemelman W. A.
Published: June 2016

Aim

The Cleveland Clinic has proposed a prognostic model of preoperative risk factors for failure of restorative proctocolectomy (RPC) with ileal pouch–anal anastomosis. The model incorporates four predictive variables: completion proctectomy, handsewn anastomosis, diabetes mellitus and Crohn's disease. The aim of the present study was to perform an external validation of this model in a new cohort of patients who had RPC.

Method

Validation was performed in a multicentre cohort of 747 consecutive patients who had an RPC between 1990 and 2015 in three tertiary‐care facilities, using a Kaplan–Meier survival analysis and Cox regression analysis. The performance of the model was expressed using the Harrell concordance error rate. The primary outcome measure was pouch survival with maintenance of anal function.

Results

During the study period, 45 (6.0%) patients experienced failure at a median interval of 31 months (interquartile range 9–82 months) from the original RPC. Multivariable analysis showed handsewn anastomosis to be the only significant independent predictor. The Harrell concordance error rate was 0.42, indicating poor performance. Anastomotic leakage and Crohn's disease of the pouch were strong postoperative predictors for pouch failure and showed a significant difference in pouch survival after 10 years (P < 0.001).

Conclusion

The poor performance of the Cleveland Clinic prognostic model makes it unsuitable for daily clinical practice. Handsewn anastomosis was associated with pouch failure in our cohort with relatively few events. A prediction model for anastomotic leakage or Crohn's disease of the pouch may be a better solution since these variables are strongly associated with pouch failure.
Adolescent development of insula‐dependent interoceptive regulation
Authors: Li Dawei , Zucker Nancy L. , Kragel Philip A. , Covington Virginia E. , LaBar Kevin S.
Published: June 2016

Adolescence is hypothesized to be a critical period for the maturation of self‐regulatory capacities, including those that depend on interoceptive sensitivity, but the neural basis of interoceptive regulation in adolescence is unknown. We used functional magnetic resonance imaging and psychophysiology to study interoceptive regulation in healthy adolescent females. Participants regulated their gut activities in response to a virtual roller coaster by deep breathing aided by visually monitoring their online electrogastrogram (EGG) activity through a virtual thermometer (i.e. gut biofeedback), or without biofeedback. Analyses focused on the insula, given its putative role in interoception. The bilateral posterior insula showed increased activation in the no‐biofeedback compared to biofeedback condition, suggesting that the participants relied more on interoceptive input when exteroceptive feedback was unavailable. The bilateral dorsal anterior insula showed activation linearly associated with age during both induction and regulation, and its activation during regulation correlated positively with change of EGG in the tachygastria frequency band from induction to regulation. Induction‐related activation in the bilateral ventral anterior insula was nonlinearly associated with age and peaked at mid‐adolescence. These results implicate different developmental trajectories of distinct sub‐regions of the insula in interoceptive processes, with implications for competing neurobiological theories of female adolescent development.
The North Atlantic Oscillation synchronises fruit production in western European forests
Authors: Fernández‐Martínez Marcos , Vicca Sara , Janssens Ivan A. , Espelta Josep Maria , Peñuelas Josep
Published: June 2016

Weather and its lagged effects have been associated with interannual variability and synchrony of fruit production for several tree species. Such relationships are used often in hypotheses relating interannual variability in fruit production with tree resources or favourable pollinating conditions and with synchrony in fruit production among sites through the Moran effect (the synchronisation of biological processes among populations driven by meteorological variability) or the local availability of pollen. Climatic teleconnections, such as the North Atlantic Oscillation (NAO), representing weather packages, however, have rarely been correlated with fruit production, despite often being better predictors of ecological processes than is local weather. The aim of this study was to test the utility of seasonal NAO indices for predicting interannual variability and synchrony in fruit production using data from 76 forests of Abies alba, Fagus sylvatica, Picea abies, Pseudotsuga menziesii, Quercus petraea, and Q. robur distributed across central Europe. Interannual variability in fruit production for all species was significantly correlated with seasonal NAO indices, which were more prominently important predictors than local meteorological variables. The relationships identified by these analyses indicated that proximal causes were mostly responsible for the interannual variability in fruit production, supporting the premise that local tree resources and favourable pollinating conditions are needed to produce large fruit crops. Synchrony in fruit production between forests was mainly associated with weather and geographical distance among sites. Also, fruit production for a given year was less variable among sites during warm and dry springs (negative spring NAO phases). Our results identify the Moran effect as the most likely mechanism for synchronisation of fruit production at large geographical scales and the possibility that pollen availability plays a role in synchronising fruit production at local scales. Our results highlight the influence of the NAO on the patterns of fruit production across western Europe.
Parallel inputs from the mediodorsal thalamus to the prefrontal cortex in the rat
Authors: Alcaraz Fabien , Marchand Alain R. , Courtand Gilles , Coutureau Etienne , Wolff Mathieu
Published: June 2016

There is a growing interest in determining the functional contribution of thalamic inputs to cortical functions. In the context of adaptive behaviours, identifying the precise role of the mediodorsal thalamus (MD) in particular remains difficult despite the large amount of experimental data available. A better understanding of the thalamocortical connectivity of this region may help to capture its functional role. To address this issue, this study focused exclusively on the specific connections from the MD to the prefrontal cortex (PFC) by means of direct comparisons of labelling produced by single and dual injections of retrograde tracers in the different subdivisions of the PFC in the rat. We show that at least three parallel and essentially separate thalamocortical pathways originate from the MD, as follows: projections to the dorsal (1) and the ventral (2) subdivisions of the mPFC follow a mediolateral topography at the thalamic level (i.e. medial thalamic neurons target the mPFC ventrally whereas lateral thalamic neurons project dorsally), whereas a considerable innervation to the OFC (3) includes thalamic cells projecting to both the lateral and the ventral OFC subdivisions. These observations provide new insight on the functions of the MD and suggest a specific focus on each of these pathways for future functional studies.
A biologically plausible mechanism for neuronal coding organized by the phase of alpha oscillations
Authors: Gips Bart , van der Eerden Jan P. J. M. , Jensen Ole
Published: June 2016

The visual system receives a wealth of sensory information of which only little is relevant for behaviour. We present a mechanism in which alpha oscillations serve to prioritize different components of visual information. By way of simulated neuronal networks, we show that inhibitory modulation in the alpha range (~ 10 Hz) can serve to temporally segment the visual information to prevent information overload. Coupled excitatory and inhibitory neurons generate a gamma rhythm in which information is segmented and sorted according to excitability in each alpha cycle. Further details are coded by distributed neuronal firing patterns within each gamma cycle. The network model produces coupling between alpha phase and gamma (40–100 Hz) amplitude in the simulated local field potential similar to that observed experimentally in human and animal recordings.
Trophic cascades in the bryosphere: the impact of global change factors on top‐down control of cyanobacterial N2‐fixation
Authors: Kardol Paul , Spitzer Clydecia M. , Gundale Michael J. , Nilsson Marie‐Charlotte , Wardle David A.
Published: June 2016

Trophic cascades in which predators regulate densities of organisms at lower trophic levels are important drivers of population dynamics, but effects of trophic cascades on ecosystem‐level fluxes and processes, and the conditions under which top‐down control is important, remain unresolved. We manipulated the structure of a food web in boreal feather mosses and found that moss‐inhabiting microfauna exerted top‐down control of N2‐fixation by moss‐associated cyanobacteria. However, the presence of higher trophic levels alleviated this top‐down control, likely through feeding on bacterivorous microfauna. These effects of food‐web structure on cyanobacterial N2‐fixation were dependent on global change factors and strongly suppressed under N fertilisation. Our findings illustrate how food web interactions and trophic cascades can regulate N cycling in boreal ecosystems, where carbon uptake is generally strongly N‐limited, and shifting trophic control of N cycling under global change is therefore likely to impact ecosystem functioning.
Long‐term socioeconomic consequences and health care costs of childhood and adolescent‐onset epilepsy
Authors: Jennum Poul , Christensen Jakob , Ibsen Rikke , Kjellberg Jakob
Published: June 2016

Objective

To estimate long‐term socioeconomic consequences and health care costs of epilepsy with onset in childhood and adolescence.

Methods

A historical prospective cohort study of Danish individuals with epilepsy, age up to 20 years at time of diagnosis between January 1981 and December 2012. Information about marital status, parenthood, educational level, employment status, income, use of the health care system, and cost of medicine was obtained from nationwide administrative and health registers.

Results

We identified 12,756 and 28,319 people with diagnosed with epilepsy, ages 0–5 and 6–20 years at onset, respectively. Using follow‐up data for a maximum of 30 years, 1,394 of those ages 0–5 years at onset were compared with 2,897 controls persons without epilepsy, and 10,195 of those ages 6–20 years at onset were compared with 20,678 controls without epilepsy. Compared with people without the epilepsy, those with epilepsy tended to have a lower level of education, to be less likely to be married, to be more likely to live alone, and to have higher divorce and unemployment rates, lower employment rates, and people with epilepsy were more likely to receive disability pension and social security. Income was lower from employment, which in part was compensated by social security, sick pay, disability pension and unemployment benefit, sick pay (public‐funded), disability pension, and other public transfers. Predicted health care costs 30 years after epilepsy onset were significantly higher among persons with epilepsy onset at 0–5 and 6–20 years, including costs for outpatient and inpatient services (hospital services), emergency room use, primary health care sector (general practice), and use of medication.

Significance

The long‐term negative effects on all aspects of health care and social domains, including marital status, parental socioeconomic status, educational level, employment status, and use of welfare benefits compared with controls without epilepsy calls for increased awareness on childhood‐ and adolescent‐onset epilepsy.
Withdrawal of valproic acid treatment during pregnancy and seizure outcome: Observations from EURAP
Authors: Tomson Torbjörn , Battino Dina , Bonizzoni Erminio , Craig John , Lindhout Dick , Perucca Emilio , Sabers Anne , Thomas Sanjeev V , Vajda Frank ,   the EURAP Study Group
Published: June 2016

Based on data from the EURAP observational International registry of antiepileptic drugs (AEDs) and pregnancy, we assessed changes in seizure control and subsequent AED changes in women who underwent attempts to withdraw valproic acid (VPA) during the first trimester of pregnancy. Applying Bayesian statistics, we compared seizure control in pregnancies where VPA was withdrawn (withdrawal group, n = 93), switched to another AED (switch group, n = 38), or maintained (maintained‐therapy group, n = 1,588) during the first trimester. The probability of primarily or secondarily generalized tonic–clonic seizures (GTCS) was lower in the maintained‐therapy group compared with the other two groups, both in the first trimester and for the entire duration of pregnancy. GTCS were twice as common during pregnancy in the withdrawal (33%) and switch groups (29%) compared with the maintained‐treatment group (16%). Limitations in the data and study design do not allow to establish a cause–effect relationship between treatment changes and seizure outcome, but these observations provide a signal that withdrawal of, or switch from, VPA during the first trimester could lead to loss of seizure control, and highlight the need for a specifically designed prospective observational study.
Risk Control: Who Cares?
Authors: Taylor Nick
Published: June 2016

The performance of recently introduced risk‐control indices is evaluated and tested with respect to a set of competing indices. Applying a method of moments methodology to these data reveals that the performance of strategies that track risk‐control indices have economic and statistical significance to investors with realistic risk aversion parameter values. However, this performance varies over time and appears to be determined by macroeconomic and liquidity conditions.
Squamous cell carcinoma and keratoacanthomas are biologically distinct and can be diagnosed by light microscopy: a review
Authors: Selmer Johan , Skov Torsten , Spelman Lynda , Weedon David
Published: June 2016

Keratoacanthomas (KAs) are self‐limiting squamoproliferative lesions usually seen on sun damaged skin. These tumours are in many ways enigmatic, and the relation between KAs and squamous cell carcinoma is still a contested topic. In this review the biology and histology of KAs will be discussed, and based on morphology, clinical outcome and recent genetic analysis of the tumour types, we conclude that KAs and SCCs are two distinct biological entities which can usually be distinguished by conventional microscopy. The sentinel observation of rapid and frequent appearance of KAs after BRAF treatment of malignant melanoma patients has paved the way for a more general understanding of the pathogenesis leading to the appearance of KAs in patients with inflammation in the skin. In BRAF treated patients, the KAs are a consequence of paradoxical activation of the MAP kinase pathway. Similarly, any external trauma or pharmaceutical interventions resulting in inflammation in the skin will activate the MAP kinase pathway. Such inflammation‐mediated MAP kinase activation in the skin will result in the development of KAs through the same pathway as demonstrated for BRAF treated patients. It is characteristic that skin tumours following short acting inflammatory stimulation of severely sun damaged skin develop almost exclusively into KAs, whereas it is exceedingly rare that such inflammatory conditions lead to formation of SCCs. The understanding that inflammatory reactions in sun‐damaged skin may activate pathways specifically leading to the formation of KAs may spare the patient the discomfort and disfigurement of needless overtreatment.
The added values of multiplex reverse transcriptase‐PCR followed by mutation screening in the initial evaluation of acute leukemia
Authors: Kim B. , Cho Y.‐U. , Bae M.‐H. , Jang S. , Seo E.‐J. , Chi H.‐S. , Park C.‐J.
Published: June 2016

Introduction

This study investigates the benefits of using multiplex reverse transcriptase‐PCR (RT‐PCR) in addition to standard karyotyping during the initial evaluation of acute leukemia.

Methods

A total of 1114 consecutive specimens from patients with acute leukemia were tested using a commercial multiplex RT‐PCR kit (HemaVision, DNA Diagnostic). NPM1 and CEBPA mutations were selectively tested in acute myeloid leukemia (AML) patients with multiplex RT‐PCR negativity.

Results

In specimens with optimal cytogenetics, the frequency of recurrent translocations was 31.3%, and cryptic translocations were detected in 2.1% of samples. The concordance rate between karyotyping and multiplex RT‐PCR was 97.5%. In addition to the established functions, we demonstrated the additional benefits of multiplex RT‐PCR, including successful molecular characterization, even in cytogenetically suboptimal specimens (5.7%); detection of submicroscopic aberrations (1.0%); detection of rare but potentially significant translocations or variants (2.5%); selection of AML candidates for mutation analysis (68.3%); and finally exclusion of recurrent translocations in patients with acute lymphoblastic leukemia or mixed phenotype acute leukemia (22.5%).

Conclusion

We reconfirmed the accuracy and reliability of multiplex RT‐PCR for diagnosing acute leukemia and demonstrated additional advantages of this system for the initial evaluation of acute leukemia. Thus, multiplex RT‐PCR is worth considering in diagnostic testing of acute leukemias.
The value of eosinophil VCS parameters in predicting hepatotoxicity of antituberculosis drugs
Authors: Shen T. , Gu D. , Zhu Y. , Shi J. , Xu D. , Cao X.
Published: June 2016

Introduction

Drug‐induced liver injury (DILI) is the most frequent cause of discontinuation of antituberculosis medication and difficult to predict. In recent years, liver eosinophilia has been associated with incidence of DILI. We hypothesize that morphologic changes in reactive eosinophils associated with DILI may be determined by LH750 (Beckman Coulter, Fullerton, CA) with VCS technology.

Methods

The absolute eosinophil (AEC), percentage of eosinophil (EOSI%), VCS parameters, and standard deviation (SD) of 500 health controls, 376 patients without DILI, and 50 DILI patients were compared in terms of diagnostic sensitivity and specificity for DILI.

Results

In DILI patients, the increased mean eosinophil volume (MEV) and size variability (MEV‐SD) were observed prior to alanine aminotransferase (ALT) elevations. The MEV was correlated well with ALT after therapy. The ROC curve analyses revealed that the MEV and MEV‐SD had larger areas under curves (0.894, 0.815, in the week prior to DILI) compared to other parameters. Using a cutoff of 163.15 fL for the MEV and a cutoff of 17.11 for MEV‐SD, the sensitivities of 81% and 72% and specificities of 82% and 80% were achieved, respectively, which are higher than other parameters prior to DILI occurred.

Conclusions

The MEV with size variability (MEV‐SD) is a quantitative, objective, and more sensitive parameter and has a potential to be an additional indicator for DILI.
Intracellular recycling and cross‐presentation by MHC class I molecules
Authors: van Endert Peter
Published: June 2016

Cross‐presentation of internalized antigens by dendritic cells requires efficient delivery of Major Histocompatibility Complex (MHC) class I molecules to peptide‐loading compartments. Strong evidence suggests that such loading can occur outside of the endoplasmic reticulum; however, the trafficking pathways and sources of class I molecules involved are poorly understood. Examination of non‐professional, non‐phagocytic cells has revealed a clathrin‐independent, Arf6‐dependent recycling pathway likely traveled by internalized optimally loaded (closed) class I molecules. Some closed and all open MHC class I molecules travel to late endosomes to be degraded but might also partly be re‐loaded with peptides and recycled. Studies of viral interference revealed pathways in which class I molecules are directed to degradation in lysosomes upon ubiquitination at the surface, or upon AP‐1 and HIV‐nef‐dependent misrouting from the Golgi network to lysosomes. While many observations made in non‐professional cells remain to be re‐examined in dendritic cells, available evidence suggests that both recycling and neo‐synthesized class I molecules can be loaded with cross‐presented peptides. Recycling molecules can be recruited to phagosomes triggered by innate signals such as TLR4 ligands, and may therefore specialize in loading with phagocytosed antigens. In contrast, AP‐1‐dependent accumulation at, or trafficking through, a Golgi compartment of newly synthesized molecules appears to be important for cross‐presentation of soluble proteins and possibly of long peptides that are processed in the so‐called vacuolar pathway. However, significant cell biological work will be required to confirm this or any other model and to integrate knowledge on MHC class I biochemistry and trafficking in models of CD8+ T‐cell priming by dendritic cells.
Regulation of protein synthesis and autophagy in activated dendritic cells: implications for antigen processing and presentation
Authors: Argüello Rafael J. , Reverendo Marisa , Gatti Evelina , Pierre Philippe
Published: June 2016

Antigenic peptides presented in the context of major histocompatibility complex (MHC) molecules originate from the degradation of both self and non‐self proteins. T cells can therefore recognize at the surface of surveyed cells, the self‐peptidome produced by the cell itself (mostly inducing tolerance) or immunogenic peptides derived from exogenous origins. The initiation of adaptive immune responses by dendritic cells (DCs), through the antigenic priming of naïve T cells, is associated to microbial pattern recognition receptors engagement. Activation of DCs by microbial product or inflammatory cytokines initiates multiple processes that maximize DC capacity to present exogenous antigens and stimulate T cells by affecting major metabolic and membrane traffic pathways. These include the modulation of protein synthesis, the regulation of MHC and co‐stimulatory molecules transport, as well as the regulation of autophagy, that, all together promote exogenous antigen presentation while limiting the display of self‐antigens by MHC molecules.
Dynamics of the membrane–cytoskeleton interface in MHC class II‐restricted antigen presentation
Authors: Bretou Marine , Kumari Anita , Malbec Odile , Moreau Hélène D. , Obino Dorian , Pierobon Paolo , Randrian Violaine , Sáez Pablo J. , Lennon‐Duménil Ana‐Maria
Published: June 2016

Antigen presentation refers to the ability of cells to show MHC‐associated determinants to T lymphocytes, leading to their activation. MHC class II molecules mainly present peptide‐derived antigens that are internalized by endocytosis in antigen‐presenting cells (APCs). Here, we describe how the interface between cellular membranes and the cytoskeleton regulates the various steps that lead to the presentation of exogenous antigens on MHC class II molecules in the two main types of APCs: dendritic cells (DCs) and B lymphocytes. This includes antigen uptake, processing, APC migration, and APC–T cell interactions. We further discuss how the interaction between APC‐specific molecules and cytoskeleton elements allows the coordination of antigen presentation and cell migration in time and space.
The role of islet antigen presenting cells and the presentation of insulin in the initiation of autoimmune diabetes in the NOD mouse
Authors: Unanue Emil R. , Ferris Stephen T. , Carrero Javier A.
Published: June 2016

We have been examining antigen presentation and the antigen presenting cells (APCs) in the islets of Langerhans of the non‐obese diabetic (NOD) mouse. The purpose is to identify the earliest events that initiate autoimmunity in this confined tissue. Islets normally have a population of macrophages that is distinct from those that inhabit the exocrine pancreas. Also found in NOD islets is a minor population of dendritic cells (DCs) that bear the CD103 integrin. We find close interactions between beta cells and the two APCs that result in the initiation of the autoimmunity. Even under non‐inflammatory conditions, beta cells transfer insulin‐containing vesicles to the APCs of the islet. This reaction requires live cells and intimate contact. The autoimmune process starts in islets with the entrance of CD4+ T cells and an increase in the CD103+ DCs. Mice deficient in the Batf3 transcription factor never develop diabetes due to the absence of the CD103/CD8α lineage of DCs. We hypothesize that the 12–20 peptide of the beta chain of insulin is responsible for activation of the initial CD4+ T‐cell response during diabetogenesis.
Influence of the Doctor Blade Shape on Tape Casting—Comparison Between Analytical, Numerical, and Experimental Results
Authors: Polfer Pit , Fu Zongwen , Breinlinger Thomas , Roosen Andreas , Kraft Torsten
Published: June 2016

In this study, the influence of the shape of the doctor blade on the flow inside the tape casting unit and on the resulting tape properties is investigated both numerically and experimentally. Using the results from the analysis of the produced tape and from the simulations of the flow inside the tape casting unit, the relationships between blade geometry and the particle orientation in the resulting tape, as well as the resulting tape thickness, are shown. Additionally, the experimentally and numerically obtained results were compared to an analytical model for the prediction of the tape thickness. The simulations were carried out using the particle‐based smoothed particle hydrodynamics method using a non‐Newtonian fluid model to describe the ceramic slurry. Both in experiment and simulation, the influence of the blade geometry on the resulting tape shows good agreement.
The quest of pain education leaders in Canada and the United States: a qualitative study
Authors: Carr Eloise C.J. , Watt‐Watson Judy , McGillion Michael , Huizinga Anne
Published: June 2016

Aims

To determine key factors that stimulate and drive the ongoing interests of leaders in the field of pain to continue to work for change and to explore how they use their own experiences in their teaching.

Background

The assessment and management of acute and chronic pain remains a challenge and the pain education of pre‐licensure/undergraduate health professionals (e.g. nurses, physicians, etc.) continues to be suboptimal. Understanding the motivations of pain leaders may provide insights to facilitate the future development of pain clinicians.

Design

A Narrative enquiry.

Methods

A purposeful sample of 17 Canadian and USA leaders in pain education participated. Data were collected between September 2012–January 2013 using recorded semi‐structured telephone interviews. Transcripts were coded to provide storied experiences (themes).

Findings

Six themes were identified as a stimulus for pain leaders: An early pain experience, mentorship and circumstances, a personal shift in understanding, catalysts (institutional or political), recognition of barriers and a determination to improve. Their work towards change appeared to be motivated by their pain ‘quest’ where leaders embraced their personal experiences of pain, a need for social action and individual change.

Conclusions

Educational approaches for health professionals usually focus on the importance of knowledge, skills and attitudes to be competent in pain care. To inspire and educate young health professionals about pain management we suggest the development of future pain leaders may require a different approach that recognizes personal stories of pain, includes a local pain champion and incorporates a model of mentorship.
Post‐fledging family space use in blue and great tit: similarities and species‐specific behaviours
Authors: van Overveld Thijs , Vardakis Michalis , Arvidsson Lisa , Stolk Kristine , Adriaensen Frank , Matthysen Erik
Published: June 2016

In birds, parental escorting of dependent young to feeding areas outside the breeding territory is a commonly observed, yet poorly documented phenomenon. Using radio‐tracking, we provide a detailed description of the post‐fledging movements of 12 blue tit Cyanistes caeruleus families and compare these observations with a much larger dataset of the closely related great tit Parus major collected over several years in the same study area. The proportion of families making excursions outside woodlots was similar in both species (± 50%), but the spatial extent of these movements tended to be larger in blue tits (mean ± SE: 1100 m ± 265, range: 643–2374, n = 6) as compared to great tits (mean ± SE: 666 m ± 42, range: 245–1898, n = 64). Blue tit families foraged significantly more in oak habitat within woodlots, independently of excursion behaviour, whereas great tits undertaking excursions shifted their range use towards more variable habitat outside woodlots. The observed excursions of blue tits appeared multiple‐day or permanent shifts of the family range, and not daily excursions as most frequently observed in great tits. Although family movements in both species may be largely driven by common underlying factors, our results also points toward species‐specific difference in spatial behaviour which may be linked with foraging specializations and post‐fledging territory fidelity.
Commentary: Supporting preterm children's parents matters – a reflection on Treyvaud et al. (2016)
Authors: Jaekel Julia
Published: June 2016

Children born preterm or with low birth weight (LBW) grow up with an increased risk for a range of neurodevelopmental, cognitive, socioemotional, and academic problems. While long‐term effects of preterm and LBW birth have traditionally been studied from a deficit perspective, Treyvaud et al. correctly state that the increased risk for impairments in this population urgently requires identification of protective factors. Their new findings add to empirical evidence from observational studies showing that sensitive parenting can protect preterm children from negative developmental outcomes. In order to identify strategies that support preterm children's life chances, well‐designed longitudinal studies, such as the one by Treyvaud et al., are indispensable. Next, we will need large randomized trials to test the causality between intervention‐induced parenting changes and preterm children's long‐term outcomes. We need interdisciplinary and international collaboration to study preterm parent–child dyads within multimethod frameworks and uncover the highly complex mechanisms that shape individual developmental trajectories.
Commentary: Predicting outcomes of treatment for anxiety disorders – using data from fear learning paradigms. A commentary on Waters and Pine (2016)
Authors: Barry Tom J. , Lau Jennifer Y. F.
Published: June 2016

Despite the apparent effectiveness of cognitive‐behavioral therapy (CBT) in the treatment of anxiety disorders, more can be done to predict individual variability in the effectiveness of CBT. One potentially useful predictor involves individual differences in fear inhibition and extinction as similar learning processes are thought to be involved in CBT. Waters and Pine (this issue) present an investigation of the relationship between pretreatment indices of fear extinction and responsiveness to CBT among children with anxiety disorders. We discuss these findings and place them within the context of supporting evidence from neurobiological and genetic research. Various novel ways in which different elements of fear inhibition and extinction can be quantified are then outlined, and the potential utility of this approach for clinicians and researchers particularly in developmental samples is discussed.
The pay‐offs of maternal care increase as offspring develop, favouring extended provisioning in an egg‐feeding frog
Authors: Dugas M. B. , Moore M. P. , Martin R. A. , Richards‐Zawacki C. L. , Sprehn C. G.
Published: June 2016

Offspring quantity and quality are components of parental fitness that cannot be maximized simultaneously. When the benefits of investing in offspring quality decline, parents are expected to shift investment towards offspring quantity (other reproductive opportunities). Even when mothers retain complete control of resource allocation, offspring control whether to allocate investment to growth or development towards independence, and this shared control may generate parent–offspring conflict over the duration of care. We examined these predictions by, in a captive colony, experimentally removing tadpoles of the strawberry poison frog (Oophaga pumilio) from the mothers that provision them with trophic eggs throughout development. Tadpoles removed from their mothers were no less likely to survive to nutritional independence (i.e. through metamorphosis) than were those that remained with their mothers, but these offspring were smaller at metamorphosis and were less likely to survive to reach adult size, even though they were fedad libitum. Tadpoles that remained with their mothers developed more slowly than those not receiving care, a pattern that might suggest that offspring extracted more care than was in mothers’ best interests. However, the fitness returns of providing care increased with offspring development, suggesting that mothers would be best off continuing care until tadpoles initiated metamorphosis. Although the benefits of parental investment in offspring quality are often thought to asymptote at high levels, driving parent–offspring conflict over weaning, this assumption may not hold over natural ranges of investment, with selection on both parents and offspring favouring extended durations of parental care.
Sibship effects on dispersal behaviour in a pre‐industrial human population
Authors: Nitsch A. , Lummaa V. , Faurie C.
Published: June 2016

Understanding dispersal behaviour and its determinants is critical for studies on life‐history maximizing strategies. Although many studies have investigated the causes of dispersal, few have focused on the importance of sibship, despite that sibling interactions are predicted to lead to intrafamilial differences in dispersal patterns. Using a large demographic data set from pre‐industrial Finland (n = 9000), we tested whether the sex‐specific probability of dispersal depended on the presence of same‐sex or opposite‐sex elder siblings who can both compete and cooperate in the family. Overall, following our predictions, the presence of same‐sex elder siblings increased the probability of dispersal from natal population for both sexes, whereas the number of opposite‐sex siblings had less influence. Among males, dispersal was strongly linked to access to land resources. Female dispersal was mainly associated with competition over availability of mates but likely mediated by competition over access to wealthy mates rather mate availabilityper se. Besides ecological constraints, sibling interactions are strongly linked with dispersal decisions and need to be better considered in the studies on the evolution of family dynamics and fitness maximizing strategies in humans and other species.
Cognitive and Neural Effects of Vision‐Based Speed‐of‐Processing Training in Older Adults with Amnestic Mild Cognitive Impairment: A Pilot Study
Authors: Lin Feng , Heffner Kathi L. , Ren Ping , Tivarus Madalina E. , Brasch Judith , Chen Ding‐Geng , Mapstone Mark , Porsteinsson Anton P. , Tadin Duje
Published: June 2016

Objectives

To examine the cognitive and neural effects of vision‐based speed‐of‐processing (VSOP) training in older adults with amnestic mild cognitive impairment (aMCI) and contrast those effects with an active control (mental leisure activities (MLA)).

Design

Randomized single‐blind controlled pilot trial.

Setting

Academic medical center.

Participants

Individuals with aMCI (N = 21).

Intervention

Six‐week computerized VSOP training.

Measurements

Multiple cognitive processing measures, instrumental activities of daily living (IADLs), and two resting state neural networks regulating cognitive processing: central executive network (CEN) and default mode network (DMN).

Results

VSOP training led to significantly greater improvements in trained (processing speed and attention: F1,19 = 6.61, partial η2 = 0.26, P = .02) and untrained (working memory: F1,19 = 7.33, partial η2 = 0.28, P = .01; IADLs: F1,19 = 5.16, partial η2 = 0.21, P = .03) cognitive domains than MLA and protective maintenance in DMN (F1, 9 = 14.63, partial η2 = 0.62, P = .004). VSOP training, but not MLA, resulted in a significant improvement in CEN connectivity (Z = −2.37, P = .02).

Conclusion

Target and transfer effects of VSOP training were identified, and links between VSOP training and two neural networks associated with aMCI were found. These findings highlight the potential of VSOP training to slow cognitive decline in individuals with aMCI. Further delineation of mechanisms underlying VSOP‐induced plasticity is necessary to understand in which populations and under what conditions such training may be most effective.
Interventions to Address Potentially Inappropriate Prescribing in Community‐Dwelling Older Adults: A Systematic Review of Randomized Controlled Trials
Authors: Clyne Barbara , Fitzgerald Ciaran , Quinlan Aisling , Hardy Colin , Galvin Rose , Fahey Tom , Smith Susan M.
Published: June 2016

Objectives

To perform a systematic review to determine the effectiveness of interventions designed to reduce potentially inappropriate prescribing (PIP) in community‐dwelling older adults.

Design

Systematic review and narrative synthesis.

Setting

Primary and community care.

Participants

Community‐dwelling older adults.

Measurements

The primary outcome was change in PIP measured using implicit or explicit tools. Studies were grouped into organizational, professional, financial, regulatory, and multifaceted interventions.

Results

Twelve randomized controlled trials were identified with baseline PIP prevalence of 18% to 100%. Four of six organizational interventions reported a reduction in PIP, particularly through pharmacists conducting medication reviews. Evidence of the effectiveness of multidisciplinary teams was weak. Both of the two professional (targeting prescriber's directly) interventions were computerized clinical decision support interventions and were effective in decreasing new PIP but not existing PIP. Three of four multifaceted approaches were effective in reducing PIP. The risk of bias was often high, particularly in reporting selection bias.

Conclusion

Interventions including organizational (pharmacist interventions), professional (computerized clinical decision support systems), and multifaceted approaches appear beneficial in terms of reducing PIP, but the range of effect sizes reported was modest, and it is unclear whether such interventions can result in clinically significant improvements in patient outcomes. Ongoing assessment of interventions to reduce PIP is needed in community‐dwelling older adults, particularly in relation to preventing initiation of PIP.