bluuebunny/crossref_metadata_2025 huggingface dataset:
High-density SNP array and genome sequencing reveal signatures of selection in a divergent selection rat model for aerobic running capacity
Authors: Ren Yu-yu , Koch Lauren G. , Britton Steven L. , Qi Nathan R. , Treutelaar Mary K. , Burant Charles F. , Li Jun Z.
Published: November 2015

We have previously established two lines of rat for studying the functional basis of aerobic exercise capacity (AEC) and its impact on metabolic health. The two lines, high capacity runners (HCR) and low capacity runners (LCR), have been selectively bred for high and low intrinsic AEC, respectively. They were started from the same genetically heterogeneous population and have now diverged in both AEC and many other physiological measures, including weight, body composition, blood pressure, body mass index, lung capacity, lipid and glucose metabolism, and natural life span. In order to exploit this rat model to understand the genomic regions under differential selection within the two lines, we used SNP genotype and whole genome pooled sequencing data to identify signatures of selection using three different statistics: runs of homozygosity, fixation index, and aberrant allele frequency spectrum, and developed a composite score that combined the three signals. we found that several pathways (ATP transport and fatty acid metabolism) are enriched in regions under differential selection. The candidate genes and pathways under selection will be integrated with the previous mRNA expression data and future F2 QTL results for a multi-omics approach to understanding the biological basis of AEC and metabolic traits.
Estimating Effect Sizes and Expected Replication Probabilities from GWAS Summary Statistics
Authors: Holland Dominic , Wang Yunpeng , Thompson Wesley K. , Schork Andrew , Chen Chi-Hua , Lo Min-Tzu , Witoelar Aree , Werge Thomas , O’Donovan Michael , Andreassen Ole A. , Dale Anders M. ,   Schizophrenia Working Group of the Psychiatric Genomics Consortium, Enhancing Neuro Imaging Genetics through Meta Analysis Consortium
Published: November 2015

Genome-wide Association Studies (GWAS) result in millions of summary statistics (“z-scores”) for single nucleotide polymorphism (SNP) associations with phenotypes. These rich datasets afford deep insights into the nature and extent of genetic contributions to complex phenotypes such as psychiatric disorders, which are understood to have substantial genetic components that arise from very large numbers of SNPs. The complexity of the datasets, however, poses a significant challenge to maximizing their utility. This is reflected in a need for better understanding the landscape of z-scores, as such knowledge would enhance causal SNP and gene discovery, help elucidate mechanistic pathways, and inform future study design. Here we present a parsimonious methodology for modeling effect sizes and replication probabilities that does not require raw genotype data, relying only on summary statistics from GWAS substudies, and a scheme allowing for direct empirical validation. We show that modeling z-scores as a mixture of Gaussians is conceptually appropriate, in particular taking into account ubiquitous non-null effects that are likely in the datasets due to weak linkage disequilibrium with causal SNPs. The four-parameter model allows for estimating the degree of polygenicity of the phenotype – the proportion of SNPs (after uniform pruning, so that large LD blocks are not over-represented) likely to be in strong LD with causal/mechanistically associated SNPs – and predicting the proportion of chip heritability explainable by genome-wide significant SNPs in future studies with larger sample sizes. We apply the model to recent GWAS of schizophrenia (N=82,315) and additionally, for purposes of illustration, putamen volume (N=12,596), with approximately 9.3 million SNP z-scores in both cases. We show that, over a broad range of z-scores and sample sizes, the model accurately predicts expectation estimates of true effect sizes and replication probabilities in multistage GWAS designs. We estimate the degree to which effect sizes are over-estimated when based on linear-regression association coefficients. We estimate the polygenicity of schizophrenia to be 0.037 and the putamen to be 0.001, while the respective sample sizes required to approach fully explaining the chip heritability are 106and 105. The model can be extended to incorporate prior knowledge such as pleiotropy and SNP annotation. The current findings suggest that the model is applicable to a broad array of complex phenotypes and will enhance understanding of their genetic architectures.
Population size and the length of the chromosome blocks identical by descent over generations
Authors: Tiret Mathieu , Hospital Frédéric
Published: November 2015

In all populations, as the time runs, crossovers break apart ancestor haplotypes, forming smaller blocks at each generation. Some blocks, and eventually all of them, become identical by descent because of the genetic drift. We have in this paper developed and benchmarked a theoretical prediction of the mean length of such blocks and used it to study a simple population model assuming panmixia, no selfing and drift as the only evolutionary pressure. Besides, we have on the one hand derived, for any user defined error threshold, the range of the parameters this prediction is reliable for, and on the other hand shown that the mean length remains constant over time in ideally large populations.
Timing of locomotor recovery modulated by thewhitegene inDrosophila
Authors: Xiao Chengfeng , Robertson R Meldrum
Published: November 2015

Locomotor recovery from anoxia follows the restoration of disordered ion distributions and neuronal excitability. The time taken for locomotor recovery after 30 s anoxia (around 10 min) is longer than the time for the propagation of action potentials to be restored (less than 1 min) inDrosophilawild-type. We report here that thewhite(w) gene modulates the timing of locomotor recovery. Wild-type flies displayed fast and consistent recovery of locomotion from anoxia, whereas mutants ofwshowed significantly delayed recovery. Genetic analysis including serial backcrossing revealed a strong association between thewlocus and the timing of locomotor recovery, and haplo-insufficient function ofw+in promoting fast locomotor recovery. The locomotor recovery phenotype was independent of classic eye pigmentation, although both are associated with thewgene. Introducing up to four copies of mini-white(mw+) into w1118 was insufficient to promote fast and consistent locomotor recovery. However, flies carryingw+duplicated to Y chromosome showed wild-type-like fast locomotor recovery. Furthermore, RNAi knockdown ofwin neurons but not glia delayed locomotor recovery, and specifically, knockdown ofwin putative subsets of serotonin neurons was sufficient to delay the locomotor recovery. These data reveal an additional role forwin modulating the timing of locomotor recovery from anoxia.
The relaxin receptor Lgr3 mediates growth coordination and developmental delay duringDrosophila melanogasterimaginal disc regeneration
Authors: Jaszczak Jacob S. , Wolpe Jacob B. , Bhandari Rajan , Jaszczak Rebecca G. , Halme Adrian
Published: November 2015

Damage toDrosophila melanogasterimaginal discs activates a regeneration checkpoint that 1) extends larval development and 2) coordinates the regeneration of the damaged disc with the growth of undamaged discs. These two systemic responses to damage are both mediated by Dilp8, a member of the insulin/IGF/relaxin family of peptide hormones, which is released by regenerating imaginal discs. Growth coordination between regenerating and undamaged imaginal discs is dependent on Dilp8 activation of NOS in the prothoracic gland (PG), which slows the growth of undamaged discs by limiting ecdysone synthesis. Here we demonstrate that theDrosophilarelaxin receptor homologue Lgr3, a leucine-rich repeat-containing G-protein coupled receptor, is required for Dilp8-dependent growth coordination and developmental delay during the regeneration checkpoint. Lgr3 regulates these responses to damage via distinct mechanisms in different tissues. Using tissue-specific RNAi disruption ofLgr3expression, we show that Lgr3 functions in the PG upstream of nitric oxide synthase (NOS), and is necessary for NOS activation and growth coordination during the regeneration checkpoint. When Lgr3 is depleted from neurons, imaginal disc damage no longer produces either developmental delay or growth inhibition. To reconcile these discrete tissue requirements for Lgr3 during regenerative growth coordination, we demonstrate that Lgr3 activity in the both the CNS and PG is necessary for NOS activation in the PG following damage. Together, these results identify new roles for a relaxin receptor in mediating damage signaling to regulate growth and developmental timing.
ASAP: A Machine-Learning Framework for Local Protein Properties
Authors: Brandes Nadav , Ofer Dan , Linial Michal
Published: November 2015

Determining residue level protein properties, such as the sites for post-translational modifications (PTMs) are vital to understanding proteins at all levels of function. Experimental methods are costly and time-consuming, thus high confidence predictions become essential for functional knowledge at a genomic scale. Traditional computational methods based on strict rules (e.g. regular expressions) fail to annotate sites that lack substantial similarity. Thus, Machine Learning (ML) methods become fundamental in annotating proteins with unknown function. We present ASAP (Amino-acid Sequence Annotation Prediction), a universal ML framework for residue-level predictions. ASAP extracts efficiently and fast large set of window-based features from raw sequences. The platform also supports easy integration of external features such as secondary structure or PSSM profiles. The features are then combined to train underlying ML classifiers. We present a detailed case study for ASAP that was used to train CleavePred, a state-of-the-art protein precursor cleavage sites predictor. Protein cleavage is a fundamental PTM shared by a wide variety of protein groups with minimal sequence similarity. Current computational methods have high false positive rates, making them suboptimal for this task. CleavePred has a simple Python API, and is freely accessible via a web-based application. The high performance of ASAP toward the task of precursor cleavage is suited for analyzing new proteomes at a genomic scale. The tool is attractive to protein design, mass spectrometry search engines and the discovery of new peptide hormones. In summary, we illustrate ASAP as an entry point for predicting PTMs. The approach and flexibility of the platform can easily be extended for additional residue specific tasks. ASAP and CleavePred source code available athttps://github.com/ddofer/asap.
Elevated gene expression of most microglial markers, and reduced expression of most pyramidal neuron and interneuron markers, in postmortem autism cortex
Authors: Borges-Monroy Rebeca , Ponting Chris P. , Belgard T. Grant
Published: November 2015

Autism Spectrum Disorders (ASD) are clinically and genetically heterogeneous. Nevertheless, a characteristic gene expression signature in postmortem cortex is shared across most ASD cases. Knowing whether this signature reflects changes in cells of particular types would help to determine the molecular, cellular, and anatomical etiology of ASD. To investigate we took advantage of cell type marker genes defined by recent single cell transcriptome sequencing from mouse or human cortex. We find that microglial markers showed significantly and substantially higher median expression in postmortem ASD than in control cortex for both mouse and human markers (21% higher for orthologous markers defined in mouse; 93% higher for human markers). In contrast, neuronal markers showed reduced median expression: 12% and 16% lower for mouse interneurons and pyramidal neurons, 40% lower for human neurons, and 36% lower for a class of human excitatory projection neurons. Cell type density alterations in ASD brains are indicated because distributions of these cell type markers are shifted concordantly. Importantly, orthologous mouse neuronal marker genes encoding proteins localized to diverse neuronal compartments all showed reduced median expression in ASD. Our results provide a framework for revealing the basis of transcriptomic differences in ASD. We propose comparing cell type density alterations in post-mortem tissue with and without these distinctive gene expression changes to reconcile results from stereological and transcriptomic studies.
Anin silicocomparison of reduced-representation and sequence-capture protocols for phylogenomics
Authors: Collins Rupert A. , Hrbek Tomas
Published: November 2015

In the age of genome-scale DNA sequencing, choice of molecular marker arguably remains an important decision in planning a phylogenetic study. Using published genomes from 23 primate species, we make a standardized comparison of four of the most frequently used protocols in phylogenomics,viz., targeted sequence-enrichment using ultraconserved element and exon-capture probes, and reduced genomic representation using restriction-site-associated DNA sequencing (RADseq and ddRAD-seq). Here we present a procedure to performin silicoextractions from genomes and create directly comparable datasets for each class of marker. We then compare these datasets in terms of both phylogenetic resolution and ability to consistently and precisely estimate clade ages using fossil-calibrated molecular-clock models. Furthermore, we were also able to directly compare these results to previously published datasets from Sanger-sequenced nuclear exons and mitochondrial genomes under the same analytical conditions. Our results show—although with the exception of the mitochondrial genome and ddRADseq datasets—that for uncontroversial nodes all data classes performed equally well, i.e. they recovered the same well supported topology. However, for one difficult-to-resolve node comprising a rapid diversification (subfamilial relationships among the Cebidae), we report well supported but conflicting topologies among the marker classes, likely the result of mismodelling of gene tree heterogeneity. Likewise, clade age estimates showed consistent discrepancies between datasets; for recent nodes, clade ages estimated by nuclear exon datasets were younger than those of the UCE, RAD and mitochondrial data, butvice versafor the deepest nodes in the primate phylogeny. This effect can be explained by temporal differences in phylogenetic informativeness and choice of clock model used. Finally, we conclude by emphasizing that while huge numbers of loci are probably not required for uncontroversial phylogenetic questions—for which practical considerations such as cost and ease of data generation/sharing/aggregating therefore become increasingly important—accurately modelling heterogeneous data remains as relevant as ever for the more recalcitrant problems.
CASH algorithm versus 3‐point checklist and its modified version in evaluation of melanocytic pigmented skin lesions: The 4‐point checklist
Authors: di Meo Nicola , Stinco Giuseppe , Bonin Serena , Gatti Alessandro , Trevisini Sara , Damiani Giovanni , Vichi Silvia , Trevisan Giusto
Published: November 2015

Dermoscopy, in expert hands, increases accuracy, sensitivity and specificity in diagnosis of pigmented skin lesions of a single operator, compared with clinical examination. Simplified algorithmic methods have been developed to help less expert dermoscopists in diagnosis of melanocytic lesions. This study included 125 melanocytic skin lesions divided into melanocytic nevi, dysplastic nevi and thin melanomas (<1 mm). We compared the 3‐point checklist and CASH algorithm to analyze different pigmented skin lesions. Based on preliminary results, we proposed a new modified algorithm, called the 4‐point checklist, whose accuracy is similar to the CASH algorithm and whose simplicity is similar to the 3‐point checklist.
Molecular cloning and functional characterization of a novel i‐type lysozyme in the freshwater mussel Cristaria plicata
Authors: Dai Wenjuan , Wu Dan , Zhang Ming , Wen Chungen , Xie Yanhai , Hu Baoqing , Jian Shaoqing , Zeng Mingyu , Tao Zhiying
Published: November 2015

The freshwater bivalve Cristaria plicata, which is widely distributed in Eastern Asia, is a key species in the pearl culture industry. In this study, a novel invertebrate‐type lysozyme, designated as CpLYZ2, was cloned from hemocytes of C. plicata. This lysozyme shares high sequence identity and is homologous to a previously identified lysozyme CpLYZ1 isolated from C. plicata and with HcLyso3 isolated from Hyriopsis cumingii. The full‐length cDNA of CpLYZ2 is 913 bp long, which includes an open reading frame (ORF) of 486 bp, a 3′ untranslated region (UTR) of 389 bp and a 5′ UTR of 38 bp. The ORF encodes a putative polypeptide of 161 amino acids with a predicted molecular mass of 18.2 kDa and a theoretical isoelectric point of 6.56. CpLYZ2 mRNA transcripts can be detected in hemocytes, hepatopancreas, muscle, gills and mantle tissues, the greatest expression being observed in the gills. CpLYZ2 expression in hemocytes, hepatopancreas and gills increased significantly after the mussel was challenged with Aeromonas hydrophila. Furthermore, the optimal pH and temperature for enzyme activity of the recombinant CpLYZ2 were 5.5 and 50°C, respectively. The recombinant lysozyme protein exhibited bacteriolytic activity against Escherichia coli, A. hydrophila, Staphyloccocus aureus, Bacillus subtilis, Streptococcus sp. and Staphylococcus epidermidis. The findings of this study help to elucidate immune responses in molluscs and will thus expedite disease management of these key freshwater species, in turn boosting pearl culture in eastern Asia.
Consumption of probiotic Lactobacillus rhamnosus (MTCC: 5897) containing fermented milk plays a key role in development of the immune system in newborn mice during the suckling–weaning transition
Authors: Saliganti Vamshi , Kapila Rajeev , Kapila Suman
Published: November 2015

Early infancy, the period when offspring rely not only on their own immunity to combat food‐borne antigens but also acquire immunity through maternal sources (via transplacental routes and breast milk), is critical for immune system development Hence the present study was designed to evaluate the effect on offspring of administration of probiotic‐containing fermented milk (PFM) either to mothers during the suckling period or to their offspring after weaning either separately or sequentially. PFM‐fed mice showed enhanced leukocyte functionality in offspring as evidenced by significantly (P < 0.05) increased release of lysosomal enzymes (β‐galactosidase, β‐glucuronidase) in peritoneal fluid and nitric oxide production in culture supernatants of activated macrophages. Further, remarkably reduced levels (P < 0.01) of inflammatory markers (TNF‐α, monocyte chemotactic protein‐1) and allergic antibodies (total and milk specific IgE) were observed in offspring where PFM was fed either to them or to their mothers. However, considerably increased levels (P < 0.05) of SIgA were found in the guts of control and experimental groups animals irrespective of their exposure to PFM. Restoration of Th1/Th2 homeostasis further confirmed the useful effects of PFM supplementation by shifting the cytokine profile (IL‐4, IFN‐γ and IL‐10) with increased IFN‐γ/IL‐4 and reduced IgE/Ig2Ga ratios. Hence, it is logical to conclude that administration of Lactobacillus rhamnosus‐containing (MTCC:5897) fermented milk to mothers during the suckling period and to their offspring after weaning has beneficial effects on the development of newborns immune systems; this effect appears to be more pronounced when mothers are fed with it.
Effect of interleukin‐2 receptor antagonists on new‐onset diabetes after liver transplantation: A retrospective cohort study
Authors: Xue Mengjuan , Lv Chaoyang , Chen Xianying , Huang Xiaowu , Sun Qiman , Wang Ting , Liang Jing , Zhang Yao , He Shunmei , Gao Jian , Zhou Jian , Yu Mingxiang , Fan Jia , Gao Xin
Published: November 2015

Background

The aim of the present retrospective observational study was to examine the effect of interleukin‐2 receptor antagonists (IL‐2Ra) on new‐onset diabetes after transplantation (NODAT) in liver transplant recipients.

Methods

Pre‐ and postoperative clinical data of 781 patients undergoing liver transplantation between April 2001 and December 2014 at Zhongshan Hospital, Fudan University, were analyzed. Patients were divided into two groups depending on the use of IL‐2Ra (IL‐2Ra and non‐IL‐2Ra). The cumulative incidence of NODAT was compared between the IL‐2Ra and non‐IL‐2Ra groups and the effect of IL‐2Ra on the incidence of NODAT in liver transplant recipients was evaluated.

Results

Of the 781 patients in the study, 451 received IL‐2Ra. During follow‐up, 138 (41.8%) and 137 (30.4%) patients in the non‐IL‐2Ra and IL‐2Ra groups, respectively, developed NODAT (P = 0.001). The cumulative incidence of NODAT at 1, 3, 5, and 8 years after transplantation in the IL‐2Ra group was 30%, 38%, 45%, and 54%, respectively; these values were substantially lower than corresponding values for the non‐IL‐2Ra group (P < 0.05). Cox regression analyses showed that IL‐2Ra was a protective factor against NODAT development (odds ratio 0.685; 95% confidence interval 0.473–0.991; P = 0.044). This was independent of age, sex, donor type, hepatitis virus infection, body mass index, history of hypertension, preoperative liver function, preoperative fasting plasma glucose, total cholesterol, and total triglyceride levels, severity of liver cirrhosis, acute rejection, initial immunosuppressant regimen type, and postoperative immunosuppressant levels.

Conclusion

In conclusion, IL‐2Ra reduces the risk of NODAT in liver transplant recipients.
Efficacy and safety of dapagliflozin in Asian patients with type 2 diabetes after metformin failure: A randomized controlled trial
Authors: Yang Wenying , Han Ping , Min Kyung‐Wan , Wang Bei , Mansfield Traci , T'Joen Caroline , Iqbal Nayyar , Johnsson Eva , Ptaszynska Agata
Published: November 2015

Background

Dapagliflozin, a highly selective sodium–glucose cotransporter 2 inhibitor, reduces hyperglycemia, body weight, and blood pressure in patients with type 2 diabetes (T2D).

Methods

This randomized double‐blind placebo‐controlled parallel‐group 24‐week study assessed the efficacy, safety, and tolerability of dapagliflozin added to metformin in Asian patients with inadequately controlled T2D (HbA1c 7.5%–10.5%). Patients were randomized to receive placebo (n = 145) or dapagliflozin 5 (n = 147) or 10 mg (n = 152).

Results

Most participants were Chinese (86.0%), with a mean age of 53.8 years and mean T2D duration of 4.9 years; 92.1% completed the study. Adjusted mean HbA1c changes from baseline at Week 24 (primary endpoint) were −0.23%, −0.82%, and −0.85% in the placebo, dapagliflozin 5 and 10 mg groups, respectively, resulting in dapagliflozin 5 and 10 mg versus placebo differences of −0.59% and −0.62%, respectively (both P < 0.0001). Dapagliflozin 5 and 10 mg differences versus placebo were, respectively: –1.2 and −1.5 mmol/L for fasting plasma glucose; −1.1 and −1.8 kg for weight; and −2.3 and −2.7 mmol/L for 2‐h postprandial glucose (all P <0.0001). In the placebo, dapagliflozin 5 and 10 mg groups, respectively: adverse events (AEs) occurred in 52.4%, 52.4%, and 55.3% of patients; serious AEs occurred in 4.1%, 2.0%, and 2.0%; urinary tract infections occurred in 4.8%, 4.1%, and 6.6%; and genital infections occurred in 0%, 2.0%, and 1.3%. No AEs of pyelonephritis or renal failure occurred.

Conclusions

Dapagliflozin 5 or 10 mg as add‐on to metformin was well tolerated in Asian patients with T2D and significantly improved glycemic control with the additional benefit of weight reduction.
Role of Pleiotropic Properties of Peroxisome Proliferator‐Activated Receptors in the Heart: Focus on the Nonmetabolic Effects in Cardiac Protection
Authors: Barlaka Eleftheria , Galatou Eleftheria , Mellidis Kyriakos , Ravingerova Tanya , Lazou Antigone
Published: November 2015

Peroxisome proliferator‐activated receptors, PPARα, PPARβ/δ, and PPARγ, are a group of nuclear receptors that function as transcriptional regulators of lipid metabolism, energy homeostasis, and inflammation. Given the role of metabolism imbalance under pathological states of the heart, PPARs have emerged as important therapeutic targets, and accumulating evidence highlights their protective role in the improvement of cardiac function under diverse pathological settings. Although the role of PPARs in the regulation of cardiac substrate utilization preference and energy homeostasis is well documented, their effects related to the regulation of cellular inflammatory and redox responses in the heart are less studied. In this review, we provide an overview on recent progress with respect to understanding the role of the nonmetabolic effects of PPARs in cardiac dysfunction, namely during ischemia/reperfusion injury, hypertrophy, and cardiac failure, and highlight the mechanisms underlying the protective effects against inflammation, oxidative stress, and cell death. The role of receptor‐independent, nongenomic effects of PPAR agonists is also discussed.
Pilot randomised trial of a brief intervention for comorbid substance misuse in psychiatric in‐patient settings
Authors: Graham H. L. , Copello A. , Griffith E. , Freemantle N. , McCrone P. , Clarke L. , Walsh K. , Stefanidou C. A. , Rana A. , Birchwood M.
Published: November 2015

Objective

This proof of principle study evaluated the effectiveness and feasibility of a brief motivational intervention, delivered in mental health in‐patient settings, to improve engagement in treatment for drug and alcohol misuse.

Method

A randomised controlled trial using concealed randomisation, blind, independent assessment of outcome at 3 months. Participants were 59 new adult admissions, to six acute mental health hospital units in one UK mental health service, with schizophrenia related or bipolar disorder diagnoses, users of community mental health services and also misusing alcohol and/or drugs. Participants were randomised to Brief Integrated Motivational Intervention (BIMI) with Treatment As Usual (TAU), or TAU alone. The BIMI took place over a 2‐week period and encouraged participants to explore substance use and its impact on mental health.

Results

Fifty‐nine in‐patients (BIMI n = 30; TAU n = 29) were randomised, the BIMI was associated with a 63% relative odds increase in the primary outcome engagement in treatment [OR 1.63 (95% CI 1.01–2.65; P = 0.047)], at 3 months. Qualitative interviews with staff and participants indicated that the BIMI was both feasible and acceptable.

Conclusion

Mental health hospital admissions present an opportunity for brief motivational interventions focussed on substance misuse and can lead to improvements in engagement.
Colorectal mucus non‐invasively collected from patients with inflammatory bowel disease and its suitability for diagnostic cytology
Authors: Bandaletova Tatiana , Chhaya Vivek , Poullis Andrew , Loktionov Alexandre
Published: November 2015

Colorectal mucus is a key component of the protective gut barrier which is altered in inflammatory bowel disease (IBD). We aimed to cytologically characterize colorectal mucus non‐invasively collected from IBD patients using our new sampling technique. Colorectal mucus was self‐collected by 58 IBD patients comprising 31 ulcerative colitis (UC) and 27 Crohn's disease (CD) cases. The samples were examined cytologically, and immunocytochemically. Large numbers of well‐preserved granulocytes were typically detected (neutrophils undergoing degradation were observed as well). Plasma cells and erythrophagocytosis were present in 18.2% and 29.1% of cases, respectively, predominantly in patients with UC and distal CD. Immunocytochemical visualization of calprotectin in neutrophils, eosinophil‐derived neurotoxin in eosinophils and tumour necrosis factor‐α in macrophages was also achieved. Correct cytological diagnosis was made in 61.8% of analysed IBD cases. Our new method of colorectal mucus sampling provides highly informative material for cytology. Findings of the presence of plasmocytes and erythrophagocytosis in colorectal mucus are unique and may reflect previously unknown mechanisms of IBD pathogenesis. Immunocytochemical detection of inflammation biomarkers demonstrates the suitability of this material for biomarker quantification. These promising results suggest a potential role for colorectal mucus cytology in the non‐invasive diagnosis of IBD.
The Role of Social Contact in the Experience of Discrimination: Implications for Subjective Health Among Marriage Migrant Women in South Korea
Authors: Cheon Yuen Mi , Chung Grace H.
Published: November 2015

Several studies have found that various social contexts could serve a protective role for minorities facing discrimination. One of these contexts is frequency of social contact, which is known to be positively associated with health outcomes. The purpose of this study was to examine the frequency of social contact with various social groups as a protective factor against the negative association between perceived discrimination and subjective health. Using data from the 2009 Korean National Survey of Multicultural Families, a total of 27,083 marriage migrant women were analyzed via hierarchical multiple regression. After controlling for socio‐demographic factors and Korean proficiency, the experience of discrimination was found to be significantly associated with lower levels of subjective health (B = −0.22; P < 0.001). More frequent meetings with one's family of origin (B = 0.02; P < 0.01) and in‐laws (B = 0.06; P < 0.001) were associated with higher levels of subjective health, while more frequent meetings with neighbors were negatively associated (B = −0.02; P < 0.001). More frequent contact with one's family of origin (B = 0.03; P < 0.05), rather than with other groups, such as friends from their country of origin, in‐laws, and neighbors, seemed to reduce the negative influence of discrimination on subjective health.
Longitudinal Effects of Economic Preparation and Social Activities on Life and Family Relationship Satisfaction among Retirees
Authors: Park Jihyun , Park Aely
Published: November 2015

This longitudinal study examined the long‐term effects of economic preparation and social activity on life and family relationship satisfaction among retirees, particularly baby boomers. Data was obtained from the 2009 and 2011 Korean Retirement & Income Panel Study. A fixed effects model was employed to estimate unobservable individual‐specific effects and to control for study participants’ individual characteristics. The results show that both economic preparation and social activities have long‐term effects on baby boomers’ life and family relationship satisfaction. This study reveals that multidimensional aspects of preparation increase the long‐term impact of life satisfaction for retirees.
Pharmacological management of anticholinergic delirium ‐ theory, evidence and practice
Authors: Dawson Andrew H. , Buckley Nicholas A.
Published: November 2015

The spectrum of anticholinergic delirium is a common complication following drug overdose. Patients with severe toxicity can have significant distress and behavioural problems that often require pharmacological management. Cholinesterase inhibitors, such as physostigmine, are effective but widespread use has been limited by concerns about safety, optimal dosing and variable supply. Case series support efficacy in reversal of anticholinergic delirium. However doses vary widely and higher doses commonly lead to cholinergic toxicity. Seizures are reported in up to 2.5% of patients and occasional cardiotoxic effects are also recorded.

This article reviews the serendipitous path whereby physostigmine evolved into the preferred anticholinesterase antidote largely without any research to indicate the optimal dosing strategy. Adverse events observed in case series should be considered in the context of pharmacokinetic/pharmacodynamic studies of physostigmine which suggest a much longer latency before the maximal increase in brain acetylcholine than had been previously assumed. This would favour protocols that use lower doses and longer re‐dosing intervals. We propose based on the evidence reviewed that the use of cholinesterase inhibitors should be considered in anticholinergic delirium that has not responded to non‐pharmacological delirium management. The optimal risk/benefit would be with a titrated dose of 0.5 to 1 mg physostigmine (0.01–0.02 mg kg−1 in children) with a minimum delay of 10–15 min before re‐dosing. Slower onset and longer acting agents such as rivastigmine would also be logical but more research is needed to guide the appropriate dose in this setting.
Priming status‐legitimizing beliefs: Examining the impact on perceived anti‐White bias, zero‐sum beliefs, and support for Affirmative Action among White people
Authors: Wellman Joseph D. , Liu Xi , Wilkins Clara L.
Published: November 2015

The current research examines how status‐legitimizing beliefs (SLBs) influence White people's perceptions of anti‐White bias, endorsement of zero‐sum beliefs, and support for Affirmative Action. We suggest that SLBs perpetuate inequality by increasing White people's perceptions of zero‐sum beliefs and anti‐White bias, which in turn lead to decreased support for Affirmative Action. White individuals primed with SLBs perceived greater anti‐White bias, endorsed greater zero‐sum beliefs, and indicated less support for Affirmative Action than individuals primed with neutral content. Mediation analysis revealed that the SLB prime decreased support for Affirmative Action by increasing perceptions of anti‐White bias. This research offers experimental evidence that SLBs contribute to White people's perceptions of anti‐White bias and to decreased support for Affirmative Action.
Factors affecting parathyroid hormone levels in different types of primary aldosteronism
Authors: Jiang Yiran , Zhang Cui , Ye Lei , Su Tingwei , Zhou Weiwei , Jiang Lei , Zhang Yifei , Wang Weiqing
Published: November 2015

Background

Recent studies have found that mild secondary hyperparathyroidism might be another clinical feature of patients with primary aldosteronims (PA), but whether serum parathyroid hormone level (PTH) is correlated with subtypes of PA and what contributes to the elevated PTH level remains unclear.

Objective

To illustrate the changes of PTH in PA and to partly explain the mechanism of how the effects of aldosterone regulating the secretion of PTH in PA.

Methods

We enrolled a total of 120 patients with primary hypertension (PH) and 242 patients with PA, which included 89 APAs (aldosterone‐producing adenoma), 119 IHAs (idiopathic hyperaldosteronism) and 34 UAHs (unilateral adrenal hyperplasia). The plasma levels of aldosterone, renin activity, parathyroid hormone and markers associated with calcium metabolism were measured.

Results

We found serum PTH level was significantly elevated in patients with PA compared with primary hypertension [9·0 (6·6, 11·7) vs 5·7 (4·4, 7·0)] pmol/l, P < 0·001]. However, no difference was found between the three PA subtypes (P > 0·05). Stepwise multiple regression analysis showed that in patients with PA, serum levels of K+ and Ca2+ were independently associated with serum PTH level. More importantly, elevated PTH level could be corrected either by unilateral adrenalectomy [9·9 (7·5, 12·8) vs 5·2 (4·4, 7·0) pmol/l, P < 0·001] or mineralocorticoid receptor (MR) antagonists treatment [11·7 (9·1, 13·4) vs 6·3 (5·1, 7·8) pmol/l, P < 0·001].

Conclusions

PTH level is elevated in PA patients and irrelevant with subtypes of PA. Serum K+ and serum Ca2+ level are main factors influence the plasma PTH level in PA patients. After medical or surgical treatment, PTH levels return to normal.
Analysis of caveolin‐1 and phosphoinositol‐3 kinase expression in primary uveal melanomas
Authors: Stenzel Miriam , Tura Aysegül , Nassar Khaled , Rohrbach Jens Martin , Grisanti Salvatore , Lüke Matthias , Lüke Julia
Published: November 2015

Background

To evaluate the regulation of blood supply in primary uveal melanomas through caveolin‐1 (Cav‐1)/phosphoinositol‐3 kinase (PI3K).

Methods

The expression of Cav‐1 and PI3K was analysed in 51 paraffin sections of metastatic (n = 30) and non‐metastastic uveal melanomas (n = 21). Two trained observers quantified Cav‐1 and PI3K immunofluorescensce expression by determining intensity of staining and percentage of positive cells. The expression was correlated with known prognostic factors. Besides angiogenesis by means of endoglin expression, the normal vasculature (von Willebrand Factor expression) was evaluated semi‐quantitatively. Vasculogenic mimicry (VM) was analysed by CD31/PAS staining.

Results

All examined specimens expressed Cav‐1 with a mean of 90.34% Cav‐1 positive cells (range, 3.23–100%). Metastatic disease was associated with a higher Cav‐1 expression. The correlation of Cav‐1 with well‐established prognostic factors showed a significant association between Cav‐1 expression and largest tumour diameter (P = 0.022), tumour node metastasis classification (P = 0.008) and invasion of optic nerve head (P = 0.048). PI3K was expressed by all uveal melanomas with a mean of 87.28% cells showing PI3K expression. A higher level of PI3K was significantly associated with larger height (P = 0.042) and progressed tumour node metastasis stage (P = 0.016). The percentage of PI3K and Cav‐1 positive cells were significantly associated (P = 0.034). For PI3K and Cav‐1 expression a non‐significant association with VM was shown (P = 0.064 and P = 0.072, respectively). No correlation of PI3K or Cav‐1 with angiogenesis or mature vasculature was seen (P > 0.05).

Conclusions

Cav‐1 expression may be especially up‐regulated in larger uveal melanomas. As it was correlated with PI3K expression and VM in this series of uveal melanoma, Cav‐1 might induce the formation of VM via the PI3K‐signalling cascade.
In vivo assessment of tumour angiogenesis in colorectal cancer: the role of confocal laser endomicroscopy
Authors: De Palma G. D. , Maione F. , Esposito D. , Luglio G. , Giglio M. C. , Siciliano S. , Gennarelli N. , Cassese G. , Campione S. , D'Armiento F. P. , Bucci L.
Published: November 2015

Aim

Tumour neoangiogenesis is a key factor in tumour progression and metastatic spread and the possibility to assess tumour angiogenesis might provide prognostic information. The aim of this study was to establish the role of probe‐based confocal laser endomicroscopy (p‐CLE) in the identification of vascular architecture and specific morphological patterns in normal colorectal mucosa and malignant lesions during routine endoscopy.

Method

Fourteen consecutive patients with colorectal cancer were included. The following features were identified and then compared between normal and neoplastic mucosa on p‐CLE images: vessel shape (straight vs irregular) vessel diameter the ‘branching patterns’ vessel permeability (fluorescein leakage) and blood flow (normal vs defective flux). Immunohistochemistry was used to confirm the presence and to study the morphology of vascular structures (CD‐34 staining) and ‘neo‐vessels’ (WT‐1 staining) on tumour and normal mucosal sections.

Results

Tumour vessels appeared as irregular, ectatic and with a highly variable calibre and branching patterns on p‐CLE images. The mean diameter of tumour vessels was significantly larger than those in normal mucosa (weighted mean difference 3.38, 95% CI 2.65–4.11, P = 0.01). Similarly, ‘vessel branching’ (OR 2.74, 95% CI 1.23–6.14, P = 0.01), fluorescent dye ‘extravasation’ (OR 3.46, 95% CI 1.39–8.57, P = 0.01) were significantly more frequent in colorectal cancer than in normal colorectal mucosa. Immunohistochemistry corroborated the p‐CLE findings, showing higher vascularity in tumour sections due to neoformed vessels, presenting irregular patterns.

Conclusion

Probe‐based confocal laser endomicroscopy provides a noninvasive characterization of the microvascular architecture of colonic mucosa. Different morphological patterns have been described, discriminating normal and malignant microvascular networks in colorectal mucosa.
Characterization of thrombopoietin kinetics within 60 days after allogeneic hematopoietic stem cell transplantation and its correlation with megakaryocyte ploidy distribution
Authors: Fu Haixia , Zhang Xiaohui , Xu Lanping , Liu Kaiyan , Huang Xiaojun
Published: November 2015

Thrombopoietin (TPO) has been identified as a key cytokine for both megakaryogenesis and thrombopoiesis. We attempt to characterize the kinetics of TPO and its correlation with megakaryocytes (MKs) ploidy distribution pattern within 60 d after allogeneic hematopoietic stem cell transplantation (allo‐HSCT). Forty‐six consecutive patients undergoing allo‐HSCT from October 2008 to December 2008 were included. TPO levels and ploidy distribution patterns of MKs were measured using ELISA and flow cytometric analysis, respectively. The results indicated that TPO levels and the platelet count followed opposite trends after allo‐HSCT. The preconditioning TPO levels and the number of transplanted CD34+ cells were significant predisposing factors for rapid platelet engraftment (p = 0.010 and 0.007, respectively) by multivariate analysis. There was a reduction of ploidy and an increase in immature MKs in patients with higher endogenous TPO levels (>250 pg/mL) on day 60 after allo‐HSCT. Moreover, lower TPO levels (≤250 pg/mL) on day 60 after allo‐HSCT were associated with significantly improved five‐yr overall survival (p = 0.021) and reduced transplant‐related mortality (p = 0.033). In conclusion, endogenous TPO levels may be associated with platelet recovery and have prognostic significance during allo‐HSCT.
Injection frequency of botulinum toxin A for spastic equinus: a randomized clinical trial
Authors: Hastings‐Ison Tandy , Blackburn Christine , Rawicki Barry , Fahey Michael , Simpson Pam , Baker Richard , Graham Kerr
Published: November 2015

Aim

We compared two botulinum toxin A (BoNT‐A) injection frequency regimens, 12‐monthly versus 4‐monthly, for spastic equinus in a randomized clinical trial. The primary outcome measure was passive ankle dorsiflexion.

Method

Forty‐two ambulant children with spastic equinus, secondary to cerebral palsy (23 males and 19 females; mean age 3y 6mo, SD 13mo; GMFCS levels I [n=20], II [n=19], III [n=3]) were randomized to receive either 12‐monthly or 4‐monthly BoNT‐A injections to the calf, over a 26‐month period. Twenty‐one children had spastic hemiplegia, 21 children had spastic diplegia. A fixed 6U/kg dose of Botox was injected into the gastrocnemius muscle of both limbs in children with diplegia and the gastrocsoleus of the affected limb in children with hemiplegia, under mask anaesthesia.

Results

Forty‐two children entered the trial with 21 participants randomized to each group. There were three withdrawals and two children received serial casting midway through the trial. There was no significant difference in passive dorsiflexion between 12‐monthly and 4‐monthly regimens (p=0.41). There were also no significant between group differences on secondary outcome measures. There were no serious adverse events – the rate was 1.2 adverse events per child per year in the 12‐monthly group and 2.2 adverse events per child per year in the 4‐monthly group. Subgroup analysis revealed a significant difference in passive dorsiflexion between children with hemiplegia and diplegia (p=0.01).

Interpretation

There was no significant difference between 12‐monthly and 4‐monthly injection regimens on passive dorsiflexion or secondary outcome measures. BoNT‐A injections for spastic equinus may be recommended on a 12‐monthly basis.
Quantifying insect predation with predator exclusion cages: the role of prey antipredator behavior as a source of bias
Authors: Castellanos Ignacio , Barbosa Pedro , Zuria Iriana , Caldas Astrid
Published: November 2015

There are limitations imposed by current methodologies to detect and quantify insect predation. However, there has been relatively little effort to experimentally document the sources of biases associated with the various methodologies. In this study, we examined how predation estimates in the field using predator exclusion cages may be biased when one fails to account for antipredator behavioral responses. To do this, we did the usual comparison of the number of insects missing from plants where predators were allowed access to the number missing from plants where predators were excluded, but also determined how many of the missing insects reacted to predators by dropping from plants and how many were actually preyed upon. Our results provide evidence that estimates of insect mortality in the field are significantly reduced if prey antipredator behavior is taken into account. As it is commonly assumed that prey missing in the field are predated, documenting the incidence of predator‐mediated ‘disappearance’ and capturing insect prey before they escape can provide with a relevant estimate of bias.
Industrial pollution affects behaviour of the leafmining moth Stigmella lapponica
Authors: Kozlov Mikhail V. , Zvereva Elena L.
Published: November 2015

We explored the impacts of industrial air pollution on the behaviour of the leafmining moth Stigmella lapponica (Wocke) (Lepidoptera: Nepticulidae) by comparing the characteristics of larval gallery mines in mountain birch [Betula pubescens ssp. czerepanovii (Orlova) Hämet‐Ahti (Betulaceae)] leaves collected from unpolluted forests and from heavily polluted industrial barrens surrounding the copper‐nickel smelter in Monchegorsk in north‐western Russia. Population density of S. lapponica, survival of larvae, length of the completed mine, and width of its terminal part did not differ between polluted and unpolluted sites. Females in unpolluted sites only rarely (16%) oviposited on the apical half of the leaf and the larval mortality in mines that started in the apical part of the leaf was 83%. A significantly larger (38%) proportion of mines started in the apical half of the leaves in polluted sites, and the larval mortality in these mines was only 45%. The between‐habitat difference in the choice of the oviposition sites by S. lapponica is the first demonstration of the adaptive plasticity of oviposition behaviour in a leafmining insect. This difference was not explained by specific leaf weight which did not vary within leaves. Larvae mining in polluted leaves extended 25% farther between turns, and the galleries turned more sharply than in unpolluted leaves. This result confirms the abilities of leafmining larvae to evaluate the quality of the ingested food and adjust their behaviour accordingly. Thus, pollution modifies both the preference of S. lapponica females for oviposition sites within a birch leaf and the behaviour of S. lapponica larvae mining these leaves. This is one of the first records of changes in insect behaviour in natural environment disturbed by industrial pollution.