bluuebunny/crossref_metadata_2025 huggingface dataset:
Impaired cognitive performance under psycho-social stress in cannabis-dependent males is mediated by attenuated precuneus activity
Authors: Zhao Weihua , Zimmermann Kaeli , Zhou Xinqi , Zhou Feng , Fu Meina , Dernbach Christian , Scheele Dirk , Weber Bernd , Eckstein Monika , Hurlemann René , Kendrick Keith M , Becker Benjamin
Published: September 2018

Background

Deficient regulation of stress plays an important role in the escalation of substance use, addiction and relapse. Accumulating evidence suggests dysregulations in cognitive and reward-related processes and the underlying neural circuitry in cannabis dependence. However, despite the important regulatory role of the endocannabinoid system in the stress response, associations between chronic cannabis use and altered stress processing on the neural level have not been systematically examined.

Methods

Against this background, the present functional magnetic resonance imaging (fMRI)study examined psycho-social stress processing in cannabis-dependent males (n = 28) and matched controls (n = 23) using an established stress-induction paradigm (Montreal Imaging Stress Task) that combines computerized (adaptive) mental arithmetic challenges with social evaluative threat.

Results

During psycho-social stress exposure, but not the no-stress condition, cannabis users demonstrated impaired performance relative to controls. In contrast, levels of experienced stress and cardiovascular stress responsivity did not differ from controls. Functional MRI data revealed that stress-induced performance deteriorations in cannabis users were accompanied by decreased precuneus activity and increased connectivity of this region with the dorsal medial prefrontal cortex.

Limitations

Only male cannabis-dependent users were examined, the generalizability in female users remains to be determined.

Conclusion

Together, the present findings provide first evidence for exaggerated stress-induced cognitive performance deteriorations in cannabis users. The neural data suggest that deficient stress-related dynamics of the precuneus may mediate the deterioration of performance on the behavioral level.
Identification of a Sulf2-dependant astrocyte subtype that stands out through the expression of Olig2 in the ventral spinal cord
Authors: Ohayon David , Escalas Nathalie , Cochard Philippe , Glise Bruno , Danesin Cathy , Soula Cathy
Published: September 2018

During spinal cord development, both spatial and temporal mechanisms operate to generate glial cell diversity. Here, we addressed the role of the Heparan Sulfate-editing enzyme Sulf2 in the control of gliogenesis in the mouse developing spinal cord and found an unanticipated function for this enzyme. Sulf2 is expressed in ventral spinal progenitors at initiation of gliogenesis, including in Olig2-expressing cells of the pMN domain known to generate most spinal cord oligodendrocyte precursor cells (OPCs). We found that Sulf2 is dispensable for OPC development but required for proper generation of an as-yet-unidentified astrocyte precursor cell (AP) subtype. These cells, like OPCs, express Olig2 while populating the spinal parenchyma at embryonic stages but also retain Olig2 expression as they differentiate into mature astrocytes. We therefore identify a spinal Olig2-expressing AP subtype that segregates early under the influence of the extracellular enzyme Sulf2.
Comparative evidence for the independent evolution of hair and sweat gland traits in primates
Authors: Kamberov Yana G. , Guhan Samantha M. , DeMarchis Alessandra , Jiang Judy , Wright Sara Sherwood , Morgan Bruce A. , Sabeti Pardis C. , Tabin Clifford J. , Lieberman Daniel E.
Published: September 2018

Humans differ in many respects from other primates, but perhaps no derived human feature is more striking than our naked skin. Long purported to be adaptive, humans’ unique external appearance is characterized by changes in both the patterning of hair follicles and eccrine sweat glands, producing decreased hair cover and increased sweat gland density. Despite the conspicuousness of these features and their potential evolutionary importance, there is a lack of clarity regarding how they evolved within the primate lineage. We thus collected and quantified the density of hair follicles and eccrine sweat glands from five regions of the skin in three species of primates: macaque, chimpanzee and human. Although human hair cover is greatly attenuated relative to that of our close relatives, we find that humans have a chimpanzee-like hair density that is significantly lower than that of macaques. In contrast, eccrine gland density is on average 10-fold higher in humans compared to chimpanzees and macaques, whose density is strikingly similar. Our findings suggest that a decrease in hair density in the ancestors of humans and apes was followed by an increase in eccrine gland density and a reduction in fur cover in humans. This work answers longstanding questions about the traits that make human skin unique and substantiates a model in which the evolution of expanded eccrine gland density was exclusive to the human lineage.
Nitrogen recycling in coupled green and brown food webs: Weak effects of herbivory and detritivory when nitrogen passes through soil
Authors: Buchkowski Robert W. , Schmitz Oswald J. , Bradford Mark A.
Published: September 2018

The study of coupled green and brown food webs has improved our ability to understand how nutrient cycling and plant communities respond to perturbations. Yet, it is still difficult to predict how rapidly and consistently changes in one food web propagate to the other. An area of particular uncertainty is the response of plants to the changes in leaf litter nitrogen release caused by herbivores and detritivores.

We combined a field experiment and theoretical analysis to assess how herbivory, fertilization, and detritivory changed leaf litter nitrogen release and plant growth. We produced leaf litter in greenhouse cages with a factorial combination of grasshopper herbivory and additional nitrogen fertilizer. Our experiment used the resulting 15N‐labelled leaf litter to measure isopod litter consumption, litter nitrogen release, and plant nitrogen uptake in the field. We then used a dynamical systems model to distinguish whether plant growth relied (a) directly on litter nitrogen release or (b) on other nitrogen pathways so that changes in litter nitrogen release have little immediate impact.

Our empirical results show that the effect of nitrogen fertilization on isopod processing of leaf litter was stronger than the effect of herbivory. Regardless, the available soil nitrogen and plant growth were independent of litter nitrogen release. Our dynamical model attributes the independence to other nitrogen sources and sinks, which buffer the plant‐available nitrogen pool. Isopods and litter with a history of herbivory reduced above‐ground plant growth when we accounted for initial field mesocosm conditions, especially the abundance of the competitively dominant goldenrods. Consequently, the impact of isopods and litter traits do propagate to influence plant growth, but do not have a large enough effect to overcome initial differences in plant biomass and community composition in one year.

Synthesis. Our results indicate animals in green and brown food webs can alter plant litter nitrogen release without any significant nutrient recycling effect on plant growth. Considering the availability of external and soil‐based nitrogen sources, as well as the current plant community and microbial biomass, may be critical to determining when plant growth will respond to animal‐mediated changes in litter decomposition.
What can deliberative mini‐publics contribute to democratic systems?
Authors: BEAUVAIS EDANA , WARREN MARK E.
Published: September 2018

Can deliberative mini‐publics contribute to deepening the democratic dimensions of electoral democracies? The question is framed in this article using a problem‐based approach to democratic theory–to count as democratic, political systems must accomplish three basic functions related to inclusion, communication and deliberation, and decision making. This approach is elaborated with an analysis of a real‐world case: a deliberative mini‐public with a citizens’ assembly design, focused on urban planning convened in Vancouver, Canada. This example was chosen because the context was one in which the city's legacy institutions of representative democracy had significant democratic deficits in all three areas, and the mini‐public was a direct response to these deficits. It was found that Vancouver's deliberative mini‐public helped policy makers, activists and affected residents move a stalemated planning process forward, and did do so in ways that improved the democratic performance of the political system. Depending on when and how they are sequenced into democratic processes, deliberative mini‐publics can supplement existing legacy institutions and practices to deepen their democratic performance.
Efficacy of Surgicel® (Fibrillar) for preventing bleeding after endoscopic submucosal dissection for gastric epithelial tumors
Authors: Hwang Jae Jin , Hong Su Jin , Han Jae Pil , Ko Bong Min , Lee Tae Hee , Lee Joon Seong
Published: September 2018

Objective

Surgicel (Fibrillar), i.e. oxidized regenerated cellulose, is used to control oozing bleeding after surgery, but few studies have assessed its effect on complications after endoscopic treatment. The aim of this study was to evaluate the efficacy of Surgicel for preventing bleeding after endoscopic submucosal dissection (ESD) for gastric epithelial tumors.

Methods

From November 2012 to December 2013 patients scheduled for ESD of gastric epithelial tumors were prospectively enrolled in this study. Patients were assigned randomly to monotherapy with a proton pump inhibitor (PPI) (the MT group) or combination therapy with Surgicel and histamine‐2 receptor antagonist (H2RA) (the CT group) for preventing bleeding after ESD. Major bleeding rates and changes in hemoglobin at 1 and 7 days after ESD were evaluated.

Results

Among the 157 patients enrolled (111 men, 46 women), 78 were assigned to the MT group and 79 to the CT group; finally, 72 and 74 patients were included in the MT and CT groups. The major bleeding rate was lower in the CT group (6/74, 8.1%) than in the MT group (12/72, 16.7%), but the difference was not significant (P = 0.354). The change in hemoglobin was significantly less marked in the CT group than the MT group 1 day after ESD ([−6.2 ± 9.0] g/L vs [−8.9 ± 6.2] g/L, P = 0.045).

Conclusions

Combination therapy with Surgicel and an H2RA decreased the rate of bleeding similarly to PPI. Adding Surgicel to H2RA could be considered for patients with bleeding tendencies, or who require continuous antiplatelet therapy to prevent bleeding after ESD.
Leveraging a Participatory Process for Restoration Return on Investment: The Nature Conservancy's Floodplain Investment Tool
Authors: Lyon Steve W. , Cunha Luciana , DiBlasio Michelle , Creveling Ellen
Published: September 2018

In this study, we develop the Floodplain Investment Tool (FPIT) to help stakeholders prioritize conservation efforts to maximize return on investments (e.g., ensure the most “bang for the buck”). We applied the FPIT for the 177 mi2 (458 km2) Paulins Kill watershed located in northwestern New Jersey, as a case study focusing on nutrient loading. The resultant FPIT reflected independently assessed habitat and ecosystem impairment scores across the watershed. Nutrient load (both total phosphorus [TP] and total nitrogen [TN]) estimates made with the FPIT were in relative agreement across scales with a more robust modeling approach and allowed for development of several application scenarios. For example, we estimated a well‐targeted budget of $2 million could reduce annual nutrient load to be approximately 530 lbs (240 kg) of TP and 5,835 lbs (2,647 kg) of TN for the watershed. Where the clear value for the FPIT can be seen is in the process by which it was pilot‐tested for application and stakeholder voices were integrated into its development. This allows for a level of transparency not available from more top‐down approaches where stakeholders are involved only at the end of the development process.
Contouring consensus guidelines in breast cancer radiotherapy: Comparison and systematic review of patterns of failure
Authors: Gee Harriet E , Moses Lauren , Stuart Kirsty , Nahar Najmun , Tiver Ken , Wang Tim , Ward Rachel , Ahern Verity
Published: September 2018

Adequate coverage of sites harbouring potential microscopic disease is paramount, where the clinical decision has been made to include regional lymph node radiotherapy for patients with breast cancer. This must be achieved in balance with minimising dose to normal tissues. Several international consensus guidelines detailing clinical target volumes (CTVs) are available, but there is currently no agreement as to which is most appropriate for a given clinical situation. Contouring guidelines are beneficial for routine practice and essential for clinical trial quality assurance. The aims of this study were as follows: to provide a single point of comparison of four commonly used contouring guidelines, including one used in a current Trans‐Tasman Radiation Oncology Group trial; and to undertake a systematic review of existing studies which map sites of breast cancer recurrence against contouring guidelines. Two international consensus guidelines (European Society for Radiotherapy and Oncology, and Radiation Therapy Oncology Group) were compared with two clinical trial guidelines (TROG 12.02 PET LABRADOR and the Proton/Photon trial NCT02603341 RADCOMP). Comprehensive literature search for patterns of failure studies was undertaken using Embase and Pubmed. We detail the small but significant differences between the breast consensus guidelines, particularly the supraclavicular (SCF) and internal mammary chain CTVs. Seven series were found mapping recurrence patterns. These results are discussed in the context of the contouring guidelines. Several studies found the SCF CTV is the area at greatest risk of geographical ‘miss’. This review will facilitate further discussion about guideline selection and modification, particularly for future clinical trials in Australia and New Zealand.
Inconsistent use of multiple comparison corrections in studies of population genetic structure: Are some type I errors more tolerable than others?
Authors: Hauser Samantha , Wakeland Kristin , Leberg Paul
Published: September 2018

Studies of genetic population structure often involve numerous tests of Hardy–Weinberg equilibrium (HWE), linkage disequilibrium (LD) and genetic differentiation. Tests of HWE or LD are important precursors to population structure assessments. When conducting multiple related statistical tests, type I error increases, e.g., familywise error rate (FWER) inflation. FWER inflation can alter the results of statistical tests and thus the conclusions. We surveyed literature from 2011 to 2013 to determine if studies of population structure assess LD and HWE and if FWER corrections were applied consistently across different types of tests. We found significantly inconsistent FWER corrections, with a bias towards less restrictive correction on genetic differentiation and more restrictive corrections with LD and HWE. While varied adjustments of FWER for different types of analyses might be justified, papers with inconsistent usage across tests of HWE, LD and genetic differentiation did not present rationale for their FWER corrections. We also found a lack of documentation of HWE, LD and FWER corrections in studies. We encourage the authors to report statistical tests and related FWER corrections, use FWER corrections consistently or justify their different methods in the same study.
Pollen metabarcoding as a tool for tracking long‐distance insect migrations
Authors: Suchan Tomasz , Talavera Gerard , Sáez Llorenç , Ronikier Michał , Vila Roger
Published: September 2018

Insects account for a large portion of Earth's biodiversity and are key players for ecosystems, notably as pollinators. While insect migration is suspected to represent a natural phenomenon of major importance, remarkably little is known about it, except for a few flagship species. The reason for this situation is mainly due to technical limitations in the study of insect movement. Here, we propose using metabarcoding of pollen carried by insects as a method for tracking their migrations. We developed a flexible and simple protocol allowing efficient multiplexing and not requiring DNA extraction, one of the most time‐consuming part of metabarcoding protocols, and apply this method to the study of the long‐distance migration of the butterfly Vanessa cardui, an emerging model for insect migration. We collected 47 butterfly samples along the Mediterranean coast of Spain in spring and performed metabarcoding of pollen collected from their bodies to test for potential arrivals from the African continent. In total, we detected 157 plant species from 23 orders, most of which (82.8%) were insect‐pollinated. Taxa present in Africa–Arabia represented 73.2% of our data set, and 19.1% were endemic to this region, strongly supporting the hypothesis that migratory butterflies colonize southern Europe from Africa in spring. Moreover, our data suggest that a northwards trans‐Saharan migration in spring is plausible for early arrivals (February) into Europe, as shown by the presence of Saharan floristic elements. Our results demonstrate the possibility of regular insect‐mediated transcontinental pollination, with potential implications for ecosystem functioning, agriculture and plant phylogeography.
Blocking FGFR4 exerts distinct anti‐tumorigenic effects in esophageal squamous cell carcinoma
Authors: Xin Zhongwei , Song Xuemin , Jiang Bin , Gongsun Xin , Song Liang , Qin Qiming , Wang Qiang , Shi Mo , Liu Xiangyan
Published: September 2018

Background

The FGFR family can be activated by FGFs and plays important roles in regulating cell growth, differentiation, migration, and angiogenesis. Recent studies have suggested that FGFR4 could regulate several processes, including tumor progression. Esophageal squamous cell carcinoma (ESCC) is a malignancy with high global occurrence. However, the molecule mechanism and the potential roles of FGFR4 in ESCC remain unknown.

Methods

Immunohistochemistry and Western blotting were used to detect FGFR4 expression in ESCC samples and cell lines. Cell counting kit‐8, and clonogenic, transwell, flow cytometric, and tumor xenograft in nude mice assays were utilized to determine the effect of blocking FGFR4 in proliferation, invasion, migration, and apoptosis of ESCC cells.

Results

FGFR4 is frequently overexpressed in ESCC tissue and cell lines. in vitro assays have shown that blocking FGFR4 by a specific blocker, H3B‐6527, significantly decreases proliferation, invasion, and migration, and alters epithelial‐mesenchymal transition markers in ESCC cells. In addition, FGFR4 blockade is associated with the induction of apoptosis and affects PI3K/Akt and MAPK/ERK pathways. Moreover, FGFR4 blockade could significantly inhibit the growth of xenograft tumors in vivo.

Conclusion

Our findings suggest that blocking FGFR4 significantly suppresses the malignant behaviors of ESCC and indicate that FGFR4 is a potential target for the treatment of ESCC.
Tight junction, mucin, and inflammasome‐related molecules are differentially expressed in eosinophilic, mixed, and neutrophilic experimental asthma in mice
Authors: Tan Hern‐Tze Tina , Hagner Stefanie , Ruchti Fiorella , Radzikowska Urszula , Tan Ge , Altunbulakli Can , Eljaszewicz Andrzej , Moniuszko Marcin , Akdis Mübeccel , Akdis Cezmi A. , Garn Holger , Sokolowska Milena
Published: September 2018

Background

Asthma is a chronic respiratory disease with marked clinical and pathophysiological heterogeneity. Specific pathways are thought to be involved in the pathomechanisms of different inflammatory phenotypes of asthma; however, direct in vivo comparison has not been performed.

Methods

We developed mouse models representing three different phenotypes of allergic airway inflammation—eosinophilic, mixed, and neutrophilic asthma via different methods of house dust mite sensitization and challenge. Transcriptomic analysis of the lungs, followed by the RT‐PCR, western blot, and confocal microscopy, was performed. Primary human bronchial epithelial cells cultured in air‐liquid interface were used to study the mechanisms revealed in the in vivo models.

Results

By whole‐genome transcriptome profiling of the lung, we found that airway tight junction (TJ), mucin, and inflammasome‐related genes are differentially expressed in these distinct phenotypes. Further analysis of proteins from these families revealed that Zo‐1 and Cldn18 were downregulated in all phenotypes, while increased Cldn4 expression was characteristic for neutrophilic airway inflammation. Mucins Clca1 (Gob5) and Muc5ac were upregulated in eosinophilic and even more in neutrophilic phenotype. Increased expression of inflammasome‐related molecules such as Nlrp3, Nlrc4, Casp‐1, and IL‐1β was characteristic for neutrophilic asthma. In addition, we showed that inflammasome/Th17/neutrophilic axis cytokine—IL‐1β—may transiently impair epithelial barrier function, while IL‐1β and IL‐17 increase mucin expressions in primary human bronchial epithelial cells.

Conclusion

Our findings suggest that differential expression of TJ, mucin, and inflammasome‐related molecules in distinct inflammatory phenotypes of asthma may be linked to pathophysiology and might reflect the differences observed in the clinic.
Using clinical and genetic data to predict pulmonary hypertension in bronchopulmonary dysplasia
Authors: Trittmann J K , Bartenschlag A , Zmuda E J , Frick J , Stewart W C L , Nelin L D
Published: September 2018

Aim

Pulmonary hypertension significantly increases morbidity and mortality in infants with bronchopulmonary dysplasia. The frequency of single nucleotide polymorphisms in arginase‐1 (ARG1 rs2781666) and dimethylarginine dimethylaminohydrolase‐1 (DDAH1 rs480414) genes has been found to differ in a cohort of bronchopulmonary dysplasia patients with pulmonary hypertension (cases) and without pulmonary hypertension (controls). Therefore, we tested the hypothesis that combining these genotypes with phenotypic data would better predict pulmonary hypertension in bronchopulmonary dysplasia patients.

Methods

Bronchopulmonary dysplasia patients (n = 79) born at <35 weeks gestation were studied. Pulmonary hypertension was diagnosed by echocardiographic criteria (n = 20). ROC curves to predict pulmonary hypertension in bronchopulmonary dysplasia were generated from genotype and/or clinical data.

Results

Cases were born at an earlier gestation and weighed less at birth than did controls. ROC curves for rs2781666 had an AUC of 0.61, while rs480414 had an AUC of 0.66. Together, the AUC was 0.70. When clinical data were added to the genetic model, AUC was 0.73.

Conclusion

These findings demonstrate that ROC predictive modelling of pulmonary hypertension in bronchopulmonary dysplasia improves with inclusion of both genotypic and phenotypic data. Further refinement of these types of models could facilitate the implementation of precision medicine approaches to pulmonary hypertension in bronchopulmonary dysplasia.
Semi-Supervised Validation of Multiple Surrogate Outcomes with Application to Electronic Medical Records Phenotyping
Authors: Hong Chuan , Liao Katherine P. , Cai Tianxi
Published: September 2018

The Electronic Medical Records (EMR) data linked with genomic data have facilitated efficient and large scale translational studies. One major challenge in using EMR for translational research is the difficulty in accurately and efficiently annotating disease phenotypes due to the low accuracy of billing codes and the time involved with manual chart review. Recent efforts such as those by the Electronic Medical Records and Genomics (eMERGE) Network and Informatics for Integrating Biology & the Bedside (i2b2) have led to an increasing number of algorithms available for classifying various disease phenotypes. Investigators can apply such algorithms to obtain predicted phenotypes for their specific EMR study. They typically perform a small validation study within their cohort to assess the algorithm performance and then subsequently treat the algorithm classification as the true phenotype for downstream genetic association analyses. Despite the superior performance compared to simple billing codes, these algorithms may not port well across institutions, leading to bias and low power for association studies. In this paper, we propose a semi-supervised method to make inferences about both the accuracy of multiple available algorithms and the effect of genetic markers on the true phenotype, leveraging information from both a large set of unlabeled data where both genetic markers and algorithm output information and a small validation data where labels are additionally available. The simulation studies show that the proposed method substantially outperforms existing methods from the missing data literature. The proposed methods are applied to an EMR study of how low density lipoprotein risk alleles affect the risk of cardiovascular disease among patients with rheumatoid arthritis.
Mid‐term safety and efficacy of the ALTIS® single‐incision sling for female stress urinary incontinence: less mesh, same results
Authors: Morán Eduardo , Pérez‐Ardavín Javier , Sánchez Jose V. , Bonillo Miguel A. , Martínez‐Cuenca Esther , Arlandis Salvador , Broseta Enric , Boronat Francisco
Published: September 2018

Objective

To analyse the mid‐term safety and efficacy of the ALTIS® single‐incision sling (Coloplast Corp., Minneapolis, MN, USA) for female stress urinary incontinence (SUI).

Patients and Methods

We conducted a prospective, single‐arm, unsponsored, observational single‐centre trial in a cohort of patients undergoing SUI surgery with the ALTIS procedure. All patients were diagnosed according to clinical reports, physical exploration and urodynamics. Body mass index (BMI) was categorised according to World Health Organization classification. Valsalva leak‐point pressure (VLPP) was categorised in three groups: <60, 60–90 and >90 cmH2O. Patients were evaluated postoperatively at 1, 6, 12 and 24 months with physical examination, International Consultation on Incontinence Questionnaire Short Form (ICIQ‐SF), and satisfaction visual scale (SVS; score 0–10). Adverse events were assessed at each visit. Multivariate analysis for risk factors of surgery failure was performed.

Results

We recruited 110 women, with a mean (SD) follow‐up of 22.34 (10.34) months. Regarding efficacy, 91 patients (82.7%) were objectively cured and 97 (88.2%) were subjectively cured. Regarding VLPP and BMI, no differences were seen between groups (P > 0.05). There was a ~20% decrease in urge UI (P = 0.04). No variable showed to be an independent risk factor for ALTIS failure (P > 0.05). Overall, nearly 96% of the women reported 9 or 10 points on the SVS. A total of 24 patients (21.8%) had some kind of complication. No mesh erosion was reported in any patient.

Conclusions

The ALTIS sling demonstrated to be an effective and safe procedure for SUI in the mid‐term setting. Objective and subjective cure rates are at least comparable to ‘gold standard’ procedures with a minimal rate of self‐limiting non‐surgical complications.
Comparing Traditional‐Residential, Personalised Residential and Personalised Non‐Residential respite services: Quality of life findings from an Irish population with mild–moderate intellectual disabilities
Authors: Nicholson Emma , Guerin Suzanne , Keogh Fiona , Dodd Philip
Published: September 2018

Accessible Summary

This study looked at differences between three types of respite care for people with intellectual disabilities.

The three types of respite care were: 1) an overnight stay in a residential facility, 2) an overnight stay, where the person could choose where they stayed and what they did during their time in respite care, and 3) a non‐overnight service where people were supported to choose what they wanted to and who they wanted to spend time with in respite care.

Where people using respite care had a choice as to how they spent their time they were reported to have higher levels of emotional well‐being, personal development, rights and interpersonal relationships.

These results are important because they show that giving people choice in how they spend time in respite care might have better outcomes than Traditional‐Residential forms of respite care.

Background

Respite care is an essential support for people with intellectual disabilities and their families; however, there is limited evidence examining different models of respite care. The present research examined quality of life among adults with intellectual disabilities using three different models of respite services in Ireland.

Method

A quasi‐experimental research method was adopted, which sought to determine differences in quality of life across the three respite care groups using two measures, 1) a self‐reported quality of life scale and 2) a quality of life questionnaire filled out by a keyworker. Participants were people with mild/moderate intellectual disabilities (n = 82) and their keyworkers (n = 81).

Results

Three distinct models of respite services were assessed: (a) Traditional‐ Residential respite; (b) Personalised Residential respite, and (c) Personalised Non‐Residential respite. No differences emerged between the groups on self‐reported quality of life; however, the groups differed on a proxy measure of quality of life with respect to Rights, emotional well‐being, personal development and interpersonal relationships.

Conclusion

The current data offer an initial exploration of self‐ and proxy‐reported quality of life among persons with intellectual disabilities in receipt of novel models of respite care in Ireland.
Diethyldithiocarbamate, an anti‐abuse drug, alleviates steatohepatitis and fibrosis in rodents through modulating lipid metabolism and oxidative stress
Authors: Liu Tianhui , Wang Ping , Cong Min , Zhao Xinyan , Zhang Dong , Xu Hufeng , Liu Lin , Jia Jidong , You Hong
Published: September 2018

Background and Purpose

Diethyldithiocarbamate (DDC) is a major metabolite of disulfiram that is a potential drug for alcoholism treatment. In the present study, we attempted to explore the possible effect of DDC on non‐alcoholic fatty liver disease (NAFLD) and related fibrosis in vivo.

Experimental Approach

C57BL/6 mice and Sprague Dawley (SD) rats received a methionine/choline‐deficient (MCD) diet to establish the model of NAFLD with or without DDC treatment. The livers and serum were assessed for histological changes and parameters related to lipid metabolism, liver injury, inflammation and fibrosis. Apoptosis and macrophage related markers were assessed by immunohistochemistry (IHC).

Key Results

DDC significantly reduced hepatic steatosis in rats with NAFLD, induced by the MCD diet. DDC reduced the oxidative stress and endoplasmic reticulum stress‐related parameters in mice with non‐alcoholic steatohepatitis, induced by the MCD diet. IHC for Bax and cleaved caspase‐3 showed that DDC inhibited the apoptosis of hepatocytes in the liver. DDC significantly reduced ballooning and Mallory−Denk bodies (MDB) in hepatocytes, accompanied by suppression of serum alanine aminotransferase, aspartate aminotransferase and MDB formation‐related genes. DDC significantly alleviated hepatic inflammation, accompanied by suppression of inflammation‐related genes. DDC suppressed the infiltration of macrophages, particularly inducible NOS‐positive pro‐inflammatory macrophages. In addition, DDC significantly alleviated liver fibrosis. Microarray analyses showed that DDC strongly affected lipid metabolism and oxidative stress‐related processes and pathways.

Conclusion and Implications

DDC improves hepatic steatosis, ballooning, inflammation and fibrosis in rodent models of NAFLD through modulating lipid metabolism and oxidative stress.
ABT‐199 (Venetoclax), a BH3‐mimetic Bcl‐2 inhibitor, does not cause Ca2+‐signalling dysregulation or toxicity in pancreatic acinar cells
Authors: Jakubowska Monika A , Kerkhofs Martijn , Martines Claudio , Efremov Dimitar G , Gerasimenko Julia V , Gerasimenko Oleg V , Petersen Ole H , Bultynck Geert , Vervliet Tim , Ferdek Pawel E
Published: September 2018

Background and Purpose

Many cancer cells depend on anti‐apoptotic B‐cell lymphoma 2 (Bcl‐2) proteins for their survival. Bcl‐2 antagonism through Bcl‐2 homology 3 (BH3) mimetics has emerged as a novel anti‐cancer therapy. ABT‐199 (Venetoclax), a recently developed BH3 mimetic that selectively inhibits Bcl‐2, was introduced into the clinic for treatment of relapsed chronic lymphocytic leukaemia. Early generations of Bcl‐2 inhibitors evoked sustained Ca2+ responses in pancreatic acinar cells (PACs) inducing cell death. Therefore, BH3 mimetics could potentially be toxic for the pancreas when used to treat cancer. Although ABT‐199 was shown to kill Bcl‐2‐dependent cancer cells without affecting intracellular Ca2+ signalling, its effects on PACs have not yet been determined. Hence, it is essential and timely to assess whether this recently approved anti‐leukaemic drug might potentially have pancreatotoxic effects.

Experimental Approach

Single‐cell Ca2+ measurements and cell death analysis were performed on isolated mouse PACs.

Key Results

Inhibition of Bcl‐2 via ABT‐199 did not elicit intracellular Ca2+ signalling on its own or potentiate Ca2+ signalling induced by physiological/pathophysiological stimuli in PACs. Although ABT‐199 did not affect cell death in PACs, under conditions that killed ABT‐199‐sensitive cancer cells, cytosolic Ca2+ extrusion was slightly enhanced in the presence of ABT‐199. In contrast, inhibition of Bcl‐xL potentiated pathophysiological Ca2+ responses in PACs, without exacerbating cell death.

Conclusion and Implications

Our results demonstrate that apart from having a modest effect on cytosolic Ca2+ extrusion, ABT‐199 does not substantially alter intracellular Ca2+ homeostasis in normal PACs and should be safe for the pancreas during cancer treatment.

Linked Articles

This article is part of a themed section on Mitochondrial Pharmacology: Featured Mechanisms and Approaches for Therapy Translation. To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v176.22/issuetoc
The immunome of soy bean allergy: Comprehensive identification and characterization of epitopes
Authors: Kern Karolin , Havenith Heide , Delaroque Nicolas , Rautenberger Paul , Lehmann Jörg , Fischer Markus , Spiegel Holger , Schillberg Stefan , Ehrentreich‐Foerster Eva , Aurich Stefanie , Treudler Regina , Szardenings Michael
Published: September 2018

Background

The precise mapping of multiple antibody epitopes recognized by patients’ sera allows a more detailed and differentiated understanding of immunological diseases. It may lead to the development of novel therapies and diagnostic tools.

Objective

Mapping soy bean specific epitopes relevant for soy bean allergy patients and persons sensitized to soy bean, and analysis of their IgE/IgG binding spectrum.

Methods

Identification of epitopes using sera, applying an optimized peptide phage display library followed by next‐generation sequencing, specially designed in silico data analysis and subsequent peptide microarray analysis.

Results

We were able to identify more than 400 potential epitope motifs in soy bean proteins. More than 60% of them have not yet been described as potential epitopes. Eighty‐three peptides, representing the 42 most frequently found epitope candidates, were validated by microarray analysis using 50 sera from people who have been tested positive in skin prick test (SPT). Of these peptides, 56 were bound by antibodies, 55 by serum IgE, 43 by serum IgG and 30 by both. Person‐specific epitope patterns were found for each individual and protein.

Conclusions

For individuals with clinical symptoms, epitope resolved analyses reveal a high prevalence of IgE binding to a few soy bean specific epitopes. Evaluation of individual immune profiles of patients with soy bean sensitization allows the identification of peptides that do facilitate studying individual IgE/IgG epitope binding patterns. This enables discrimination of sensitization from disease, such assay test has the potential to replace SPT assays
Health‐related quality of life improves 1 year after parathyroidectomy in primary hyperparathyroidism: A prospective cohort study
Authors: Ejlsmark‐Svensson Henriette , Sikjaer Tanja , Webb Susan M. , Rejnmark Lars , Rolighed Lars
Published: September 2018

Objective

Impaired quality of life (QoL) in primary hyperparathyroidism (PHPT) is commonly present. Patients may complain about nonspecific neurocognitive symptoms which can be difficult to quantify. Two different disease‐specific questionnaires have been developed, that is, the parathyroid assessment of symptoms score (PAS) and the primary hyperparathyroidism quality of life (PHPQoL). Using these two questionnaires, we assessed relationship between QoL and biochemical indices in PHPT and effects of parathyroidectomy (PTX).

Design

A prospective cohort study.

Methods

Patients with PHPT diagnosed from 2015 to 2017 were asked to answer the questionnaires before and 12 months after PTX. Biochemistry was obtained on both occasions.

Results

A total of 104 PHPT patients answered PAS and PHPQoL questionnaires at baseline, with a median age of 64 years (73% females). PHPQoL score correlated inversely with ionized calcium and PTH at baseline (P ˂ 0.04). Total PAS and PHPQoL score did not differ between those with and without osteoporosis, renal calcifications and impaired renal function. Based on levels of ionized calcium, PHPQoL differed significantly between patients with mild‐ and moderate‐severe hypercalcemia (P = 0.01). Fifty‐three patients answered PAS and PHPQoL 12 months after PTX showing an improved QoL at follow‐up (Pall ˂ 0.02). Stratifying patients into groups based on levels of ionized calcium showed a significantly improved PHPQoL score in patients with mild (˂1.45 mmol/L) as well as moderate‐severe hypercalcemia (≥1.45 mmol/L) at follow‐up (Pall ˂ 0.03).

Conclusion

Quality of life improved 12 months after PTX in PHPT patients. Impaired QoL seems to be associated with the degree of hypercalcemia rather than organ manifestations attributable to PHPT.
Whole exome sequencing resolves complex phenotype and identifies CC2D2A mutations underlying non‐syndromic rod‐cone dystrophy
Authors: Méjécase Cécile , Hummel Aurélie , Mohand‐Saïd Saddek , Andrieu Camille , El Shamieh Said , Antonio Aline , Condroyer Christel , Boyard Fiona , Foussard Marine , Blanchard Steven , Letexier Mélanie , Saraiva Jean‐Paul , Sahel José‐Alain , Zeitz Christina , Audo Isabelle
Published: September 2018

Genetic investigations were performed in three brothers from a consanguineous union, the two oldest diagnosed with rod‐cone dystrophy (RCD), the youngest with early‐onset cone‐rod dystrophy and the two youngest with nephrotic‐range proteinuria. Targeted next‐generation sequencing did not identify homozygous pathogenic variant in the oldest brother. Whole exome sequencing (WES) applied to the family identified compound heterozygous variants in CC2D2A (c.2774G>C p.(Arg925Pro); c.4730_4731delinsTGTATA p.(Ala1577Valfs*5)) in the three brothers with a homozygous deletion in CNGA3 (c.1235_1236del p.(Glu412Valfs*6)) in the youngest correcting his diagnosis to achromatopsia plus RCD. None of the three subjects had cerebral abnormalities or learning disabilities inconsistent with Meckel‐Gruber and Joubert syndromes, usually associated with CC2D2A mutations. Interestingly, an African woman with RCD shared the CC2D2A missense variant (c.2774G>C p.(Arg925Pro); with c.3182+355_3825del p.(?)). The two youngest also carried compound heterozygous variants in CUBN (c.7906C>T rs137998687 p.(Arg2636*); c.10344C>G p.(Cys3448Trp)) that may explain their nephrotic‐range proteinuria. Our study identifies for the first time CC2D2A mutations in isolated RCD and underlines the power of WES to decipher complex phenotypes.
Clinical and radiographic outcomes of a surgical reconstructive approach in the treatment of peri‐implantitis lesions: A 5‐year prospective case series
Authors: La Monaca Gerardo , Pranno Nicola , Annibali Susanna , Cristalli Maria Paola , Polimeni Antonella
Published: September 2018

Objectives

The aim of this study was to evaluate the 5‐year clinical and radiographic outcomes following reconstructive therapy of peri‐implantitis lesions using mineralized dehydrated bone allograft and resorbable membrane in the nonsubmerged mode of wound healing.

Materials and methods

Thirty‐four patients with at least one implant diagnosed with peri‐implantitis were treated by mechanical debridement; chemical decontamination using hydrogen peroxide (3%), chlorhexidine (0.2%), and a tetracycline hydrochloride solution; and bone defect filling with mineralized dehydrated bone allograft and resorbable membrane. Clinical and radiographic assessments were obtained during 5‐year follow‐up. The primary outcome was the absence of additional marginal peri‐implant bone loss ≥1.0 mm after surgery, and the composite outcome included the additional marginal peri‐implant bone loss, absence of probing depth (PD) ≥5 mm, and absence of bleeding on probing (BoP)/suppuration.

Results

According to the primary and composite outcomes, the success rate of 34 implants included in the study was 100% and 91% (N = 31), at 1 year after surgery, and decreased progressively to 77% (N = 26) and to 59% (N = 20) at 5‐year follow‐up, respectively. Five years following treatment, only the BoP reduction was statistically significant compared to baseline (p < 0.001), and no difference was found in PD (p = 0.318) and in marginal peri‐implant bone level (p = 0.064).

Conclusions

At 1‐year follow‐up, the surgical reconstructive therapy showed clinical improvement and radiographic defect filling. However, the results appeared to be unpredictable over time, due to a progressive decrease in the bone filling of the peri‐implant defects and an increase in the mean PD.
Guided bone regeneration using beta‐tricalcium phosphate with and without fibronectin—An experimental study in rats
Authors: Escoda‐Francolí Jaume , Sánchez‐Garcés María Ángeles , Gimeno‐Sandig Álvaro , Muñoz‐Guzón Fernando , Barbany‐Cairó Joan R. , Badiella‐Busquets Llorenç , Gay‐Escoda Cosme
Published: September 2018

Objective

This histomorphometric study compared bone regeneration potential of beta‐tricalcium phosphate with fibronectin (β‐TCP‐Fn) in critical‐sized calvarial defects (CSDs) in rats to assess whether fibronectin (Fn) improved new bone formation.

Material and methods

Critical‐sized calvarial defects were created in 30 adult male Sprague Dawley rats, which were divided into four groups according to the time of euthanasia (6 or 8 weeks of healing) and type of filling (β‐TCP‐Fn/6 weeks, β‐TCP/6 weeks, β‐TCP‐Fn/8 weeks and β‐TCP/8 weeks). The primary variables related to new bone formation were augmented area (AA) and gained tissue (GT; sum of mineralized bone matrix [MBM] and bone substitute [BS]). Secondary variables were the diameter of the defect, MBM, non‐mineralized tissue (NMT) and BS.

Results

A total of 29 rats and 58 histological samples were evaluated, 28 (48.3%) samples obtained at 6 weeks and 30 (51.7%) at 8 weeks, homogeneously distributed between right and left sides. Thirteen (22.4%) were treated with β‐TCP‐Fn, 16 (27.6%) with β‐TCP and 29 (50%) were controls. At 8 weeks, histomorphometric analysis showed significant differences in AA using β‐TCP and β‐TCP‐Fn versus controls (p = 0.001 and p = 0.005, respectively). Bone turnover expressed as % within the target area was slightly higher but not statistically significant in the β‐TCP‐Fn than in β‐TCP (MBM) at 6 weeks versus 8 weeks (p = 0.067 and p = 0.335, respectively). Finally, the total GT area in mm2 was higher using β‐TCP‐Fn as compared to β‐TCP (p = 0.044).

Conclusions

β‐TCP‐Fn was slightly but non‐significantly more effective than β‐TCP without Fn for improving the volume of regenerated bone in CSDs of rats, possibly allowing a more efficient bone remodelling process. This effect however should continue being investigated.
A retrospective cohort study of peri‐implant condition in Chinese patients with different periodontal condition and maintenance frequency
Authors: Xie Yesi , Meng Huanxin , Han Jie , Xu Li , Zhang Li , Li Wenjing
Published: September 2018

Objectives

To compare the periodontal and peri‐implant conditions of Chinese patients with a history of moderate or severe periodontitis and periodontally healthy patients (PHP); to evaluate the influence of maintenance therapy frequency on the outcome of implant therapy.

Methods

A total of 140 participants with 227 sand‐blasted acidetched (SLA) implants were divided into three groups: PHP, moderate periodontally compromised patients (PCP) and severe PCP. The three groups were further categorized into two groups based on the frequency of maintenance (MF): MF ≥ 1 per year and MF < 1 per year. The following clinical parameters of implants were assessed: implant survival/loss, peri‐implant probing depth (PDi), peri‐implant bleeding index (BIi), peri‐implant bleeding on probing (BOPi), implant bone loss (BLi). Comparisons of the peri‐implant conditions were performed between the patients with different periodontal conditions.

Results

Implant survival rate was 100% for all three groups. The severe PCP group showed significantly higher deepest PDi, mean PDi, mean BIi, and PLIi compared with PHP (p < 0.05). The severe PCP group had more implants affected with PDi ≥ 5 mm and BOPi+ compared with the PHP group (Adjusted OR = 10.89, 95% CI: 2.34, 50.74). In the patients with severe PCP, the MF < 1 per year group had a greater prevalence of PDi ≥ 5 mm and BOPi+ compared with the MF ≥ 1 per year group (Adjusted OR = 8.23, 95% CI: 2.44, 27.78).

Conclusions

The patients in the severe PCP group were at greater risk of peri‐implant disease than those in the PHP group. In particular, severe PCP who had poor adherence to maintenance care showed a higher incidence of biologic complications.
A cost–utility analysis of decompressive hemicraniectomy versus medical treatment in the management of space‐occupying brain oedema post middle cerebral artery infarction
Authors: Bhattacharyya A. , Tahir A. , Chandrashekar A. , Vasisht S. , Stinson L. , Omatseye J.
Published: September 2018

Background and purpose

Data from randomly controlled trials have indicated that a decompressive hemicraniectomy is more clinically effective than medical treatment in the management of space‐occupying brain oedema post middle cerebral artery infarction. This economic evaluation compares the impact of the two options in the UK. No recent study has conducted an economic evaluation on this topic for the UK.

Method

A cost–utility analysis over a time period of 1 year was used, measuring benefits in terms of quality adjusted life years (QALYs) and costs in pound sterling, discounted to 2015 prices. The evaluation was from the perspective of the National Health Service, the largest healthcare provider in the UK.

Results

The cost–utility analysis found an incremental cost effectiveness of £116 595.10 for every QALY gained if patients were offered a decompressive hemicraniectomy compared to the best medical treatment.

Discussion

This is above the National Institute for Health and Care Excellence (NICE) ‘cost‐effective’ threshold of £20 000–£30 000 per QALY, but lower mortality rates associated with the surgical alternative raises ethical considerations for healthcare providers in the UK.