Behavioural phenotypes predict disease susceptibility and infectiousness

PubMed Central

Araujo, Alessandra; Kirschman, Lucas

2016-01-01

Behavioural phenotypes may provide a means for identifying individuals that disproportionally contribute to disease spread and epizootic outbreaks. For example, bolder phenotypes may experience greater exposure and susceptibility to pathogenic infection because of distinct interactions with conspecifics and their environment. We tested the value of behavioural phenotypes in larval amphibians for predicting ranavirus transmission in experimental trials. We found that behavioural phenotypes characterized by latency-to-food and swimming profiles were predictive of disease susceptibility and infectiousness defined as the capacity of an infected host to transmit an infection by contacts. While viral shedding rates were positively associated with transmission, we also found an inverse relationship between contacts and infections. Together these results suggest intrinsic traits that influence behaviour and the quantity of pathogens shed during conspecific interactions may be an important contributor to ranavirus transmission. These results suggest that behavioural phenotypes provide a means to identify individuals more likely to spread disease and thus give insights into disease outbreaks that threaten wildlife and humans. PMID:27555652

Behavioural phenotypes predict disease susceptibility and infectiousness.

PubMed

Araujo, Alessandra; Kirschman, Lucas; Warne, Robin W

2016-08-01

Behavioural phenotypes may provide a means for identifying individuals that disproportionally contribute to disease spread and epizootic outbreaks. For example, bolder phenotypes may experience greater exposure and susceptibility to pathogenic infection because of distinct interactions with conspecifics and their environment. We tested the value of behavioural phenotypes in larval amphibians for predicting ranavirus transmission in experimental trials. We found that behavioural phenotypes characterized by latency-to-food and swimming profiles were predictive of disease susceptibility and infectiousness defined as the capacity of an infected host to transmit an infection by contacts. While viral shedding rates were positively associated with transmission, we also found an inverse relationship between contacts and infections. Together these results suggest intrinsic traits that influence behaviour and the quantity of pathogens shed during conspecific interactions may be an important contributor to ranavirus transmission. These results suggest that behavioural phenotypes provide a means to identify individuals more likely to spread disease and thus give insights into disease outbreaks that threaten wildlife and humans. © 2016 The Author(s).

A Testosterone-Related Structural Brain Phenotype Predicts Aggressive Behavior From Childhood to Adulthood

PubMed Central

Nguyen, Tuong-Vi; McCracken, James T; Albaugh, Matthew D; Botteron, Kelly N.; Hudziak, James J; Ducharme, Simon

2015-01-01

Structural covariance, the examination of anatomic correlations between brain regions, has emerged recently as a valid and useful measure of developmental brain changes. Yet the exact biological processes leading to changes in covariance, and the relation between such covariance and behavior, remain largely unexplored. The steroid hormone testosterone represents a compelling mechanism through which this structural covariance may be developmentally regulated in humans. Although steroid hormone receptors can be found throughout the central nervous system, the amygdala represents a key target for testosterone-specific effects, given its high density of androgen receptors. In addition, testosterone has been found to impact cortical thickness (CTh) across the whole brain, suggesting that it may also regulate the structural relationship, or covariance, between the amygdala and CTh. Here we examined testosterone-related covariance between amygdala volumes and whole-brain CTh, as well as its relationship to aggression levels, in a longitudinal sample of children, adolescents, and young adults 6 to 22 years old. We found: (1) testosterone-specific modulation of the covariance between the amygdala and medial prefrontal cortex (mPFC); (2) a significant relationship between amygdala-mPFC covariance and levels of aggression; and (3) mediation effects of amygdala-mPFC covariance on the relationship between testosterone and aggression. These effects were independent of sex, age, pubertal stage, estradiol levels and anxious-depressed symptoms. These findings are consistent with prior evidence that testosterone targets the neural circuits regulating affect and impulse regulation, and show, for the first time in humans, how androgen-dependent organizational effects may regulate a very specific, aggression-related structural brain phenotype from childhood to young adulthood. PMID:26431805

A testosterone-related structural brain phenotype predicts aggressive behavior from childhood to adulthood.

PubMed

Nguyen, Tuong-Vi; McCracken, James T; Albaugh, Matthew D; Botteron, Kelly N; Hudziak, James J; Ducharme, Simon

2016-01-01

Structural covariance, the examination of anatomic correlations between brain regions, has emerged recently as a valid and useful measure of developmental brain changes. Yet the exact biological processes leading to changes in covariance, and the relation between such covariance and behavior, remain largely unexplored. The steroid hormone testosterone represents a compelling mechanism through which this structural covariance may be developmentally regulated in humans. Although steroid hormone receptors can be found throughout the central nervous system, the amygdala represents a key target for testosterone-specific effects, given its high density of androgen receptors. In addition, testosterone has been found to impact cortical thickness (CTh) across the whole brain, suggesting that it may also regulate the structural relationship, or covariance, between the amygdala and CTh. Here, we examined testosterone-related covariance between amygdala volumes and whole-brain CTh, as well as its relationship to aggression levels, in a longitudinal sample of children, adolescents, and young adults 6-22 years old. We found: (1) testosterone-specific modulation of the covariance between the amygdala and medial prefrontal cortex (mPFC); (2) a significant relationship between amygdala-mPFC covariance and levels of aggression; and (3) mediation effects of amygdala-mPFC covariance on the relationship between testosterone and aggression. These effects were independent of sex, age, pubertal stage, estradiol levels and anxious-depressed symptoms. These findings are consistent with prior evidence that testosterone targets the neural circuits regulating affect and impulse regulation, and show, for the first time in humans, how androgen-dependent organizational effects may regulate a very specific, aggression-related structural brain phenotype from childhood to young adulthood. Copyright © 2015 Elsevier Ltd. All rights reserved.

Evolutionary history of human disease genes reveals phenotypic connections and comorbidity among genetic diseases

NASA Astrophysics Data System (ADS)

Park, Solip; Yang, Jae-Seong; Kim, Jinho; Shin, Young-Eun; Hwang, Jihye; Park, Juyong; Jang, Sung Key; Kim, Sanguk

2012-10-01

The extent to which evolutionary changes have impacted the phenotypic relationships among human diseases remains unclear. In this work, we report that phenotypically similar diseases are connected by the evolutionary constraints on human disease genes. Human disease groups can be classified into slowly or rapidly evolving classes, where the diseases in the slowly evolving class are enriched with morphological phenotypes and those in the rapidly evolving class are enriched with physiological phenotypes. Our findings establish a clear evolutionary connection between disease classes and disease phenotypes for the first time. Furthermore, the high comorbidity found between diseases connected by similar evolutionary constraints enables us to improve the predictability of the relative risk of human diseases. We find the evolutionary constraints on disease genes are a new layer of molecular connection in the network-based exploration of human diseases.

Evolutionary history of human disease genes reveals phenotypic connections and comorbidity among genetic diseases.

PubMed

Park, Solip; Yang, Jae-Seong; Kim, Jinho; Shin, Young-Eun; Hwang, Jihye; Park, Juyong; Jang, Sung Key; Kim, Sanguk

2012-01-01

The extent to which evolutionary changes have impacted the phenotypic relationships among human diseases remains unclear. In this work, we report that phenotypically similar diseases are connected by the evolutionary constraints on human disease genes. Human disease groups can be classified into slowly or rapidly evolving classes, where the diseases in the slowly evolving class are enriched with morphological phenotypes and those in the rapidly evolving class are enriched with physiological phenotypes. Our findings establish a clear evolutionary connection between disease classes and disease phenotypes for the first time. Furthermore, the high comorbidity found between diseases connected by similar evolutionary constraints enables us to improve the predictability of the relative risk of human diseases. We find the evolutionary constraints on disease genes are a new layer of molecular connection in the network-based exploration of human diseases.

Mapping Gene Associations in Human Mitochondria using Clinical Disease Phenotypes

PubMed Central

Scharfe, Curt; Lu, Henry Horng-Shing; Neuenburg, Jutta K.; Allen, Edward A.; Li, Guan-Cheng; Klopstock, Thomas; Cowan, Tina M.; Enns, Gregory M.; Davis, Ronald W.

2009-01-01

Nuclear genes encode most mitochondrial proteins, and their mutations cause diverse and debilitating clinical disorders. To date, 1,200 of these mitochondrial genes have been recorded, while no standardized catalog exists of the associated clinical phenotypes. Such a catalog would be useful to develop methods to analyze human phenotypic data, to determine genotype-phenotype relations among many genes and diseases, and to support the clinical diagnosis of mitochondrial disorders. Here we establish a clinical phenotype catalog of 174 mitochondrial disease genes and study associations of diseases and genes. Phenotypic features such as clinical signs and symptoms were manually annotated from full-text medical articles and classified based on the hierarchical MeSH ontology. This classification of phenotypic features of each gene allowed for the comparison of diseases between different genes. In turn, we were then able to measure the phenotypic associations of disease genes for which we calculated a quantitative value that is based on their shared phenotypic features. The results showed that genes sharing more similar phenotypes have a stronger tendency for functional interactions, proving the usefulness of phenotype similarity values in disease gene network analysis. We then constructed a functional network of mitochondrial genes and discovered a higher connectivity for non-disease than for disease genes, and a tendency of disease genes to interact with each other. Utilizing these differences, we propose 168 candidate genes that resemble the characteristic interaction patterns of mitochondrial disease genes. Through their network associations, the candidates are further prioritized for the study of specific disorders such as optic neuropathies and Parkinson disease. Most mitochondrial disease phenotypes involve several clinical categories including neurologic, metabolic, and gastrointestinal disorders, which might indicate the effects of gene defects within the

Expression Profiling of Primary and Metastatic Ovarian Tumors Reveals Differences Indicative of Aggressive Disease

PubMed Central

Brodsky, Alexander S.; Fischer, Andrew; Miller, Daniel H.; Vang, Souriya; MacLaughlan, Shannon; Wu, Hsin-Ta; Yu, Jovian; Steinhoff, Margaret; Collins, Colin; Smith, Peter J. S.; Raphael, Benjamin J.; Brard, Laurent

2014-01-01

The behavior and genetics of serous epithelial ovarian cancer (EOC) metastasis, the form of the disease lethal to patients, is poorly understood. The unique properties of metastases are critical to understand to improve treatments of the disease that remains in patients after debulking surgery. We sought to identify the genetic and phenotypic landscape of metastatic progression of EOC to understand how metastases compare to primary tumors. DNA copy number and mRNA expression differences between matched primary human tumors and omental metastases, collected at the same time during debulking surgery before chemotherapy, were measured using microarrays. qPCR and immunohistochemistry validated findings. Pathway analysis of mRNA expression revealed metastatic cancer cells are more proliferative and less apoptotic than primary tumors, perhaps explaining the aggressive nature of these lesions. Most cases had copy number aberrations (CNAs) that differed between primary and metastatic tumors, but we did not detect CNAs that are recurrent across cases. A six gene expression signature distinguishes primary from metastatic tumors and predicts overall survival in independent datasets. The genetic differences between primary and metastatic tumors, yet common expression changes, suggest that the major clone in metastases is not the same as in primary tumors, but the cancer cells adapt to the omentum similarly. Together, these data highlight how ovarian tumors develop into a distinct, more aggressive metastatic state that should be considered for therapy development. PMID:24732363

Aggressiveness, violence, homicidality, homicide, and Lyme disease

PubMed Central

Bransfield, Robert C

2018-01-01

Background No study has previously analyzed aggressiveness, homicide, and Lyme disease (LD). Materials and methods Retrospective LD chart reviews analyzed aggressiveness, compared 50 homicidal with 50 non-homicidal patients, and analyzed homicides. Results Most aggression with LD was impulsive, sometimes provoked by intrusive symptoms, sensory stimulation or frustration and was invariably bizarre and senseless. About 9.6% of LD patients were homicidal with the average diagnosis delay of 9 years. Postinfection findings associated with homicidality that separated from the non-homicidal group within the 95% confidence interval included suicidality, sudden abrupt mood swings, explosive anger, paranoia, anhedonia, hypervigilance, exaggerated startle, disinhibition, nightmares, depersonalization, intrusive aggressive images, dissociative episodes, derealization, intrusive sexual images, marital/family problems, legal problems, substance abuse, depression, panic disorder, memory impairments, neuropathy, cranial nerve symptoms, and decreased libido. Seven LD homicides included predatory aggression, poor impulse control, and psychosis. Some patients have selective hyperacusis to mouth sounds, which I propose may be the result of brain dysfunction causing a disinhibition of a primitive fear of oral predation. Conclusion LD and the immune, biochemical, neurotransmitter, and the neural circuit reactions to it can cause impairments associated with violence. Many LD patients have no aggressiveness tendencies or only mild degrees of low frustration tolerance and irritability and pose no danger; however, a lesser number experience explosive anger, a lesser number experience homicidal thoughts and impulses, and much lesser number commit homicides. Since such large numbers are affected by LD, this small percent can be highly significant. Much of the violence associated with LD can be avoided with better prevention, diagnosis, and treatment of LD. PMID:29576731

Phenotype at diagnosis predicts recurrence rates in Crohn's disease.

PubMed

Wolters, F L; Russel, M G; Sijbrandij, J; Ambergen, T; Odes, S; Riis, L; Langholz, E; Politi, P; Qasim, A; Koutroubakis, I; Tsianos, E; Vermeire, S; Freitas, J; van Zeijl, G; Hoie, O; Bernklev, T; Beltrami, M; Rodriguez, D; Stockbrügger, R W; Moum, B

2006-08-01

In Crohn's disease (CD), studies associating phenotype at diagnosis and subsequent disease activity are important for patient counselling and health care planning. To calculate disease recurrence rates and to correlate these with phenotypic traits at diagnosis. A prospectively assembled uniformly diagnosed European population based inception cohort of CD patients was classified according to the Vienna classification for disease phenotype at diagnosis. Surgical and non-surgical recurrence rates throughout a 10 year follow up period were calculated. Multivariate analysis was performed to classify risk factors present at diagnosis for recurrent disease. A total of 358 were classified for phenotype at diagnosis, of whom 262 (73.2%) had a first recurrence and 113 patients (31.6%) a first surgical recurrence during the first 10 years after diagnosis. Patients with upper gastrointestinal disease at diagnosis had an excess risk of recurrence (hazard ratio 1.54 (95% confidence interval (CI) 1.13-2.10)) whereas age >/=40 years at diagnosis was protective (hazard ratio 0.82 (95% CI 0.70-0.97)). Colonic disease was a protective characteristic for resective surgery (hazard ratio 0.38 (95% CI 0.21-0.69)). More frequent resective surgical recurrences were reported from Copenhagen (hazard ratio 3.23 (95% CI 1.32-7.89)). A mild course of disease in terms of disease recurrence was observed in this European cohort. Phenotype at diagnosis had predictive value for disease recurrence with upper gastrointestinal disease being the most important positive predictor. A phenotypic North-South gradient in CD may be present, illustrated by higher surgery risks in some of the Northern European centres.

Characterisation of aggression in Huntington's disease: rates, types and antecedents in an inpatient rehabilitation setting.

PubMed

Brown, Anahita; Sewell, Katherine; Fisher, Caroline A

2017-10-01

To systematically review aggression in an inpatient Huntington's cohort examining rates, types and antecedents. Although the prevalence of aggression in Huntington's disease is high, research into this problematic behaviour has been limited. Few studies have investigated the nature of aggressive behaviour in Huntington's disease or antecedents that contribute to its occurrence. A systematic, double-coded, electronic medical file audit. The electronic hospital medical records of 10 people with Huntington's disease admitted to a brain disorders unit were audited for a 90-day period using the Overt Aggression Scale-Modified for Neurorehabilitation framework, yielding 900 days of clinical data. Nine of 10 clients exhibited aggression during the audit period. Both verbal (37·1%) aggression and physical aggression were common (33·8%), along with episodes of mixed verbal and physical aggression (15·2%), while aggression to objects/furniture was less prevalent (5·5%). The most common antecedent was physical guidance with personal care, far exceeding any other documented antecedents, and acting as the most common trigger for four of the nine clients who exhibited aggression. For the remaining five clients, there was intraindividual heterogeneity in susceptibility to specific antecedents. In Huntington's sufferers at mid- to late stages following disease onset, particular care should be made with personal care assistance due to the propensity for these procedures to elicit an episode of aggression. However, given the degree of intraindividual heterogeneity in susceptibility to specific antecedents observed in the present study, individualised behaviour support plans and sensory modulation interventions may be the most useful in identifying triggers and managing aggressive episodes. Rates of aggression in Huntington's disease inpatients can be high. Knowledge of potential triggers, such as personal care, is important for nursing and care staff, so that attempts can be

Co-clustering phenome–genome for phenotype classification and disease gene discovery

PubMed Central

Hwang, TaeHyun; Atluri, Gowtham; Xie, MaoQiang; Dey, Sanjoy; Hong, Changjin; Kumar, Vipin; Kuang, Rui

2012-01-01

Understanding the categorization of human diseases is critical for reliably identifying disease causal genes. Recently, genome-wide studies of abnormal chromosomal locations related to diseases have mapped >2000 phenotype–gene relations, which provide valuable information for classifying diseases and identifying candidate genes as drug targets. In this article, a regularized non-negative matrix tri-factorization (R-NMTF) algorithm is introduced to co-cluster phenotypes and genes, and simultaneously detect associations between the detected phenotype clusters and gene clusters. The R-NMTF algorithm factorizes the phenotype–gene association matrix under the prior knowledge from phenotype similarity network and protein–protein interaction network, supervised by the label information from known disease classes and biological pathways. In the experiments on disease phenotype–gene associations in OMIM and KEGG disease pathways, R-NMTF significantly improved the classification of disease phenotypes and disease pathway genes compared with support vector machines and Label Propagation in cross-validation on the annotated phenotypes and genes. The newly predicted phenotypes in each disease class are highly consistent with human phenotype ontology annotations. The roles of the new member genes in the disease pathways are examined and validated in the protein–protein interaction subnetworks. Extensive literature review also confirmed many new members of the disease classes and pathways as well as the predicted associations between disease phenotype classes and pathways. PMID:22735708

Temporal Change in Phenotypic Behaviour in Patients with Crohn's Disease: Do Indian Patients Behave Differently from Western and Other Asian Patients?

PubMed

Kalaria, Rishikesh; Desai, Devendra; Abraham, Philip; Joshi, Anand; Gupta, Tarun; Shah, Sudeep

2016-03-01

In Western studies, one-third of patients with Crohn's disease have stricturing or penetrating disease at presentation and one-half will progress to complicated disease in 20 years. Asian studies indicate that the Asian disease phenotype may be different. Our aim was to study the disease behaviour in Indian patients with Crohn's disease. In this hospital-based study, we analysed [Montreal classification] disease phenotype, presence of perianal disease, need for intestinal surgery, and changes in the Montreal classification over time in Crohn's disease patients from our database. In the 178 patients (median age 35, interquartile range [IQR] 21 years; 97 males) with Crohn's disease, the proportion of various features was as follows. More patients had ileo-colonic[L3: 43.8%] than ileal[L1: 27.5%] or colonic[L2: 28.7%] disease. Perianal disease was seen in 11.8% at baseline. Non-stricturing, non-fistulising disease[B1] was seen in 74.7%, 65.7%, 50%, and 44.4% at baseline, at 5, 10 and 15 years, respectively. Stricturing disease[B2] was seen in 21.4%, 21.9%, 28.9%, and 33.3%; penetrating disease[B3] in 3.9%, 11.4%, 21%, and 16.7%; and intestinal surgery was required in 10.7%, 20%, 34.2%, and 55.5%, respectively. KaplanMeier analysis showed no association between progression of disease and patient age or the location of the disease. Gender distribution and predominant ileo-colonic location of disease were similar to earlier Asian reports on Crohn's disease. Perianal disease was less frequent than reported in Western and other Asian studies. One-fourth of Indian patients had aggressive disease at diagnosis, but the tendency to progress towards aggressive disease over time was less pronounced than in Western patients. Copyright © 2015 European Crohn’s and Colitis Organisation (ECCO). Published by Oxford University Press. All rights reserved. For permissions, please email: journals.permissions@oup.com.

Phenotype at diagnosis predicts recurrence rates in Crohn's disease

PubMed Central

Wolters, F L; Russel, M G; Sijbrandij, J; Ambergen, T; Odes, S; Riis, L; Langholz, E; Politi, P; Qasim, A; Koutroubakis, I; Tsianos, E; Vermeire, S; Freitas, J; van Zeijl, G; Hoie, O; Bernklev, T; Beltrami, M; Rodriguez, D; Stockbrügger, R W; Moum, B

2006-01-01

Background In Crohn's disease (CD), studies associating phenotype at diagnosis and subsequent disease activity are important for patient counselling and health care planning. Aims To calculate disease recurrence rates and to correlate these with phenotypic traits at diagnosis. Methods A prospectively assembled uniformly diagnosed European population based inception cohort of CD patients was classified according to the Vienna classification for disease phenotype at diagnosis. Surgical and non‐surgical recurrence rates throughout a 10 year follow up period were calculated. Multivariate analysis was performed to classify risk factors present at diagnosis for recurrent disease. Results A total of 358 were classified for phenotype at diagnosis, of whom 262 (73.2%) had a first recurrence and 113 patients (31.6%) a first surgical recurrence during the first 10 years after diagnosis. Patients with upper gastrointestinal disease at diagnosis had an excess risk of recurrence (hazard ratio 1.54 (95% confidence interval (CI) 1.13–2.10)) whereas age ⩾40 years at diagnosis was protective (hazard ratio 0.82 (95% CI 0.70–0.97)). Colonic disease was a protective characteristic for resective surgery (hazard ratio 0.38 (95% CI 0.21–0.69)). More frequent resective surgical recurrences were reported from Copenhagen (hazard ratio 3.23 (95% CI 1.32–7.89)). Conclusions A mild course of disease in terms of disease recurrence was observed in this European cohort. Phenotype at diagnosis had predictive value for disease recurrence with upper gastrointestinal disease being the most important positive predictor. A phenotypic North‐South gradient in CD may be present, illustrated by higher surgery risks in some of the Northern European centres. PMID:16361306

Linking rare and common disease: mapping clinical disease-phenotypes to ontologies in therapeutic target validation.

PubMed

Sarntivijai, Sirarat; Vasant, Drashtti; Jupp, Simon; Saunders, Gary; Bento, A Patrícia; Gonzalez, Daniel; Betts, Joanna; Hasan, Samiul; Koscielny, Gautier; Dunham, Ian; Parkinson, Helen; Malone, James

2016-01-01

The Centre for Therapeutic Target Validation (CTTV - https://www.targetvalidation.org/) was established to generate therapeutic target evidence from genome-scale experiments and analyses. CTTV aims to support the validity of therapeutic targets by integrating existing and newly-generated data. Data integration has been achieved in some resources by mapping metadata such as disease and phenotypes to the Experimental Factor Ontology (EFO). Additionally, the relationship between ontology descriptions of rare and common diseases and their phenotypes can offer insights into shared biological mechanisms and potential drug targets. Ontologies are not ideal for representing the sometimes associated type relationship required. This work addresses two challenges; annotation of diverse big data, and representation of complex, sometimes associated relationships between concepts. Semantic mapping uses a combination of custom scripting, our annotation tool 'Zooma', and expert curation. Disease-phenotype associations were generated using literature mining on Europe PubMed Central abstracts, which were manually verified by experts for validity. Representation of the disease-phenotype association was achieved by the Ontology of Biomedical AssociatioN (OBAN), a generic association representation model. OBAN represents associations between a subject and object i.e., disease and its associated phenotypes and the source of evidence for that association. The indirect disease-to-disease associations are exposed through shared phenotypes. This was applied to the use case of linking rare to common diseases at the CTTV. EFO yields an average of over 80% of mapping coverage in all data sources. A 42% precision is obtained from the manual verification of the text-mined disease-phenotype associations. This results in 1452 and 2810 disease-phenotype pairs for IBD and autoimmune disease and contributes towards 11,338 rare diseases associations (merged with existing published work [Am J Hum Genet

Towards building a disease-phenotype knowledge base: extracting disease-manifestation relationship from literature

PubMed Central

Xu, Rong; Li, Li; Wang, QuanQiu

2013-01-01

Motivation: Systems approaches to studying phenotypic relationships among diseases are emerging as an active area of research for both novel disease gene discovery and drug repurposing. Currently, systematic study of disease phenotypic relationships on a phenome-wide scale is limited because large-scale machine-understandable disease–phenotype relationship knowledge bases are often unavailable. Here, we present an automatic approach to extract disease–manifestation (D-M) pairs (one specific type of disease–phenotype relationship) from the wide body of published biomedical literature. Data and Methods: Our method leverages external knowledge and limits the amount of human effort required. For the text corpus, we used 119 085 682 MEDLINE sentences (21 354 075 citations). First, we used D-M pairs from existing biomedical ontologies as prior knowledge to automatically discover D-M–specific syntactic patterns. We then extracted additional pairs from MEDLINE using the learned patterns. Finally, we analysed correlations between disease manifestations and disease-associated genes and drugs to demonstrate the potential of this newly created knowledge base in disease gene discovery and drug repurposing. Results: In total, we extracted 121 359 unique D-M pairs with a high precision of 0.924. Among the extracted pairs, 120 419 (99.2%) have not been captured in existing structured knowledge sources. We have shown that disease manifestations correlate positively with both disease-associated genes and drug treatments. Conclusions: The main contribution of our study is the creation of a large-scale and accurate D-M phenotype relationship knowledge base. This unique knowledge base, when combined with existing phenotypic, genetic and proteomic datasets, can have profound implications in our deeper understanding of disease etiology and in rapid drug repurposing. Availability: http://nlp.case.edu/public/data/DMPatternUMLS/ Contact: rxx@case.edu PMID:23828786

PCAN: phenotype consensus analysis to support disease-gene association.

PubMed

Godard, Patrice; Page, Matthew

2016-12-07

Bridging genotype and phenotype is a fundamental biomedical challenge that underlies more effective target discovery and patient-tailored therapy. Approaches that can flexibly and intuitively, integrate known gene-phenotype associations in the context of molecular signaling networks are vital to effectively prioritize and biologically interpret genes underlying disease traits of interest. We describe Phenotype Consensus Analysis (PCAN); a method to assess the consensus semantic similarity of phenotypes in a candidate gene's signaling neighborhood. We demonstrate that significant phenotype consensus (p < 0.05) is observable for ~67% of 4,549 OMIM disease-gene associations, using a combination of high quality String interactions + Metabase pathways and use Joubert Syndrome to demonstrate the ease with which a significant result can be interrogated to highlight discriminatory traits linked to mechanistically related genes. We advocate phenotype consensus as an intuitive and versatile method to aid disease-gene association, which naturally lends itself to the mechanistic deconvolution of diverse phenotypes. We provide PCAN to the community as an R package ( http://bioconductor.org/packages/PCAN/ ) to allow flexible configuration, extension and standalone use or integration to supplement existing gene prioritization workflows.

Huntington's Disease: Relationship Between Phenotype and Genotype.

PubMed

Sun, Yi-Min; Zhang, Yan-Bin; Wu, Zhi-Ying

2017-01-01

Huntington's disease (HD) is an autosomal dominant inherited neurodegenerative disease with the typical manifestations of involuntary movements, psychiatric and behavior disorders, and cognitive impairment. It is caused by the dynamic mutation in CAG triplet repeat number in exon 1 of huntingtin (HTT) gene. The symptoms of HD especially the age at onset are related to the genetic characteristics, both the CAG triplet repeat and the modified factors. Here, we reviewed the recent advancement on the genotype-phenotype relationship of HD, mainly focus on the characteristics of different expanded CAG repeat number, genetic modifiers, and CCG repeat number in the 3' end of CAG triplet repeat and their effects on the phenotype. We also reviewed the special forms of HD (juvenile HD, atypical onset HD, and homozygous HD) and their phenotype-genotype correlations. The review will aid clinicians to predict the onset age and disease course of HD, give the genetic counseling, and accelerate research into the HD mechanism.

Chrna7 deficient mice manifest no consistent neuropsychiatric and behavioral phenotypes.

PubMed

Yin, Jiani; Chen, Wu; Yang, Hongxing; Xue, Mingshan; Schaaf, Christian P

2017-01-03

The alpha7 nicotinic acetylcholine receptor, encoded by the CHRNA7 gene, has been implicated in various psychiatric and behavioral disorders, including schizophrenia, bipolar disorder, epilepsy, autism, Alzheimer's disease, and Parkinson's disease, and is considered a potential target for therapeutic intervention. 15q13.3 microdeletion syndrome is a rare genetic disorder, caused by submicroscopic deletions on chromosome 15q. CHRNA7 is the only gene in this locus that has been deleted entirely in cases involving the smallest microdeletions. Affected individuals manifest variable neurological and behavioral phenotypes, which commonly include developmental delay/intellectual disability, epilepsy, and autism spectrum disorder. Subsets of patients have short attention spans, aggressive behaviors, mood disorders, or schizophrenia. Previous behavioral studies suggested that Chrna7 deficient mice had attention deficits, but were normal in baseline behavioral responses, learning, memory, and sensorimotor gating. Given a growing interest in CHRNA7-related diseases and a better appreciation of its associated human phenotypes, an in-depth behavioral characterization of the Chrna7 deficient mouse model appeared prudent. This study was designed to investigate whether Chrna7 deficient mice manifest phenotypes related to those seen in human individuals, using an array of 12 behavioral assessments and electroencephalogram (EEG) recordings on freely-moving mice. Examined phenotypes included social interaction, compulsive behaviors, aggression, hyperactivity, anxiety, depression, and somatosensory gating. Our data suggests that mouse behavior and EEG recordings are not sensitive to decreased Chrna7 copy number.

An autophagy-driven pathway of ATP secretion supports the aggressive phenotype of BRAFV600E inhibitor-resistant metastatic melanoma cells.

PubMed

Martin, Shaun; Dudek-Peric, Aleksandra M; Garg, Abhishek D; Roose, Heleen; Demirsoy, Seyma; Van Eygen, Sofie; Mertens, Freya; Vangheluwe, Peter; Vankelecom, Hugo; Agostinis, Patrizia

2017-09-02

The ingrained capacity of melanoma cells to rapidly evolve toward an aggressive phenotype is manifested by their increased ability to develop drug-resistance, evident in the case of vemurafenib, a therapeutic-agent targeting BRAF V600E . Previous studies indicated a tight correlation between heightened melanoma-associated macroautophagy/autophagy and acquired Vemurafenib resistance. However, how this vesicular trafficking pathway supports Vemurafenib resistance remains unclear. Here, using isogenic human and murine melanoma cell lines of Vemurafenib-resistant and patient-derived melanoma cells with primary resistance to the BRAF V600E inhibitor, we found that the enhanced migration and invasion of the resistant melanoma cells correlated with an enhanced autophagic capacity and autophagosome-mediated secretion of ATP. Extracellular ATP (eATP) was instrumental for the invasive phenotype and the expansion of a subset of Vemurafenib-resistant melanoma cells. Compromising the heightened autophagy in these BRAF V600E inhibitor-resistant melanoma cells through the knockdown of different autophagy genes (ATG5, ATG7, ULK1), reduced their invasive and eATP-secreting capacity. Furthermore, eATP promoted the aggressive nature of the BRAF V600E inhibitor-resistant melanoma cells by signaling through the purinergic receptor P2RX7. This autophagy-propelled eATP-dependent autocrine-paracrine pathway supported the maintenance and expansion of a drug-resistant melanoma phenotype. In conclusion, we have identified an autophagy-driven response that relies on the secretion of ATP to drive P2RX7-based migration and expansion of the Vemurafenib-resistant phenotype. This emphasizes the potential of targeting autophagy in the treatment and management of metastatic melanoma.

Development of the Ovarian Cancer Cohort Consortium: Risk Factor Associations by Heterogeneity of Disease

DTIC Science & Technology

2016-12-01

Lifestyle, & Health (CSDLH)4 39,618 90 58 B, D Cancer Prevention Study II (CPS2) 65,975 549 62 B, FU, D Campaign Against Cancer & Heart Disease ...stronger positive associations for less aggressive disease phenotypes. Only very aggressive disease was associated with current versus never smoking (HR...history of ovarian cancer with less aggressive disease is supported by reports of better survival in BRCA mutation carriers. The BMI association with

Glucose-regulated protein of 94 kDa contributes to the development of an aggressive phenotype in breast cancer cells.

PubMed

Buc Calderon, Pedro; Sennesael, Anne-Laure; Glorieux, Christophe

2018-05-28

Grp94 plays an essential role in protein assembly. We previously suggested that Grp94 overexpression is involved in tumor aggressiveness. However, the underlying mechanisms remain unknown. Since many tumors display high Grp94 levels, we investigated the effects of tumor microenvironment on the regulation of this chaperone expression. First, we found out that hypoxia did not change Grp94 expression in the human tumor cell lines MCF-7 (breast cancer) and HepG2 (liver cancer). Second, glucose deprivation significantly increased Grp94 protein levels. Subsequently, we focused in the putative role of Grp94 in the acquisition of an aggressive phenotype by cancer cells. Using a more aggressive cancer cell model (MDA-MB-231 breast tumor cells), we found out that Grp94 knockdown using siRNA decreased the invasive capacity of cancer cells. Moreover, cells with decreased Grp94 levels displayed an enhanced sensitivity of tumor cells to doxorubicin, a standard drug in the treatment of breast cancer. Taken together, our results suggest that the expression of Grp94 is linked to tumor aggressiveness. Therefore, targeting Grp94 could be an effective way to inhibit tumor growth improving chemotherapy outcome. Copyright © 2018 Elsevier Masson SAS. All rights reserved.

Factors and processes modulating phenotypes in neuronopathic lysosomal storage diseases.

PubMed

Jakóbkiewicz-Banecka, Joanna; Gabig-Cimińska, Magdalena; Banecka-Majkutewicz, Zyta; Banecki, Bogdan; Węgrzyn, Alicja; Węgrzyn, Grzegorz

2014-03-01

Lysosomal storage diseases are inherited metabolic disorders caused by genetic defects causing deficiency of various lysosomal proteins, and resultant accumulation of non-degraded compounds. They are multisystemic diseases, and in most of them (>70%) severe brain dysfunctions are evident. However, expression of various phenotypes in particular diseases is extremely variable, from non-neuronopathic to severely neurodegenerative in the deficiency of the same enzyme. Although all lysosomal storage diseases are monogenic, clear genotype-phenotype correlations occur only in some cases. In this article, we present an overview on various factors and processes, both general and specific for certain disorders, that can significantly modulate expression of phenotypes in these diseases. On the basis of recent reports describing studies on both animal models and clinical data, we propose a hypothesis that efficiency of production of compounds that cannot be degraded due to enzyme deficiency might be especially important in modulation of phenotypes of patients suffering from lysosomal storage diseases.

The Human Phenotype Ontology: Semantic Unification of Common and Rare Disease

PubMed Central

Groza, Tudor; Köhler, Sebastian; Moldenhauer, Dawid; Vasilevsky, Nicole; Baynam, Gareth; Zemojtel, Tomasz; Schriml, Lynn Marie; Kibbe, Warren Alden; Schofield, Paul N.; Beck, Tim; Vasant, Drashtti; Brookes, Anthony J.; Zankl, Andreas; Washington, Nicole L.; Mungall, Christopher J.; Lewis, Suzanna E.; Haendel, Melissa A.; Parkinson, Helen; Robinson, Peter N.

2015-01-01

The Human Phenotype Ontology (HPO) is widely used in the rare disease community for differential diagnostics, phenotype-driven analysis of next-generation sequence-variation data, and translational research, but a comparable resource has not been available for common disease. Here, we have developed a concept-recognition procedure that analyzes the frequencies of HPO disease annotations as identified in over five million PubMed abstracts by employing an iterative procedure to optimize precision and recall of the identified terms. We derived disease models for 3,145 common human diseases comprising a total of 132,006 HPO annotations. The HPO now comprises over 250,000 phenotypic annotations for over 10,000 rare and common diseases and can be used for examining the phenotypic overlap among common diseases that share risk alleles, as well as between Mendelian diseases and common diseases linked by genomic location. The annotations, as well as the HPO itself, are freely available. PMID:26119816

The Human Phenotype Ontology: Semantic Unification of Common and Rare Disease

DOE PAGES

Groza, Tudor; Köhler, Sebastian; Moldenhauer, Dawid; ...

2015-06-25

The Human Phenotype Ontology (HPO) is widely used in the rare disease community for differential diagnostics, phenotype-driven analysis of next-generation sequence-variation data, and translational research, but a comparable resource has not been available for common disease. Here, we have developed a concept-recognition procedure that analyzes the frequencies of HPO disease annotations as identified in over five million PubMed abstracts by employing an iterative procedure to optimize precision and recall of the identified terms. We derived disease models for 3,145 common human diseases comprising a total of 132,006 HPO annotations. The HPO now comprises over 250,000 phenotypic annotations for over 10,000more » rare and common diseases and can be used for examining the phenotypic overlap among common diseases that share risk alleles, as well as between Mendelian diseases and common diseases linked by genomic location. The annotations, as well as the HPO itself, are freely available.« less

Cannibalism as an interacting phenotype: precannibalistic aggression is influenced by social partners in the endangered Socorro Isopod (Thermosphaeroma thermophilum).

PubMed

Bleakley, B H; Welter, S M; McCauley-Cole, K; Shuster, S M; Moore, A J

2013-04-01

Models for the evolution of cannibalism highlight the importance of asymmetries between individuals in initiating cannibalistic attacks. Studies may include measures of body size but typically group individuals into size/age classes or compare populations. Such broad comparisons may obscure the details of interactions that ultimately determine how socially contingent characteristics evolve. We propose that understanding cannibalism is facilitated by using an interacting phenotypes perspective that includes the influences of the phenotype of a social partner on the behaviour of a focal individual and focuses on variation in individual pairwise interactions. We investigated how relative body size, a composite trait between a focal individual and its social partner, and the sex of the partners influenced precannibalistic aggression in the endangered Socorro isopod, Thermosphaeroma thermophilum. We also investigated whether differences in mating interest among males and females influenced cannibalism in mixed sex pairs. We studied these questions in three populations that differ markedly in range of body size and opportunities for interactions among individuals. We found that relative body size influences the probability of and latency to attack. We observed differences in the likelihood of and latency to attack based on both an individual's sex and the sex of its partner but found no evidence of sexual conflict. The instigation of precannibalistic aggression in these isopods is therefore a property of both an individual and its social partner. Our results suggest that interacting phenotype models would be improved by incorporating a new conditional ψ, which describes the strength of a social partner's influence on focal behaviour. © 2013 The Authors. Journal of Evolutionary Biology © 2013 European Society For Evolutionary Biology.

ACE phenotyping in Gaucher disease.

PubMed

Danilov, Sergei M; Tikhomirova, Victoria E; Metzger, Roman; Naperova, Irina A; Bukina, Tatiana M; Goker-Alpan, Ozlem; Tayebi, Nahid; Gayfullin, Nurshat M; Schwartz, David E; Samokhodskaya, Larisa M; Kost, Olga A; Sidransky, Ellen

2018-04-01

Gaucher disease is characterized by the activation of splenic and hepatic macrophages, accompanied by dramatically increased levels of angiotensin-converting enzyme (ACE). To evaluate the source of the elevated blood ACE, we performed complete ACE phenotyping using blood, spleen and liver samples from patients with Gaucher disease and controls. ACE phenotyping included 1) immunohistochemical staining for ACE; 2) measuring ACE activity with two substrates (HHL and ZPHL); 3) calculating the ratio of the rates of substrate hydrolysis (ZPHL/HHL ratio); 4) assessing the conformational fingerprint of ACE by evaluating the pattern of binding of monoclonal antibodies to 16 different ACE epitopes. We show that in patients with Gaucher disease, the dramatically increased levels of ACE originate from activated splenic and/or hepatic macrophages (Gaucher cells), and that both its conformational fingerprint and kinetic characteristics (ZPHL/HHL ratio) differ from controls and from patients with sarcoid granulomas. Furthermore, normal spleen was found to produce high levels of endogenous ACE inhibitors and a novel, tightly-bound 10-30 kDa ACE effector which is deficient in Gaucher spleen. The conformation of ACE is tissue-specific. In Gaucher disease, ACE produced by activated splenic macrophages differs from that in hepatic macrophages, as well as from macrophages and dendritic cells in sarcoid granulomas. The observed differences are likely due to altered ACE glycosylation or sialylation in these diseased organs. The conformational differences in ACE may serve as a specific biomarker for Gaucher disease. Copyright © 2018 Elsevier Inc. All rights reserved.

Elevated expression of Thoc1 is associated with aggressive phenotype and poor prognosis in colorectal cancer

DOE Office of Scientific and Technical Information (OSTI.GOV)

Liu, Chenchen; Yue, Ben; Yuan, Chenwei

The THO complex 1 (Thoc1) is a nuclear matrix protein playing vital roles in transcription elongation and mRNA export. Recently, aberrant expression of Thoc1 has been reported in an increasing array of tumor types. However, the clinical significance of Thoc1 expression in colorectal cancer (CRC) is still unknown. The present study aimed to characterize the expression of Thoc1 in human CRC and evaluate its clinical significance. Quantitative real-time polymerase chain reaction (qRT-PCR) and Western blotting analyses showed that the mRNA and protein expression of Thoc1 in CRC specimens was significantly higher than that in adjacent normal colon mucosae. Immunohistochemistry (IHC)more » was conducted to characterize the expression pattern of Thoc1 in 185 archived paraffin-embedded CRC specimens. Statistical analyses revealed that high levels of Thoc1 expression were associated with the clinical stages and tumor differentiation. CRC patients with high levels of Thoc1 expression had poorer overall-survival and disease-free survival, whereas those with lower levels of Thoc1 expression survived longer. Furthermore, multivariate Cox regression analyses demonstrated that Thoc1 expression remained an independent prognostic factor for increased disease recurrence and decreased survival. Our results suggest for the first time that Thoc1 is involved in the development and progression of CRC, and elevated expression of Thoc1 is associated with aggressive phenotype and poor prognosis in CRC. These findings may prove to be clinically useful for developing a new therapeutic target of CRC treatment.« less

Analysis of the human diseasome using phenotype similarity between common, genetic, and infectious diseases

NASA Astrophysics Data System (ADS)

Hoehndorf, Robert; Schofield, Paul N.; Gkoutos, Georgios V.

2015-06-01

Phenotypes are the observable characteristics of an organism arising from its response to the environment. Phenotypes associated with engineered and natural genetic variation are widely recorded using phenotype ontologies in model organisms, as are signs and symptoms of human Mendelian diseases in databases such as OMIM and Orphanet. Exploiting these resources, several computational methods have been developed for integration and analysis of phenotype data to identify the genetic etiology of diseases or suggest plausible interventions. A similar resource would be highly useful not only for rare and Mendelian diseases, but also for common, complex and infectious diseases. We apply a semantic text-mining approach to identify the phenotypes (signs and symptoms) associated with over 6,000 diseases. We evaluate our text-mined phenotypes by demonstrating that they can correctly identify known disease-associated genes in mice and humans with high accuracy. Using a phenotypic similarity measure, we generate a human disease network in which diseases that have similar signs and symptoms cluster together, and we use this network to identify closely related diseases based on common etiological, anatomical as well as physiological underpinnings.

Airway disease phenotypes in animal models of cystic fibrosis.

PubMed

McCarron, Alexandra; Donnelley, Martin; Parsons, David

2018-04-02

In humans, cystic fibrosis (CF) lung disease is characterised by chronic infection, inflammation, airway remodelling, and mucus obstruction. A lack of pulmonary manifestations in CF mouse models has hindered investigations of airway disease pathogenesis, as well as the development and testing of potential therapeutics. However, recently generated CF animal models including rat, ferret and pig models demonstrate a range of well characterised lung disease phenotypes with varying degrees of severity. This review discusses the airway phenotypes of currently available CF animal models and presents potential applications of each model in airway-related CF research.

Drug Discovery for Neglected Diseases: Molecular Target-Based and Phenotypic Approaches

PubMed Central

2013-01-01

Drug discovery for neglected tropical diseases is carried out using both target-based and phenotypic approaches. In this paper, target-based approaches are discussed, with a particular focus on human African trypanosomiasis. Target-based drug discovery can be successful, but careful selection of targets is required. There are still very few fully validated drug targets in neglected diseases, and there is a high attrition rate in target-based drug discovery for these diseases. Phenotypic screening is a powerful method in both neglected and non-neglected diseases and has been very successfully used. Identification of molecular targets from phenotypic approaches can be a way to identify potential new drug targets. PMID:24015767

Addressing the challenges of phenotyping pediatric pulmonary vascular disease

PubMed Central

Goss, Kara N.; Everett, Allen D.; Mourani, Peter M.; Baker, Christopher D.; Abman, Steven H.

2017-01-01

Pediatric pulmonary vascular disease (PVD) and pulmonary hypertension (PH) represent phenotypically and pathophysiologically diverse disease categories, contributing substantial morbidity and mortality to a complex array of pediatric conditions. Here, we review the multifactorial nature of pediatric PVD, with an emphasis on improved recognition, phenotyping, and endotyping strategies for pediatric PH. Novel tailored approaches to diagnosis and treatment in pediatric PVD, as well as the implications for long-term outcomes, are highlighted. PMID:28680562

PhenoLines: Phenotype Comparison Visualizations for Disease Subtyping via Topic Models.

PubMed

Glueck, Michael; Naeini, Mahdi Pakdaman; Doshi-Velez, Finale; Chevalier, Fanny; Khan, Azam; Wigdor, Daniel; Brudno, Michael

2018-01-01

PhenoLines is a visual analysis tool for the interpretation of disease subtypes, derived from the application of topic models to clinical data. Topic models enable one to mine cross-sectional patient comorbidity data (e.g., electronic health records) and construct disease subtypes-each with its own temporally evolving prevalence and co-occurrence of phenotypes-without requiring aligned longitudinal phenotype data for all patients. However, the dimensionality of topic models makes interpretation challenging, and de facto analyses provide little intuition regarding phenotype relevance or phenotype interrelationships. PhenoLines enables one to compare phenotype prevalence within and across disease subtype topics, thus supporting subtype characterization, a task that involves identifying a proposed subtype's dominant phenotypes, ages of effect, and clinical validity. We contribute a data transformation workflow that employs the Human Phenotype Ontology to hierarchically organize phenotypes and aggregate the evolving probabilities produced by topic models. We introduce a novel measure of phenotype relevance that can be used to simplify the resulting topology. The design of PhenoLines was motivated by formative interviews with machine learning and clinical experts. We describe the collaborative design process, distill high-level tasks, and report on initial evaluations with machine learning experts and a medical domain expert. These results suggest that PhenoLines demonstrates promising approaches to support the characterization and optimization of topic models.

Is there a common pathogenesis in aggressive periodontitis & ankylosing spondylitis in HLA-B27 patient?

PubMed

Agrawal, Neeraj; Agarwal, Kavita; Varshney, Atul; Agrawal, Navneet; Dubey, Ashutosh

2016-05-01

HLA-B27 is having strong association to ankylosing spondylitis (AS) and other inflammatory diseases collectively known as seronegative spondyloarthropathy. In literature, although the evidence for association between AS and periodontitis as well as AS and HLA-B27 are there but the association of aggressive periodontitis in HLA-B27 positive patient with AS are not there. We hypothesize that there may be a common pathogenesis in aggressive periodontitis and ankylosing spondylitis in HLA-B27 patient. A 27-years-old female presented with the features of generalized aggressive periodontitis and difficulty in walking. On complete medical examination, ankylosing spondylitis was diagnosed with further positive HLA-B27 phenotype and negative rheumatic factor. This report may open up a new link to explore in the pathogenesis of aggressive periodontitis. Copyright © 2016 Elsevier Ltd. All rights reserved.

Explaining the disease phenotype of intergenic SNP through predicted long range regulation

PubMed Central

Chen, Jingqi; Tian, Weidong

2016-01-01

Thousands of disease-associated SNPs (daSNPs) are located in intergenic regions (IGR), making it difficult to understand their association with disease phenotypes. Recent analysis found that non-coding daSNPs were frequently located in or approximate to regulatory elements, inspiring us to try to explain the disease phenotypes of IGR daSNPs through nearby regulatory sequences. Hence, after locating the nearest distal regulatory element (DRE) to a given IGR daSNP, we applied a computational method named INTREPID to predict the target genes regulated by the DRE, and then investigated their functional relevance to the IGR daSNP's disease phenotypes. 36.8% of all IGR daSNP-disease phenotype associations investigated were possibly explainable through the predicted target genes, which were enriched with, were functionally relevant to, or consisted of the corresponding disease genes. This proportion could be further increased to 60.5% if the LD SNPs of daSNPs were also considered. Furthermore, the predicted SNP-target gene pairs were enriched with known eQTL/mQTL SNP-gene relationships. Overall, it's likely that IGR daSNPs may contribute to disease phenotypes by interfering with the regulatory function of their nearby DREs and causing abnormal expression of disease genes. PMID:27280978

Phenotypic plasticity in a population of odonates.

PubMed

Bowman, Randi M; Schmidt, Sharol; Weeks, Chelsea; Clark, Hunter; Brown, Christopher; Latta, Leigh C; Edgehouse, Michael

2018-05-31

The maintenance of phenotypic plasticity within a species ensures survival through environmental flux. Plastic strategies are increasingly important given the number and magnitude of modern anthropogenic threats to the environment. We tested for phenotypic plasticity in the odonate Argia vivida in response to resource limitation. By limiting food availability, effectively inducing hunger, we were able to quantify shifts in agonistic behavior during intraspecific interactions. Scoring behavior in one-on-one combat trials after 1 and 4 days without food revealed phenotypic plasticity. Three classes of genotypes were identified, genotypes exhibiting either increased aggression, decreased aggression, or no phenotypic plasticity, in response to resource limitation. The variable plastic strategies in this population of odonates likely aids in maintaining fitness in fluctuating environments.

Matching disease and phenotype ontologies in the ontology alignment evaluation initiative.

PubMed

Harrow, Ian; Jiménez-Ruiz, Ernesto; Splendiani, Andrea; Romacker, Martin; Woollard, Peter; Markel, Scott; Alam-Faruque, Yasmin; Koch, Martin; Malone, James; Waaler, Arild

2017-12-02

The disease and phenotype track was designed to evaluate the relative performance of ontology matching systems that generate mappings between source ontologies. Disease and phenotype ontologies are important for applications such as data mining, data integration and knowledge management to support translational science in drug discovery and understanding the genetics of disease. Eleven systems (out of 21 OAEI participating systems) were able to cope with at least one of the tasks in the Disease and Phenotype track. AML, FCA-Map, LogMap(Bio) and PhenoMF systems produced the top results for ontology matching in comparison to consensus alignments. The results against manually curated mappings proved to be more difficult most likely because these mapping sets comprised mostly subsumption relationships rather than equivalence. Manual assessment of unique equivalence mappings showed that AML, LogMap(Bio) and PhenoMF systems have the highest precision results. Four systems gave the highest performance for matching disease and phenotype ontologies. These systems coped well with the detection of equivalence matches, but struggled to detect semantic similarity. This deserves more attention in the future development of ontology matching systems. The findings of this evaluation show that such systems could help to automate equivalence matching in the workflow of curators, who maintain ontology mapping services in numerous domains such as disease and phenotype.

Previously unrecognized behavioral phenotype in Gaucher disease type 3

PubMed Central

Potegal, Michael; Shapiro, Elsa G.; Nestrasil, Igor

2017-01-01

Objective: To provide a comprehensive description of abnormal behaviors in patients with Gaucher disease type 3 (GD3) and relate these behaviors to demographic, neurodevelopmental, and neurologic characteristics. Methods: Thirty-four Egyptian patients with GD3 (mean age of 7.9 years) were enrolled in the study. They were selected based on parent report and/or physician observation of one or more abnormal behaviors documented in 2 settings and by 2 different individuals and/or by video recording. Behaviors were grouped into 4 categories: Crying/Withdrawal, Impatience/Overactivity, Anger/Aggression, and Repetitive Acts. Baseline and follow-up 6–12 monthly neurologic evaluations included IQ assessment and an EEG. All patients were receiving enzyme replacement therapy (30–60 IU/kg every 2 weeks) and were followed for periods of 3–10 years. Results: Supranuclear palsy of horizontal gaze, and of both horizontal and vertical gaze, bulbar symptoms, seizures, convergent strabismus, abnormal gait, and neck retroflexion were present in 97.1%, 50%, 55.9%, 29.4%, 29.4%, 20.6%, and 4.4% of patients, respectively. The most abnormal behavioral features were excessive anger (88.2%) and aggression (64.7%), and both were significantly higher in males. Anger/Aggression scores were highly correlated with IQ but not with either EEG/Seizure status or neurologic signs. Conclusions: We describe behavioral problems with a unique pattern of excessive anger and aggression in patients with GD3. Defining these components using quantitative behavioral scoring methods holds promise to provide a marker of neurologic disease progression and severity. PMID:28634598

Text-mined phenotype annotation and vector-based similarity to improve identification of similar phenotypes and causative genes in monogenic disease patients.

PubMed

Saklatvala, Jake R; Dand, Nick; Simpson, Michael A

2018-05-01

The genetic diagnosis of rare monogenic diseases using exome/genome sequencing requires the true causal variant(s) to be identified from tens of thousands of observed variants. Typically a virtual gene panel approach is taken whereby only variants in genes known to cause phenotypes resembling the patient under investigation are considered. With the number of known monogenic gene-disease pairs exceeding 5,000, manual curation of personalized virtual panels using exhaustive knowledge of the genetic basis of the human monogenic phenotypic spectrum is challenging. We present improved probabilistic methods for estimating phenotypic similarity based on Human Phenotype Ontology annotation. A limitation of existing methods for evaluating a disease's similarity to a reference set is that reference diseases are typically represented as a series of binary (present/absent) observations of phenotypic terms. We evaluate a quantified disease reference set, using term frequency in phenotypic text descriptions to approximate term relevance. We demonstrate an improved ability to identify related diseases through the use of a quantified reference set, and that vector space similarity measures perform better than established information content-based measures. These improvements enable the generation of bespoke virtual gene panels, facilitating more accurate and efficient interpretation of genomic variant profiles from individuals with rare Mendelian disorders. These methods are available online at https://atlas.genetics.kcl.ac.uk/~jake/cgi-bin/patient_sim.py. © 2018 Wiley Periodicals, Inc.

Evolutionary perspectives on the links between mitochondrial genotype and disease phenotype.

PubMed

Dowling, Damian K

2014-04-01

Disorders of the mitochondrial respiratory chain are heterogeneous in their symptoms and underlying genetics. Simple links between candidate mutations and expression of disease phenotype typically do not exist. It thus remains unclear how the genetic variation in the mitochondrial genome contributes to the phenotypic expression of complex traits and disease phenotypes. I summarize the basic genetic processes known to underpin mitochondrial disease. I highlight other plausible processes, drawn from the evolutionary biological literature, whose contribution to mitochondrial disease expression remains largely empirically unexplored. I highlight recent advances to the field, and discuss common-ground and -goals shared by researchers across medical and evolutionary domains. Mitochondrial genetic variance is linked to phenotypic variance across a variety of traits (e.g. reproductive function, life expectancy) fundamental to the upkeep of good health. Evolutionary theory predicts that mitochondrial genomes are destined to accumulate male-harming (but female-friendly) mutations, and this prediction has received proof-of-principle support. Furthermore, mitochondrial effects on the phenotype are typically manifested via interactions between mitochondrial and nuclear genes. Thus, whether a mitochondrial mutation is pathogenic in effect can depend on the nuclear genotype in which is it expressed. Many disease phenotypes associated with OXPHOS malfunction might be determined by the outcomes of mitochondrial-nuclear interactions, and by the evolutionary forces that historically shaped mitochondrial DNA (mtDNA) sequences. Concepts and results drawn from the evolutionary sciences can have broad, but currently under-utilized, applicability to the medical sciences and provide new insights into understanding the complex genetics of mitochondrial disease. This article is part of a Special Issue entitled Frontiers of Mitochondrial Research. Copyright © 2013. Published by Elsevier B.V.

Explaining the disease phenotype of intergenic SNP through predicted long range regulation.

PubMed

Chen, Jingqi; Tian, Weidong

2016-10-14

Thousands of disease-associated SNPs (daSNPs) are located in intergenic regions (IGR), making it difficult to understand their association with disease phenotypes. Recent analysis found that non-coding daSNPs were frequently located in or approximate to regulatory elements, inspiring us to try to explain the disease phenotypes of IGR daSNPs through nearby regulatory sequences. Hence, after locating the nearest distal regulatory element (DRE) to a given IGR daSNP, we applied a computational method named INTREPID to predict the target genes regulated by the DRE, and then investigated their functional relevance to the IGR daSNP's disease phenotypes. 36.8% of all IGR daSNP-disease phenotype associations investigated were possibly explainable through the predicted target genes, which were enriched with, were functionally relevant to, or consisted of the corresponding disease genes. This proportion could be further increased to 60.5% if the LD SNPs of daSNPs were also considered. Furthermore, the predicted SNP-target gene pairs were enriched with known eQTL/mQTL SNP-gene relationships. Overall, it's likely that IGR daSNPs may contribute to disease phenotypes by interfering with the regulatory function of their nearby DREs and causing abnormal expression of disease genes. © The Author(s) 2016. Published by Oxford University Press on behalf of Nucleic Acids Research.

[Phenotypic heterogeneity of chronic obstructive pulmonary disease].

PubMed

Garcia-Aymerich, Judith; Agustí, Alvar; Barberà, Joan A; Belda, José; Farrero, Eva; Ferrer, Antoni; Ferrer, Jaume; Gáldiz, Juan B; Gea, Joaquim; Gómez, Federico P; Monsó, Eduard; Morera, Josep; Roca, Josep; Sauleda, Jaume; Antó, Josep M

2009-03-01

A functional definition of chronic obstructive pulmonary disease (COPD) based on airflow limitation has largely dominated the field. However, a view has emerged that COPD involves a complex array of cellular, organic, functional, and clinical events, with a growing interest in disentangling the phenotypic heterogeneity of COPD. The present review is based on the opinion of the authors, who have extensive research experience in several aspects of COPD. The starting assumption of the review is that current knowledge on the pathophysiology and clinical features of COPD allows us to classify phenotypic information in terms of the following dimensions: respiratory symptoms and health status, acute exacerbations, lung function, structural changes, local and systemic inflammation, and systemic effects. Twenty-six phenotypic traits were identified and assigned to one of the 6 dimensions. For each dimension, a summary is provided of the best evidence on the relationships among phenotypic traits, in particular among those corresponding to different dimensions, and on the relationship between these traits and relevant events in the natural history of COPD. The information has been organized graphically into a phenotypic matrix where each cell representing a pair of phenotypic traits is linked to relevant references. The information provided has the potential to increase our understanding of the heterogeneity of COPD phenotypes and help us plan future studies on aspects that are as yet unexplored.

Adaptive shaping of the behavioural and neuroendocrine phenotype during adolescence

PubMed Central

Kaiser, Sylvia; Hennessy, Michael B.; Sachser, Norbert

2017-01-01

Environmental conditions during early life can adaptively shape the phenotype for the prevailing environment. Recently, it has been suggested that adolescence represents an additional temporal window for adaptive developmental plasticity, though supporting evidence is scarce. Previous work has shown that male guinea pigs living in large mixed-sex colonies develop a low-aggressive phenotype as part of a queuing strategy that is adaptive for integrating into large unfamiliar colonies. By contrast, males living in pairs during adolescence become highly aggressive towards strangers. Here, we tested whether the high-aggressive phenotype is adaptive under conditions of low population density, namely when directly competing with a single opponent for access to females. For that purpose, we established groups of one pair-housed male (PM), one colony-housed male (CM) and two females. PMs directed more aggression towards the male competitor and more courtship and mating towards females than did CMs. In consequence, PMs attained the dominant position in most cases and sired significantly more offspring. Moreover, they showed distinctly higher testosterone concentrations and elevated cortisol levels, which probably promoted enhanced aggressiveness while mobilizing necessary energy. Taken together, our results provide the clearest evidence to date for adaptive shaping of the phenotype by environmental influences during adolescence. PMID:28202817

A comprehensive global genotype-phenotype database for rare diseases.

PubMed

Trujillano, Daniel; Oprea, Gabriela-Elena; Schmitz, Yvonne; Bertoli-Avella, Aida M; Abou Jamra, Rami; Rolfs, Arndt

2017-01-01

The ability to discover genetic variants in a patient runs far ahead of the ability to interpret them. Databases with accurate descriptions of the causal relationship between the variants and the phenotype are valuable since these are critical tools in clinical genetic diagnostics. Here, we introduce a comprehensive and global genotype-phenotype database focusing on rare diseases. This database (CentoMD ® ) is a browser-based tool that enables access to a comprehensive, independently curated system utilizing stringent high-quality criteria and a quickly growing repository of genetic and human phenotype ontology (HPO)-based clinical information. Its main goals are to aid the evaluation of genetic variants, to enhance the validity of the genetic analytical workflow, to increase the quality of genetic diagnoses, and to improve evaluation of treatment options for patients with hereditary diseases. The database software correlates clinical information from consented patients and probands of different geographical backgrounds with a large dataset of genetic variants and, when available, biomarker information. An automated follow-up tool is incorporated that informs all users whenever a variant classification has changed. These unique features fully embedded in a CLIA/CAP-accredited quality management system allow appropriate data quality and enhanced patient safety. More than 100,000 genetically screened individuals are documented in the database, resulting in more than 470 million variant detections. Approximately, 57% of the clinically relevant and uncertain variants in the database are novel. Notably, 3% of the genetic variants identified and previously reported in the literature as being associated with a particular rare disease were reclassified, based on internal evidence, as clinically irrelevant. The database offers a comprehensive summary of the clinical validity and causality of detected gene variants with their associated phenotypes, and is a valuable tool

Effective diagnosis of genetic disease by computational phenotype analysis of the disease-associated genome

PubMed Central

Zemojtel, Tomasz; Köhler, Sebastian; Mackenroth, Luisa; Jäger, Marten; Hecht, Jochen; Krawitz, Peter; Graul-Neumann, Luitgard; Doelken, Sandra; Ehmke, Nadja; Spielmann, Malte; Øien, Nancy Christine; Schweiger, Michal R.; Krüger, Ulrike; Frommer, Götz; Fischer, Björn; Kornak, Uwe; Flöttmann, Ricarda; Ardeshirdavani, Amin; Moreau, Yves; Lewis, Suzanna E.; Haendel, Melissa; Smedley, Damian; Horn, Denise; Mundlos, Stefan; Robinson, Peter N.

2015-01-01

Less than half of patients with suspected genetic disease receive a molecular diagnosis. We have therefore integrated next-generation sequencing (NGS), bioinformatics, and clinical data into an effective diagnostic workflow. We used variants in the 2741 established Mendelian disease genes [the disease-associated genome (DAG)] to develop a targeted enrichment DAG panel (7.1 Mb), which achieves a coverage of 20-fold or better for 98% of bases. Furthermore, we established a computational method [Phenotypic Interpretation of eXomes (PhenIX)] that evaluated and ranked variants based on pathogenicity and semantic similarity of patients’ phenotype described by Human Phenotype Ontology (HPO) terms to those of 3991 Mendelian diseases. In computer simulations, ranking genes based on the variant score put the true gene in first place less than 5% of the time; PhenIX placed the correct gene in first place more than 86% of the time. In a retrospective test of PhenIX on 52 patients with previously identified mutations and known diagnoses, the correct gene achieved a mean rank of 2.1. In a prospective study on 40 individuals without a diagnosis, PhenIX analysis enabled a diagnosis in 11 cases (28%, at a mean rank of 2.4). Thus, the NGS of the DAG followed by phenotype-driven bioinformatic analysis allows quick and effective differential diagnostics in medical genetics. PMID:25186178

Effective diagnosis of genetic disease by computational phenotype analysis of the disease-associated genome.

PubMed

Zemojtel, Tomasz; Köhler, Sebastian; Mackenroth, Luisa; Jäger, Marten; Hecht, Jochen; Krawitz, Peter; Graul-Neumann, Luitgard; Doelken, Sandra; Ehmke, Nadja; Spielmann, Malte; Oien, Nancy Christine; Schweiger, Michal R; Krüger, Ulrike; Frommer, Götz; Fischer, Björn; Kornak, Uwe; Flöttmann, Ricarda; Ardeshirdavani, Amin; Moreau, Yves; Lewis, Suzanna E; Haendel, Melissa; Smedley, Damian; Horn, Denise; Mundlos, Stefan; Robinson, Peter N

2014-09-03

Less than half of patients with suspected genetic disease receive a molecular diagnosis. We have therefore integrated next-generation sequencing (NGS), bioinformatics, and clinical data into an effective diagnostic workflow. We used variants in the 2741 established Mendelian disease genes [the disease-associated genome (DAG)] to develop a targeted enrichment DAG panel (7.1 Mb), which achieves a coverage of 20-fold or better for 98% of bases. Furthermore, we established a computational method [Phenotypic Interpretation of eXomes (PhenIX)] that evaluated and ranked variants based on pathogenicity and semantic similarity of patients' phenotype described by Human Phenotype Ontology (HPO) terms to those of 3991 Mendelian diseases. In computer simulations, ranking genes based on the variant score put the true gene in first place less than 5% of the time; PhenIX placed the correct gene in first place more than 86% of the time. In a retrospective test of PhenIX on 52 patients with previously identified mutations and known diagnoses, the correct gene achieved a mean rank of 2.1. In a prospective study on 40 individuals without a diagnosis, PhenIX analysis enabled a diagnosis in 11 cases (28%, at a mean rank of 2.4). Thus, the NGS of the DAG followed by phenotype-driven bioinformatic analysis allows quick and effective differential diagnostics in medical genetics. Copyright © 2014, American Association for the Advancement of Science.

Next generation phenotyping using narrative reports in a rare disease clinical data warehouse.

PubMed

Garcelon, Nicolas; Neuraz, Antoine; Salomon, Rémi; Bahi-Buisson, Nadia; Amiel, Jeanne; Picard, Capucine; Mahlaoui, Nizar; Benoit, Vincent; Burgun, Anita; Rance, Bastien

2018-05-31

Secondary use of data collected in Electronic Health Records opens perspectives for increasing our knowledge of rare diseases. The clinical data warehouse (named Dr. Warehouse) at the Necker-Enfants Malades Children's Hospital contains data collected during normal care for thousands of patients. Dr. Warehouse is oriented toward the exploration of clinical narratives. In this study, we present our method to find phenotypes associated with diseases of interest. We leveraged the frequency and TF-IDF to explore the association between clinical phenotypes and rare diseases. We applied our method in six use cases: phenotypes associated with the Rett, Lowe, Silver Russell, Bardet-Biedl syndromes, DOCK8 deficiency and Activated PI3-kinase Delta Syndrome (APDS). We asked domain experts to evaluate the relevance of the top-50 (for frequency and TF-IDF) phenotypes identified by Dr. Warehouse and computed the average precision and mean average precision. Experts concluded that between 16 and 39 phenotypes could be considered as relevant in the top-50 phenotypes ranked by descending frequency discovered by Dr. Warehouse (resp. between 11 and 41 for TF-IDF). Average precision ranges from 0.55 to 0.91 for frequency and 0.52 to 0.95 for TF-IDF. Mean average precision was 0.79. Our study suggests that phenotypes identified in clinical narratives stored in Electronic Health Record can provide rare disease specialists with candidate phenotypes that can be used in addition to the literature. Clinical Data Warehouses can be used to perform Next Generation Phenotyping, especially in the context of rare diseases. We have developed a method to detect phenotypes associated with a group of patients using medical concepts extracted from free-text clinical narratives.

Pleiotropic Contribution of MECOM and AVPR1A to Aggression and Subcortical Brain Volumes

PubMed Central

van Donkelaar, Marjolein M. J.; Hoogman, Martine; Pappa, Irene; Tiemeier, Henning; Buitelaar, Jan K.; Franke, Barbara; Bralten, Janita

2018-01-01

Reactive and proactive subtypes of aggression have been recognized to help parse etiological heterogeneity of this complex phenotype. With a heritability of about 50%, genetic factors play a role in the development of aggressive behavior. Imaging studies implicate brain structures related to social behavior in aggression etiology, most notably the amygdala and striatum. This study aimed to gain more insight into the pathways from genetic risk factors for aggression to aggression phenotypes. To this end, we conducted genome-wide gene-based cross-trait meta-analyses of aggression with the volumes of amygdala, nucleus accumbens and caudate nucleus to identify genes influencing both aggression and aggression-related brain volumes. We used data of large-scale genome-wide association studies (GWAS) of: (a) aggressive behavior in children and adolescents (EAGLE, N = 18,988); and (b) Magnetic Resonance Imaging (MRI)-based volume measures of aggression-relevant subcortical brain regions (ENIGMA2, N = 13,171). Second, the identified genes were further investigated in a sample of healthy adults (mean age (SD) = 25.28 (4.62) years; 43% male) who had genome-wide genotyping data and questionnaire data on aggression subtypes available (Brain Imaging Genetics, BIG, N = 501) to study their effect on reactive and proactive subtypes of aggression. Our meta-analysis identified two genes, MECOM and AVPR1A, significantly associated with both aggression risk and nucleus accumbens (MECOM) and amygdala (AVPR1A) brain volume. Subsequent in-depth analysis of these genes in healthy adults (BIG), including sex as an interaction term in the model, revealed no significant subtype-specific gene-wide associations. Using cross-trait meta-analysis of brain measures and psychiatric phenotypes, this study generated new hypotheses about specific links between genes, the brain and behavior. Results indicate that MECOM and AVPR1A may exert an effect on aggression through mechanisms involving nucleus

A Quantitative Systems Pharmacology Approach to Infer Pathways Involved in Complex Disease Phenotypes.

PubMed

Schurdak, Mark E; Pei, Fen; Lezon, Timothy R; Carlisle, Diane; Friedlander, Robert; Taylor, D Lansing; Stern, Andrew M

2018-01-01

Designing effective therapeutic strategies for complex diseases such as cancer and neurodegeneration that involve tissue context-specific interactions among multiple gene products presents a major challenge for precision medicine. Safe and selective pharmacological modulation of individual molecular entities associated with a disease often fails to provide efficacy in the clinic. Thus, development of optimized therapeutic strategies for individual patients with complex diseases requires a more comprehensive, systems-level understanding of disease progression. Quantitative systems pharmacology (QSP) is an approach to drug discovery that integrates computational and experimental methods to understand the molecular pathogenesis of a disease at the systems level more completely. Described here is the chemogenomic component of QSP for the inference of biological pathways involved in the modulation of the disease phenotype. The approach involves testing sets of compounds of diverse mechanisms of action in a disease-relevant phenotypic assay, and using the mechanistic information known for the active compounds, to infer pathways and networks associated with the phenotype. The example used here is for monogenic Huntington's disease (HD), which due to the pleiotropic nature of the mutant phenotype has a complex pathogenesis. The overall approach, however, is applicable to any complex disease.

Identifying Multimodal Intermediate Phenotypes between Genetic Risk Factors and Disease Status in Alzheimer’s Disease

PubMed Central

Hao, Xiaoke; Yao, Xiaohui; Yan, Jingwen; Risacher, Shannon L.; Saykin, Andrew J.; Zhang, Daoqiang; Shen, Li

2016-01-01

Neuroimaging genetics has attracted growing attention and interest, which is thought to be a powerful strategy to examine the influence of genetic variants (i.e., single nucleotide polymorphisms (SNPs)) on structures or functions of human brain. In recent studies, univariate or multivariate regression analysis methods are typically used to capture the effective associations between genetic variants and quantitative traits (QTs) such as brain imaging phenotypes. The identified imaging QTs, although associated with certain genetic markers, may not be all disease specific. A useful, but underexplored, scenario could be to discover only those QTs associated with both genetic markers and disease status for revealing the chain from genotype to phenotype to symptom. In addition, multimodal brain imaging phenotypes are extracted from different perspectives and imaging markers consistently showing up in multimodalities may provide more insights for mechanistic understanding of diseases (i.e., Alzheimer’s disease (AD)). In this work, we propose a general framework to exploit multi-modal brain imaging phenotypes as intermediate traits that bridge genetic risk factors and multi-class disease status. We applied our proposed method to explore the relation between the well-known AD risk SNP APOE rs429358 and three baseline brain imaging modalities (i.e., structural magnetic resonance imaging (MRI), fluorodeoxyglucose positron emission tomography (FDG-PET) and F-18 florbetapir PET scans amyloid imaging (AV45)) from the Alzheimer’s Disease Neuroimaging Initiative (ADNI) database. The empirical results demonstrate that our proposed method not only helps improve the performances of imaging genetic associations, but also discovers robust and consistent regions of interests (ROIs) across multi-modalities to guide the disease-induced interpretation. PMID:27277494

Brain Monoamine Oxidase-A Activity Predicts Trait Aggression

PubMed Central

Alia-Klein, Nelly; Goldstein, Rita Z.; Kriplani, Aarti; Logan, Jean; Tomasi, Dardo; Williams, Benjamin; Telang, Frank; Shumay, Elena; Biegon, Anat; Craig, Ian W.; Henn, Fritz; Wang, Gene-Jack; Volkow, Nora D.; Fowler, Joanna S.

2008-01-01

The genetic deletion of monoamine oxidase A (MAO A, an enzyme which breaks down the monoamine neurotransmitters norepinephrine, serotonin and dopamine) produces aggressive phenotypes across species. Therefore, a common polymorphism in the MAO A gene (MAOA, MIM 309850, referred to as high or low based on transcription in non-neuronal cells) has been investigated in a number of externalizing behavioral and clinical phenotypes. These studies provide evidence linking the low MAOA genotype and violent behavior but only through interaction with severe environmental stressors during childhood. Here, we hypothesized that in healthy adult males the gene product of MAO A in the brain, rather than the gene per se, would be associated with regulating the concentration of brain amines involved in trait aggression. Brain MAO A activity was measured in-vivo in healthy non-smoking men with positron emission tomography using a radioligand specific for MAO A (clorgyline labeled with carbon 11). Trait aggression was measured with the Multidimensional Personality Questionnaire (MPQ). Here we report for the first time that brain MAO A correlates inversely with the MPQ trait measure of aggression (but not with other personality traits) such that the lower the MAO A activity in cortical and subcortical brain regions the higher the self-reported aggression (in both MAOA genotype groups) contributing to more than a third of the variability. Since trait aggression is a measure used to predict antisocial behavior, these results underscore the relevance of MAO A as a neurochemical substrate of aberrant aggression. PMID:18463263

The neuropsychiatric phenotype in Darier disease.

PubMed

Gordon-Smith, K; Jones, L A; Burge, S M; Munro, C S; Tavadia, S; Craddock, N

2010-09-01

Darier disease (DD) is a rare autosomal dominantly inherited skin disorder in which co-occurrence of neuropsychiatric abnormalities has been frequently reported by dermatologists. It is caused by mutations in a single gene, ATP2A2, which is expressed in the skin and brain. To conduct the first systematic investigation of the neuropsychiatric phenotype in DD. One hundred unrelated individuals with DD were assessed using a battery of standardized neuropsychiatric measures. Data were also obtained on a number of clinical features of DD. Individuals with DD were found to have high lifetime rates of mood disorders (50%), specifically major depression (30%) and bipolar disorder (4%), and suicide attempts (13%) and suicidal thoughts (31%). These were more common in DD when compared with general population data. The prevalence of epilepsy (3%) in the sample was also higher than the prevalence in the general population. There was no consistent association of specific dermatological features of DD and presence of psychiatric features. These findings highlight the need for clinicians to assess and recognize neuropsychiatric symptoms in DD. The results do not suggest that neuropsychiatric symptoms are simply a psychological reaction to having a skin disease, but are consistent with the pleiotropy hypothesis that mutations in the ATP2A2 gene, in addition to causing DD, confer susceptibility to neuropsychiatric features. Further research is needed to investigate genotype-phenotype correlations between the types and/or locations of pathogenic mutations within ATP2A2 and the expressed neuropsychiatric phenotypes. © 2010 The Authors. Journal Compilation © 2010 British Association of Dermatologists.

Rare diseases, rare presentations: recognizing atypical inherited kidney disease phenotypes in the age of genomics.

PubMed

Ars, Elisabet; Torra, Roser

2017-10-01

A significant percentage of adults (10%) and children (20%) on renal replacement therapy have an inherited kidney disease (IKD). The new genomic era, ushered in by the next generation sequencing techniques, has contributed to the identification of new genes and facilitated the genetic diagnosis of the highly heterogeneous IKDs. Consequently, it has also allowed the reclassification of diseases and has broadened the phenotypic spectrum of many classical IKDs. Various genetic, epigenetic and environmental factors may explain 'atypical' phenotypes. In this article, we examine different mechanisms that may contribute to phenotypic variability and also provide case examples that illustrate them. The aim of the article is to raise awareness, among nephrologists and geneticists, of rare presentations that IKDs may show, to facilitate diagnosis.

Aggression in fragile X syndrome.

PubMed

Wheeler, A C; Raspa, M; Bishop, E; Bailey, D B

2016-02-01

Individuals with fragile X syndrome (FXS), especially men, have long been described as presenting with significant behavioural challenges. Despite this known aspect of the phenotype, there has been little research exploring the prevalence, frequency, nature or consequences of aggressive behaviour in FXS. This study used survey methodology to gather caregiver reports on the types, frequency and severity of aggressive behaviour in 774 individuals with FXS. Based on caregiver report, nearly all (>90%) male and female individuals were reported to have engaged in some aggression over the previous 12 months, with a third of male cases and slightly fewer than 20% of female cases being described as engaging in moderate to severe aggression or being diagnosed or treated for aggression. Further, aggressive behaviours in male individuals were serious enough that 30% had caused injuries to caregivers and 22% had caused injuries to peers or friends. Sensory issues and hyperactivity were significant predictors of the frequency of aggressive acts, while sensory issues and anxiety were predictive of the severity of aggression. Traditional behaviour management techniques as well as medication was described as the most common and successful treatment options. Aggressive behaviours are a significant concern for a subsample of both male and female individuals with FXS. Given that sensory concerns were predictive of both the frequency and the severity of aggression suggests these behaviours may be a reactive means of escaping uncomfortable situations. © 2015 MENCAP and International Association of the Scientific Study of Intellectual and Developmental Disabilities and John Wiley & Sons Ltd.

Quantitative phenotyping of X-disease resistance in chokecherry using real-time PCR.

PubMed

Huang, Danqiong; Walla, James A; Dai, Wenhao

2014-03-01

A quantitative real-time SYBR Green PCR (qPCR) assay has been developed to detect and quantify X-disease phytoplasmas in chokecherry. An X-disease phytoplasma-specific and high sensitivity primer pair was designed based on the 16S rRNA gene sequence of X-disease phytoplasmas. This primer pair was specific to the 16SrIII group (X-disease) phytoplasmas. The qPCR method can quantify phytoplasmas from a DNA mix (a mix of both chokecherry and X-disease phytoplasma DNA) at as low as 0.001 ng, 10-fold lower than conventional PCR using the same primer pair. A significant correlation between the copy number of phytoplasmas and visual phenotypic rating scores of X-disease resistance in chokecherry plants was observed. Disease resistant chokecherries had a significantly lower titer of X-disease phytoplasmas than susceptible plants. This suggests that the qPCR assay provides a more objective tool to phenotype phytoplasma disease severity, particularly for early evaluation of host resistance; therefore, this method will facilitate quantitative phenotyping of disease resistance and has great potential in enhancing plant breeding. Copyright © 2013 Elsevier B.V. All rights reserved.

Prediction of reduction in aggressive behaviour of growing pigs using skin lesion traits as selection criteria.

PubMed

Desire, S; Turner, S P; D'Eath, R B; Doeschl-Wilson, A B; Lewis, C R G; Roehe, R

2016-08-01

Aggression at regrouping is a common issue in pig farming. Skin lesions are genetically and phenotypically correlated with aggression and have been shown to have a significant heritable component. This study predicts the magnitude of reduction in complex aggressive behavioural traits when using lesion numbers on different body regions at two different time points as selection criteria, to identify the optimum skin lesion trait for selection purposes. In total, 1146 pigs were mixed into new social groups, and skin lesions were counted 24 h (SL24h) and 3 weeks (SL3wk) post-mixing, on the anterior, centre and posterior regions of the body. An animal model was used to estimate genetic parameters for skin lesion traits and 14 aggressive behavioural traits. Estimated breeding values (EBVs) and phenotypic values were scaled and standardised to allow direct comparison across multiple traits. Individuals with SL24h and SL3wk EBVs in the least aggressive 10% of the population were compared with the population mean to predict the expected genetic and phenotypic response in aggressive behaviour to selection. At mixing, selection for low anterior lesions was predicted to affect substantially more behavioural traits of aggressiveness than lesions obtained on other body parts, with EBVs between -0.21 and -1.17 SD below the population mean. Individuals with low central SL24h EBVs also had low EBVs for aggressive traits (-0.33 to -0.55). Individuals with high SL3wk EBVs had low EBVs for aggression at mixing (between -0.24 and -0.53 SD below the population mean), although this was predicted to affect fewer traits than selection against SL24h. These results suggest that selection against anterior SL24h would result in the greatest genetic and phenotypic reduction in aggressive behaviour recorded at mixing. Selection for increased SL3wk was predicted to reduce aggression at mixing; however, current understanding about aggressive behaviour under stable social conditions is insufficient

PhenomeExpress: a refined network analysis of expression datasets by inclusion of known disease phenotypes.

PubMed

Soul, Jamie; Hardingham, Timothy E; Boot-Handford, Raymond P; Schwartz, Jean-Marc

2015-01-29

We describe a new method, PhenomeExpress, for the analysis of transcriptomic datasets to identify pathogenic disease mechanisms. Our analysis method includes input from both protein-protein interaction and phenotype similarity networks. This introduces valuable information from disease relevant phenotypes, which aids the identification of sub-networks that are significantly enriched in differentially expressed genes and are related to the disease relevant phenotypes. This contrasts with many active sub-network detection methods, which rely solely on protein-protein interaction networks derived from compounded data of many unrelated biological conditions and which are therefore not specific to the context of the experiment. PhenomeExpress thus exploits readily available animal model and human disease phenotype information. It combines this prior evidence of disease phenotypes with the experimentally derived disease data sets to provide a more targeted analysis. Two case studies, in subchondral bone in osteoarthritis and in Pax5 in acute lymphoblastic leukaemia, demonstrate that PhenomeExpress identifies core disease pathways in both mouse and human disease expression datasets derived from different technologies. We also validate the approach by comparison to state-of-the-art active sub-network detection methods, which reveals how it may enhance the detection of molecular phenotypes and provide a more detailed context to those previously identified as possible candidates.

Analysis of salivary phenotypes of generalized aggressive and chronic periodontitis through nuclear magnetic resonance-based metabolomics.

PubMed

Romano, Federica; Meoni, Gaia; Manavella, Valeria; Baima, Giacomo; Tenori, Leonardo; Cacciatore, Stefano; Aimetti, Mario

2018-06-07

Recent findings about the differential gene expression signature of periodontal lesions have raised the hypothesis of distinctive biological phenotypes expressed by generalized chronic periodontitis (GCP) and generalized aggressive periodontitis (GAgP) patients. Therefore, this cross-sectional investigation was planned, primarily, to determine the ability of nuclear magnetic resonance (NMR) spectroscopic analysis of unstimulated whole saliva to discriminate GCP and GAgP disease-specific metabolomic fingerprint and, secondarily, to assess potential metabolites discriminating periodontitis patients from periodontally healthy individuals (HI). NMR-metabolomics spectra were acquired from salivary samples of patients with a clinical diagnosis of GCP (n = 33) or GAgP (n = 28) and from HI (n = 39). The clustering of HI, GCP and GAgP patients was achieved by using a combination of the Principal Component Analysis and Canonical Correlation Analysis on the NMR profiles. These analyses revealed a significant predictive accuracy discriminating HI from GCP, and discriminating HI from GAgP patients (both 81%). In contrast, the GAgP and GCP saliva samples seem to belong to the same metabolic space (60% predictive accuracy). Significantly lower levels (P < 0.05) of pyruvate, N-acetyl groups and lactate and higher levels (P < 0.05) of proline, phenylalanine, and tyrosine were found in GCP and GAgP patients compared with HI. Within the limitations of this study, CGP and GAgP metabolomic profiles were not unequivocally discriminated through a NMR-based spectroscopic analysis of saliva. This article is protected by copyright. All rights reserved. This article is protected by copyright. All rights reserved.

Aggressive behavior in transgenic animal models: A systematic review.

PubMed

Jager, Amanda; Maas, Dorien A; Fricke, Kim; de Vries, Rob B; Poelmans, Geert; Glennon, Jeffrey C

2018-08-01

Aggressive behavior is often core or comorbid to psychiatric and neurodegenerative disorders. Transgenic animal models are commonly used to study the neurobiological mechanisms underlying aggressive phenotypes and have led to new insights into aggression. This systematic review critically evaluates the available literature on transgenic animal models tested for aggression with the resident-intruder test. By combining the available literature on this topic, we sought to highlight effective methods for laboratory aggression testing and provide recommendations for study design as well as aggression induction and measurement in rodents that are translational to humans, taking into consideration possible confounding factors. In addition, we built a molecular landscape of interactions between the proteins encoded by the aggression-linked genes from our systematic search. Some molecular pathways within this landscape overlap with psychiatric and neurodegenerative disorders and the landscapes point towards a number of putative (drug) targets for aggression that need to be validated in future studies. Copyright © 2017 Elsevier Ltd. All rights reserved.

The added value of using mutational profiling in addition to cytology in diagnosing aggressive pancreaticobiliary disease: review of clinical cases at a single center

PubMed Central

2014-01-01

Background This study aimed to better understand the supporting role that mutational profiling (MP) of DNA from microdissected cytology slides and supernatant specimens may play in the diagnosis of malignancy in fine-needle aspirates (FNA) and biliary brushing specimens from patients with pancreaticobiliary masses. Methods Cytology results were examined in a total of 30 patients with associated surgical (10) or clinical (20) outcomes. MP of DNA from microdissected cytology slides and from discarded supernatant fluid was analyzed in 26 patients with atypical, negative or indeterminate cytology. Results Cytology correctly diagnosed aggressive disease in 4 patients. Cytological diagnoses for the remaining 26 were as follows: 16 negative (9 false negative), 9 atypical, 1 indeterminate. MP correctly determined aggressive disease in 1 false negative cytology case and confirmed a negative cytology diagnosis in 7 of 7 cases of non-aggressive disease. Of the 9 atypical cytology cases, MP correctly diagnosed 7 as positive and 1 as negative for aggressive disease. One specimen that was indeterminate by cytology was correctly diagnosed as non-aggressive by MP. When first line malignant (positive) cytology results were combined with positive second line MP results, 12/21 cases of aggressive disease were identified, compared to 4/21 cases identified by positive cytology alone. Conclusions When first line cytology results were uncertain (atypical), questionable (negative), or not possible (non-diagnostic/indeterminate), MP provided additional information regarding the presence of aggressive disease. When used in conjunction with first line cytology, MP increased detection of aggressive disease without compromising specificity in patients that were difficult to diagnose by cytology alone. PMID:25084836

High phenotypic variability in Gerstmann-Sträussler-Scheinker disease.

PubMed

Smid, Jerusa; Studart, Adalberto; Landemberger, Michele Christine; Machado, Cleiton Fagundes; Nóbrega, Paulo Ribeiro; Canedo, Nathalie Henriques Silva; Schultz, Rodrigo Rizek; Naslavsky, Michel Satya; Rosemberg, Sérgio; Kok, Fernando; Chimelli, Leila; Martins, Vilma Regina; Nitrini, Ricardo

2017-06-01

Gerstmann-Sträussler-Scheinker is a genetic prion disease and the most common mutation is p.Pro102Leu. We report clinical, molecular and neuropathological data of seven individuals, belonging to two unrelated Brazilian kindreds, carrying the p.Pro102Leu. Marked differences among patients were observed regarding age at onset, disease duration and clinical presentation. In the first kindred, two patients had rapidly progressive dementia and three exhibited predominantly ataxic phenotypes with variable ages of onset and disease duration. In this family, age at disease onset in the mother and daughter differed by 39 years. In the second kindred, different phenotypes were also reported and earlier ages of onset were associated with 129 heterozygosis. No differences were associated with apoE genotype. In these kindreds, the codon 129 polymorphism could not explain the clinical variability and 129 heterozygosis was associated with earlier disease onset. Neuropathological examination in two patients confirmed the presence of typical plaques and PrPsc immunopositivity.

Neural/Bayes network predictor for inheritable cardiac disease pathogenicity and phenotype.

PubMed

Burghardt, Thomas P; Ajtai, Katalin

2018-04-11

The cardiac muscle sarcomere contains multiple proteins contributing to contraction energy transduction and its regulation during a heartbeat. Inheritable heart disease mutants affect most of them but none more frequently than the ventricular myosin motor and cardiac myosin binding protein c (mybpc3). These co-localizing proteins have mybpc3 playing a regulatory role to the energy transducing motor. Residue substitution and functional domain assignment of each mutation in the protein sequence decides, under the direction of a sensible disease model, phenotype and pathogenicity. The unknown model mechanism is decided here using a method combing neural and Bayes networks. Missense single nucleotide polymorphisms (SNPs) are clues for the disease mechanism summarized in an extensive database collecting mutant sequence location and residue substitution as independent variables that imply the dependent disease phenotype and pathogenicity characteristics in 4 dimensional data points (4ddps). The SNP database contains entries with the majority having one or both dependent data entries unfulfilled. A neural network relating causes (mutant residue location and substitution) and effects (phenotype and pathogenicity) is trained, validated, and optimized using fulfilled 4ddps. It then predicts unfulfilled 4ddps providing the implicit disease model. A discrete Bayes network interprets fulfilled and predicted 4ddps with conditional probabilities for phenotype and pathogenicity given mutation location and residue substitution thus relating the neural network implicit model to explicit features of the motor and mybpc3 sequence and structural domains. Neural/Bayes network forecasting automates disease mechanism modeling by leveraging the world wide human missense SNP database that is in place and expanding. Copyright © 2018 The Authors. Published by Elsevier Ltd.. All rights reserved.

Microbiome Heterogeneity Characterizing Intestinal Tissue and Inflammatory Bowel Disease Phenotype.

PubMed

Tyler, Andrea D; Kirsch, Richard; Milgrom, Raquel; Stempak, Joanne M; Kabakchiev, Boyko; Silverberg, Mark S

2016-04-01

Inflammatory bowel disease has been associated with differential abundance of numerous organisms when compared to healthy controls (HCs); however, few studies have investigated variability in the microbiome across intestinal locations and how this variability might be related to disease location and phenotype. In this study, we have analyzed the microbiome of a large cohort of individuals recruited at Mount Sinai Hospital in Toronto, Canada. Biopsies were taken from subjects with Crohn's disease, ulcerative colitis, and HC, and also individuals having undergone ileal pouch-anal anastomosis for treatment of ulcerative colitis or familial adenomatous polyposis. Microbial 16S rRNA was sequenced using the Illumina MiSeq platform. We observed a great deal of variability in the microbiome characterizing different sampling locations. Samples from pouch and afferent limb were comparable in microbial composition. When comparing sigmoid and terminal ileum samples, more differences were observed. The greatest number of differentially abundant microbes was observed when comparing either pouch or afferent limb samples to sigmoid or terminal ileum. Despite these differences, we were able to observe modest microbial variability between inflammatory bowel disease phenotypes and HCs, even when controlling for sampling location and additional experimental factors. Most detected associations were observed between HCs and Crohn's disease, with decreases in specific genera in the families Ruminococcaceae and Lachnospiraceae characterizing tissue samples from individuals with Crohn's disease. This study highlights important considerations when analyzing the composition of the microbiome and also provides useful insight into differences in the microbiome characterizing these seemingly related phenotypes.

The mitochondrial and kidney disease phenotypes of kd/kd mice under germfree conditions

PubMed Central

Hallman, Troy M.; Peng, Min; Meade, Ray; Hancock, Wayne W.; Madaio, Michael P.; Gasser, David L.

2008-01-01

Interstitial nephritis occurs spontaneously in kd/kd mice, but the mechanisms leading to this disease have not been fully elucidated. The earliest manifestation of a phenotype is the appearance of ultrastructural defects in the mitochondria of mice as young as 42 days of age. To examine the influence of the environment on the phenotype, homozygous B6.kd/kd mice were transferred from specific pathogen-free (SPF) conditions to a germfree (GF) environment, and the development of the disease was observed. The GF state resulted in a highly significant reduction in the frequency of tubulointerstitial nephritis. In addition, GF conditions markedly reduced the appearance of the mitochondrial phenotype, with no sign of mitochondrial abnormalities in GF mice of up to 155 days of age. These results suggest that environmental factors are involved in the progression of all known manifestations of this disease phenotype. PMID:16337774

Understanding gene functions and disease mechanisms: Phenotyping pipelines in the German Mouse Clinic.

PubMed

Fuchs, Helmut; Aguilar-Pimentel, Juan Antonio; Amarie, Oana V; Becker, Lore; Calzada-Wack, Julia; Cho, Yi-Li; Garrett, Lillian; Hölter, Sabine M; Irmler, Martin; Kistler, Martin; Kraiger, Markus; Mayer-Kuckuk, Philipp; Moreth, Kristin; Rathkolb, Birgit; Rozman, Jan; da Silva Buttkus, Patricia; Treise, Irina; Zimprich, Annemarie; Gampe, Kristine; Hutterer, Christine; Stöger, Claudia; Leuchtenberger, Stefanie; Maier, Holger; Miller, Manuel; Scheideler, Angelika; Wu, Moya; Beckers, Johannes; Bekeredjian, Raffi; Brielmeier, Markus; Busch, Dirk H; Klingenspor, Martin; Klopstock, Thomas; Ollert, Markus; Schmidt-Weber, Carsten; Stöger, Tobias; Wolf, Eckhard; Wurst, Wolfgang; Yildirim, Ali Önder; Zimmer, Andreas; Gailus-Durner, Valérie; Hrabě de Angelis, Martin

2017-09-29

Since decades, model organisms have provided an important approach for understanding the mechanistic basis of human diseases. The German Mouse Clinic (GMC) was the first phenotyping facility that established a collaboration-based platform for phenotype characterization of mouse lines. In order to address individual projects by a tailor-made phenotyping strategy, the GMC advanced in developing a series of pipelines with tests for the analysis of specific disease areas. For a general broad analysis, there is a screening pipeline that covers the key parameters for the most relevant disease areas. For hypothesis-driven phenotypic analyses, there are thirteen additional pipelines with focus on neurological and behavioral disorders, metabolic dysfunction, respiratory system malfunctions, immune-system disorders and imaging techniques. In this article, we give an overview of the pipelines and describe the scientific rationale behind the different test combinations. Copyright © 2017 Elsevier B.V. All rights reserved.

Bidirectional Regulation of Aggression in Mice by Hippocampal Alpha-7 Nicotinic Acetylcholine Receptors.

PubMed

Lewis, Alan S; Pittenger, Steven T; Mineur, Yann S; Stout, Dawson; Smith, Philip H; Picciotto, Marina R

2018-05-01

Humans with 15q13.3 microdeletion syndrome (15q13.3DS) are typically hemizygous for CHRNA7, the gene coding for the α7 nicotinic acetylcholine receptor (nAChR), and manifest a variable neuropsychiatric phenotype that frequently includes persistent aggression. In mice, nAChR activation by nicotine is anti-aggressive, or 'serenic,' an effect which requires α7 nAChRs and is recapitulated by GTS-21, an α7 nAChR partial agonist. Pharmacotherapies potentiating α7 nAChR signaling have also been shown to reduce aggression in human 15q13.3DS. These findings identify the α7 nAChR as an important regulator of aggressive behavior, but the underlying neurobiological substrates remain to be determined. We therefore investigated the brain regions and potential neural circuits in which α7 nAChRs regulate aggressive behavior in male mice. As in 15q13.3DS, mice heterozygous for Chrna7 were significantly more aggressive compared to wild-type controls in the resident-intruder test. We subsequently examined the hippocampus, where α7 nAChRs are highly expressed, particularly in GABAergic interneurons. Resident-intruder interactions strongly activated granule cells in the dentate gyrus (DG). In contrast, GTS-21, which reduces aggression in mice, reduced DG granule cell activity during resident-intruder interactions. Short hairpin RNA knockdown of Chrna7 in the DG enhanced baseline aggression and eliminated the serenic effects of both nicotine and GTS-21 on attack latency. These data further implicate α7 nAChRs in regulation of aggression, and demonstrate that hippocampal α7 nAChR signaling is necessary and sufficient to limit aggression. These findings suggest that nAChR-mediated regulation of hippocampal excitatory-inhibitory balance could be a promising therapeutic intervention for aggression arising in certain forms of neuropsychiatric disease.

IDH1 mutation diminishes aggressive phenotype in glioma stem cells.

PubMed

Yao, Qi; Cai, Gang; Yu, Qi; Shen, Jianhong; Gu, Zhikai; Chen, Jian; Shi, Wei; Shi, Jinlong

2018-01-01

The R132H mutation in isocitrate dehydrogenase 1 (IDH1-R132H) is associated with better prognosis in glioma patients. Glioma stem cells (GSCs) in glioma are believed to be responsible for glioma growth and maintenance. However, the relation between the R132H mutation and GSCs is not fully understood. In the present study, GSC markers were detected in patients with IDH1-R132H or wild-type IDH1 (IDH1-wt) by tissue microarray immunohistochemistry (TMA-IHC). The relationship between the expression patterns of GSC markers and the clinicopathological characteristics in glioma were analyzed. To confirm this mutation's role in GSCs, the IDH1-R132H in GSCs isolated from glioblastoma patients with IDH1 mutations was overexpressed by using lentiviral constructs in vitro, and then the proliferation, differentiation, apoptosis, migration and invasion of the transfected GSCs were explored. At the molecular level, we detected Wnt/β-catenin signaling expression to verify its role in regulating the cellular properties of GSCs. The results showed that the positive rate of GSCs in patients with IDH1-R132H was significantly less than that in patients with IDH1-wt. The positive rate of GSCs was correlated with IDH1 mutation, TNM stage and poor overall survive. After transfection in vitro, IDH1-R132H overexpression led to reduced GSCs proliferation, migration and invasion, inducing apoptosis and improving GSC differentiation, accompanied by a significant reduction in activity of β-catenin. Several mediators, effectors and targets of the Wnt/β-catenin signaling were downregulated. The data demonstrate that IDH1 mutation reduces the malignant progression of glioma by causing a less aggressive phenotype of GSCs which are involved in the Wnt/β‑catenin signaling.

Phenotypic and Genotypic Characterisation of Inflammatory Bowel Disease Presenting Before the Age of 2 years

PubMed Central

Dziubak, Robert; Pescarin, Matilde; Drury, Suzanne; Godwin, Heather; Reeve, Kate; Chadokufa, Sibongile; Huggett, Bonita; Sider, Sara; James, Chela; Acton, Nikki; Cernat, Elena; Gasparetto, Marco; Noble-Jamieson, Gabi; Kiparissi, Fevronia; Elawad, Mamoun; Beales, Phil L.; Sebire, Neil J.; Gilmour, Kimberly; Uhlig, Holm H.; Bacchelli, Chiara; Shah, Neil

2017-01-01

Abstract Objectives: Inflammatory bowel disease [IBD] presenting in early childhood is extremely rare. More recently, progress has been made to identify children with monogenic forms of IBD predominantly presenting very early in life. In this study, we describe the heterogeneous phenotypes and genotypes of patients with IBD presenting before the age of 2 years and establish phenotypic features associated with underlying monogenicity. Methods: Phenotype data of 62 children with disease onset before the age of 2 years presenting over the past 20 years were reviewed. Children without previously established genetic diagnosis were prospectively recruited for next-generation sequencing. Results: In all, 62 patients [55% male] were identified. The median disease onset was 3 months of age (interquartile range [IQR]: 1 to 11). Conventional IBD classification only applied to 15 patients with Crohn’s disease [CD]-like [24%] and three with ulcerative colitis [UC]-like [5%] phenotype; 44 patients [71%] were diagnosed with otherwise unclassifiable IBD. Patients frequently required parenteral nutrition [40%], extensive immunosuppression [31%], haematopoietic stem-cell transplantation [29%], and abdominal surgery [19%]. In 31% of patients, underlying monogenic diseases were established [EPCAM, IL10, IL10RA, IL10RB, FOXP3, LRBA, SKIV2L, TTC37, TTC7A]. Phenotypic features significantly more prevalent in monogenic IBD were: consanguinity, disease onset before the 6th month of life, stunting, extensive intestinal disease and histological evidence of epithelial abnormalities. Conclusions: IBD in children with disease onset before the age of 2 years is frequently unclassifiable into Crohn’s disease and ulcerative colitis, particularly treatment resistant, and can be indistinguishable from monogenic diseases with IBD-like phenotype. PMID:27302973

Paradigms in Chronic Obstructive Pulmonary Disease: Phenotypes, Immunobiology, and Therapy with a Focus on Vascular Disease

PubMed Central

Schivo, Michael; Albertson, Timothy E.; Haczku, Angela; Kenyon, Nicholas J.; Zeki, Amir A.; Kuhn, Brooks T.; Louie, Samuel; Avdalovic, Mark V.

2018-01-01

Chronic obstructive pulmonary disease (COPD) is a complex and heterogenous syndrome that represents a major global health burden. COPD phenotypes have recently emerged based on large cohort studies addressing the need to better characterize the syndrome. Though comprehensive phenotyping is still at an early stage, factors such as ethnicity and radiographic, serum, and exhaled breath biomarkers have shown promise. COPD is also an immunological disease where innate and adaptive immune responses to the environment and tobacco smoke are altered. The frequent overlap between COPD and other systemic diseases, such as cardiovascular disease, have influenced COPD therapy, and treatments for both conditions may lead to improved patient outcomes. Here we discuss current paradigms that center on improving the definition of COPD, understanding the immunological overlap between COPD and vascular inflammation, and the treatment of COPD—with a focus on comorbid cardiovascular disease. PMID:28258130

Phenotypic and Genotypic Characterisation of Inflammatory Bowel Disease Presenting Before the Age of 2 years.

PubMed

Kammermeier, Jochen; Dziubak, Robert; Pescarin, Matilde; Drury, Suzanne; Godwin, Heather; Reeve, Kate; Chadokufa, Sibongile; Huggett, Bonita; Sider, Sara; James, Chela; Acton, Nikki; Cernat, Elena; Gasparetto, Marco; Noble-Jamieson, Gabi; Kiparissi, Fevronia; Elawad, Mamoun; Beales, Phil L; Sebire, Neil J; Gilmour, Kimberly; Uhlig, Holm H; Bacchelli, Chiara; Shah, Neil

2017-01-01

Inflammatory bowel disease [IBD] presenting in early childhood is extremely rare. More recently, progress has been made to identify children with monogenic forms of IBD predominantly presenting very early in life. In this study, we describe the heterogeneous phenotypes and genotypes of patients with IBD presenting before the age of 2 years and establish phenotypic features associated with underlying monogenicity. Phenotype data of 62 children with disease onset before the age of 2 years presenting over the past 20 years were reviewed. Children without previously established genetic diagnosis were prospectively recruited for next-generation sequencing. In all, 62 patients [55% male] were identified. The median disease onset was 3 months of age (interquartile range [IQR]: 1 to 11). Conventional IBD classification only applied to 15 patients with Crohn's disease [CD]-like [24%] and three with ulcerative colitis [UC]-like [5%] phenotype; 44 patients [71%] were diagnosed with otherwise unclassifiable IBD. Patients frequently required parenteral nutrition [40%], extensive immunosuppression [31%], haematopoietic stem-cell transplantation [29%], and abdominal surgery [19%]. In 31% of patients, underlying monogenic diseases were established [EPCAM, IL10, IL10RA, IL10RB, FOXP3, LRBA, SKIV2L, TTC37, TTC7A]. Phenotypic features significantly more prevalent in monogenic IBD were: consanguinity, disease onset before the 6th month of life, stunting, extensive intestinal disease and histological evidence of epithelial abnormalities. IBD in children with disease onset before the age of 2 years is frequently unclassifiable into Crohn's disease and ulcerative colitis, particularly treatment resistant, and can be indistinguishable from monogenic diseases with IBD-like phenotype. Copyright © 2016 European Crohn’s and Colitis Organisation (ECCO). Published by Oxford University Press. All rights reserved. For permissions, please email: journals.permissions@oup.com.

Versican and the regulation of cell phenotype in disease.

PubMed

Wight, Thomas N; Kinsella, Michael G; Evanko, Stephen P; Potter-Perigo, Susan; Merrilees, Mervyn J

2014-08-01

Versican is an extracellular matrix (ECM) proteoglycan that is present in the pericellular environment of most tissues and increases in many different diseases. Versican interacts with cells to influence the ability of cells to proliferate, migrate, adhere and assemble an ECM. The structure of the versican molecule is briefly reviewed and studies highlighting those factors that promote versican synthesis and degradation and their impact on cell phenotype in disease are discussed. Particular attention is given to vascular disease, but other diseases where versican is important are covered as well, most notably different forms of cancers. Attention is given to mechanisms(s) by which versican influences cell behaviors through either direct or indirect processes. Versican produced by either stromal cells or myeloid cells can have a major impact influencing immunity and inflammation. Finally, studies controlling versican accumulation that either delay or inhibit the progression of disease will be highlighted. Versican is one component of the ECM that can influence the ability of cells to proliferate, migrate, adhere, and remodel the ECM. Targeting versican as a way to control cell phenotype offers a novel approach in the treatment of disease. ECM molecules such as versican contribute to the structural integrity of tissues and interact with cells through direct and indirect means to regulate, in part, cellular events that form the basis of disease. This article is part of a Special Issue entitled Matrix-mediated cell behaviour and properties. Copyright © 2014 Elsevier B.V. All rights reserved.

Heterospecific aggression bias towards a rarer colour morph.

PubMed

Lehtonen, Topi K; Sowersby, Will; Wong, Bob B M

2015-09-22

Colour polymorphisms are a striking example of phenotypic diversity, yet the sources of selection that allow different morphs to persist within populations remain poorly understood. In particular, despite the importance of aggression in mediating social dominance, few studies have considered how heterospecific aggression might contribute to the maintenance or divergence of different colour morphs. To redress this gap, we carried out a field-based study in a Nicaraguan crater lake to investigate patterns of heterospecific aggression directed by the cichlid fish, Hypsophrys nicaraguensis, towards colour polymorphic cichlids in the genus Amphilophus. We found that H. nicaraguensis was the most frequent territorial neighbour of the colour polymorphic A. sagittae. Furthermore, when manipulating territorial intrusions using models, H. nicaraguensis were more aggressive towards the gold than dark colour morph of the sympatric Amphilophus species, including A. sagittae. Such a pattern of heterospecific aggression should be costly to the gold colour morph, potentially accounting for its lower than expected frequency and, more generally, highlighting the importance of considering heterospecific aggression in the context of morph frequencies and coexistence in the wild. © 2015 The Author(s).

New approaches to the representation and analysis of phenotype knowledge in human diseases and their animal models.

PubMed

Schofield, Paul N; Sundberg, John P; Hoehndorf, Robert; Gkoutos, Georgios V

2011-09-01

The systematic investigation of the phenotypes associated with genotypes in model organisms holds the promise of revealing genotype-phenotype relations directly and without additional, intermediate inferences. Large-scale projects are now underway to catalog the complete phenome of a species, notably the mouse. With the increasing amount of phenotype information becoming available, a major challenge that biology faces today is the systematic analysis of this information and the translation of research results across species and into an improved understanding of human disease. The challenge is to integrate and combine phenotype descriptions within a species and to systematically relate them to phenotype descriptions in other species, in order to form a comprehensive understanding of the relations between those phenotypes and the genotypes involved in human disease. We distinguish between two major approaches for comparative phenotype analyses: the first relies on evolutionary relations to bridge the species gap, while the other approach compares phenotypes directly. In particular, the direct comparison of phenotypes relies heavily on the quality and coherence of phenotype and disease databases. We discuss major achievements and future challenges for these databases in light of their potential to contribute to the understanding of the molecular mechanisms underlying human disease. In particular, we discuss how the use of ontologies and automated reasoning can significantly contribute to the analysis of phenotypes and demonstrate their potential for enabling translational research.

Metabolic phenotyping and systems biology approaches to understanding metabolic syndrome and fatty liver disease.

PubMed

Dumas, Marc-Emmanuel; Kinross, James; Nicholson, Jeremy K

2014-01-01

Metabolic syndrome, a cluster of risk factors for type 2 diabetes mellitus and cardiovascular disease, is becoming an increasing global health concern. Insulin resistance is often associated with metabolic syndrome and also typical hepatic manifestations such as nonalcoholic fatty liver disease. Profiling of metabolic products (metabolic phenotyping or metabotyping) has provided new insights into metabolic syndrome and nonalcoholic fatty liver disease. Data from nuclear magnetic resonance spectroscopy and mass spectrometry combined with statistical modeling and top-down systems biology have allowed us to analyze and interpret metabolic signatures in terms of metabolic pathways and protein interaction networks and to identify the genomic and metagenomic determinants of metabolism. For example, metabolic phenotyping has shown that relationships between host cells and the microbiome affect development of the metabolic syndrome and fatty liver disease. We review recent developments in metabolic phenotyping and systems biology technologies and how these methodologies have provided insights into the mechanisms of metabolic syndrome and nonalcoholic fatty liver disease. We discuss emerging areas of research in this field and outline our vision for how metabolic phenotyping could be used to study metabolic syndrome and fatty liver disease. Copyright © 2014 AGA Institute. Published by Elsevier Inc. All rights reserved.

Particularities of COPD exacerbations in different phenotypes of the disease in Tunisia.

PubMed

Zendah, Ines; Ayed, Khadija; Kwas, Hamida; Khattab, Amel; Ghédira, Habib

2016-03-01

Chronic Obstructive Pulmonary Disease is defined by a limitation of airflow. This disease is characterized by exacerbations that threaten the patient's life and worsens his prognosis. Moreover, COPD patients are different according to many parameters that define different phenotypes. Characteristics of exacerbations may depend on these phenotypes according to few recent studies. To determine the characteristics and the prognosis of the exacerbations in each phenotype of COPD patients phenotype in Tunisia. Retrospective study including 153 male patients hospitalized for COPD exacerbation from January 2009 to June 2012. Patients were classified into 4 phenotypes according to Burgel's classification. Patients were divided into four phenotypes: phenotype (PH)1: (n=68), PH2: (n=33), PH3: (n=25) and PH4: (n=27). Mean age for PH1, 2, 3 and 4 was: 61, 74, 56 and 72 years. The number of exacerbations per year was higher in PH1. Dyspnea was more important in PH1 and 4. Hypercapnia on admission was higher in PH4. Non invasive ventilation and transfer to resuscitation unit were more frequently mandatory in PH3 and 4.   Death occurred 2% of PH1 and 5% of PH4. Hospitalization duration was more important in PH4. COPD patients are heterogenous and belong to different phenotypes. The characteristics of the exacerbations and their prognosis widely differ according to these different groups. In Tunisia, it seems that patients who had moderate respiratory functional tests impairment are the lowest responders to treatment with a higher frequency of resuscitation unit transfer.

A Novel Lung Disease Phenotype Adjusted for Mortality Attrition for Cystic Fibrosis Genetic Modifier Studies

PubMed Central

Taylor, Chelsea; Commander, Clayton W.; Collaco, Joseph M.; Strug, Lisa J.; Li, Weili; Wright, Fred A.; Webel, Aaron D.; Pace, Rhonda G.; Stonebraker, Jaclyn R.; Naughton, Kathleen; Dorfman, Ruslan; Sandford, Andrew; Blackman, Scott M.; Berthiaume, Yves; Paré, Peter; Drumm, Mitchell L.; Zielenski, Julian; Durie, Peter; Cutting, Garry R.; Knowles, Michael R.; Corey, Mary

2011-01-01

SUMMARY Genetic studies of lung disease in Cystic Fibrosis are hampered by the lack of a severity measure that accounts for chronic disease progression and mortality attrition. Further, combining analyses across studies requires common phenotypes that are robust to study design and patient ascertainment. Using data from the North American Cystic Fibrosis Modifier Consortium (Canadian Consortium for CF Genetic Studies, Johns Hopkins University CF Twin and Sibling Study, and University of North Carolina/Case Western Reserve University Gene Modifier Study), the authors calculated age-specific CF percentile values of FEV1 which were adjusted for CF age-specific mortality data. The phenotype was computed for 2061 patients representing the Canadian CF population, 1137 extreme phenotype patients in the UNC/Case Western study, and 1323 patients from multiple CF sib families in the CF Twin and Sibling Study. Despite differences in ascertainment and median age, our phenotype score was distributed in all three samples in a manner consistent with ascertainment differences, reflecting the lung disease severity of each individual in the underlying population. The new phenotype score was highly correlated with the previously recommended complex phenotype, but the new phenotype is more robust for shorter follow-up and for extreme ages. A disease progression and mortality adjusted phenotype reduces the need for stratification or additional covariates, increasing statistical power and avoiding possible distortions. This approach will facilitate large scale genetic and environmental epidemiological studies which will provide targeted therapeutic pathways for the clinical benefit of patients with CF. PMID:21462361

Honey bee aggression supports a link between gene regulation and behavioral evolution.

PubMed

Alaux, Cédric; Sinha, Saurabh; Hasadsri, Linda; Hunt, Greg J; Guzmán-Novoa, Ernesto; DeGrandi-Hoffman, Gloria; Uribe-Rubio, José Luis; Southey, Bruce R; Rodriguez-Zas, Sandra; Robinson, Gene E

2009-09-08

A prominent theory states that animal phenotypes arise by evolutionary changes in gene regulation, but the extent to which this theory holds true for behavioral evolution is not known. Because "nature and nurture" are now understood to involve hereditary and environmental influences on gene expression, we studied whether environmental influences on a behavioral phenotype, i.e., aggression, could have evolved into inherited differences via changes in gene expression. Here, with microarray analysis of honey bees, we show that aggression-related genes with inherited patterns of brain expression are also environmentally regulated. There were expression differences in the brain for hundreds of genes between the highly aggressive Africanized honey bee compared with European honey bee (EHB) subspecies. Similar results were obtained for EHB in response to exposure to alarm pheromone (which provokes aggression) and when comparing old and young bees (aggressive tendencies increase with age). There was significant overlap of the gene lists generated from these three microarray experiments. Moreover, there was statistical enrichment of several of the same cis regulatory motifs in promoters of genes on all three gene lists. Aggression shows a remarkably robust brain molecular signature regardless of whether it occurs because of inherited, age-related, or environmental (social) factors. It appears that one element in the evolution of different degrees of aggressive behavior in honey bees involved changes in regulation of genes that mediate the response to alarm pheromone.

Stargardt disease: towards developing a model to predict phenotype.

PubMed

Heathfield, Laura; Lacerda, Miguel; Nossek, Christel; Roberts, Lisa; Ramesar, Rajkumar S

2013-10-01

Stargardt disease is an ABCA4-associated retinopathy, which generally follows an autosomal recessive inheritance pattern and is a frequent cause of macular degeneration in childhood. ABCA4 displays significant allelic heterogeneity whereby different mutations can cause retinal diseases with varying severity and age of onset. A genotype-phenotype model has been proposed linking ABCA4 mutations, purported ABCA4 functional protein activity and severity of disease, as measured by degree of visual loss and the age of onset. It has, however, been difficult to verify this model statistically in observational studies, as the number of individuals sharing any particular mutation combination is typically low. Seven founder mutations have been identified in a large number of Caucasian Afrikaner patients in South Africa, making it possible to test the genotype-phenotype model. A generalised linear model was developed to predict and assess the relative pathogenic contribution of the seven mutations to the age of onset of Stargardt disease. It is shown that the pathogenicity of an individual mutation can differ significantly depending on the genetic context in which it occurs. The results reported here may be used to identify suitable candidates for inclusion in clinical trials, as well as guide the genetic counselling of affected individuals and families.

Stargardt Disease: towards developing a model to predict phenotype

PubMed Central

Heathfield, Laura; Lacerda, Miguel; Nossek, Christel; Roberts, Lisa; Ramesar, Rajkumar S

2013-01-01

Stargardt disease is an ABCA4-associated retinopathy, which generally follows an autosomal recessive inheritance pattern and is a frequent cause of macular degeneration in childhood. ABCA4 displays significant allelic heterogeneity whereby different mutations can cause retinal diseases with varying severity and age of onset. A genotype–phenotype model has been proposed linking ABCA4 mutations, purported ABCA4 functional protein activity and severity of disease, as measured by degree of visual loss and the age of onset. It has, however, been difficult to verify this model statistically in observational studies, as the number of individuals sharing any particular mutation combination is typically low. Seven founder mutations have been identified in a large number of Caucasian Afrikaner patients in South Africa, making it possible to test the genotype–phenotype model. A generalised linear model was developed to predict and assess the relative pathogenic contribution of the seven mutations to the age of onset of Stargardt disease. It is shown that the pathogenicity of an individual mutation can differ significantly depending on the genetic context in which it occurs. The results reported here may be used to identify suitable candidates for inclusion in clinical trials, as well as guide the genetic counselling of affected individuals and families. PMID:23695285

Genetic Factors in Systemic Lupus Erythematosus: Contribution to Disease Phenotype

PubMed Central

Ceccarelli, Fulvia; Perricone, Carlo; Borgiani, Paola; Ciccacci, Cinzia; Rufini, Sara; Cipriano, Enrica; Alessandri, Cristiano; Spinelli, Francesca Romana; Sili Scavalli, Antonio; Novelli, Giuseppe; Valesini, Guido; Conti, Fabrizio

2015-01-01

Genetic factors exert an important role in determining Systemic Lupus Erythematosus (SLE) susceptibility, interplaying with environmental factors. Several genetic studies in various SLE populations have identified numerous susceptibility loci. From a clinical point of view, SLE is characterized by a great heterogeneity in terms of clinical and laboratory manifestations. As widely demonstrated, specific laboratory features are associated with clinical disease subset, with different severity degree. Similarly, in the last years, an association between specific phenotypes and genetic variants has been identified, allowing the possibility to elucidate different mechanisms and pathways accountable for disease manifestations. However, except for Lupus Nephritis (LN), no studies have been designed to identify the genetic variants associated with the development of different phenotypes. In this review, we will report data currently known about this specific association. PMID:26798662

Heterogeneity in the development of proactive and reactive aggression in childhood: Common and specific genetic - environmental factors

PubMed Central

Lacourse, Eric; Brendgen, Mara; Vitaro, Frank; Dionne, Ginette; Tremblay, Richard Ernest; Boivin, Michel

2017-01-01

Background Few studies are grounded in a developmental framework to study proactive and reactive aggression. Furthermore, although distinctive correlates, predictors and outcomes have been highlighted, proactive and reactive aggression are substantially correlated. To our knowledge, no empirical study has examined the communality of genetic and environmental underpinning of the development of both subtypes of aggression. The current study investigated the communality and specificity of genetic-environmental factors related to heterogeneity in proactive and reactive aggression’s development throughout childhood. Methods Participants were 223 monozygotic and 332 dizygotic pairs. Teacher reports of aggression were obtained at 6, 7, 9, 10 and 12 years of age. Joint development of both phenotypes were analyzed through a multivariate latent growth curve model. Set point, differentiation, and genetic maturation/environmental modulation hypotheses were tested using a biometric decomposition of intercepts and slopes. Results Common genetic factors accounted for 64% of the total variation of proactive and reactive aggression’s intercepts. Two other sets of uncorrelated genetic factors accounted for reactive aggression’s intercept (17%) on the one hand, and for proactive (43%) and reactive (13%) aggression’s slopes on the other. Common shared environmental factors were associated with proactive aggression’s intercept (21%) and slope (26%) and uncorrelated shared environmental factors were also associated with reactive aggression’s slope (14%). Common nonshared environmental factors explained most of the remaining variability of proactive and reactive aggression slopes. Conclusions A genetic differentiation hypothesis common to both phenotypes was supported by common genetic factors associated with the developmental heterogeneity of proactive and reactive aggression in childhood. A genetic maturation hypothesis common to both phenotypes, albeit stronger for

Cutaneous double-hit B-cell lymphoma: an aggressive form of B-cell lymphoma with a propensity for cutaneous dissemination.

PubMed

Magro, Cynthia M; Wang, Xuan; Subramaniyam, Shivakumar; Darras, Natasha; Mathew, Susan

2014-04-01

Diffuse large cell B-cell lymphoma of the skin is most commonly represented by diffuse large cell variants of primary cutaneous follicle center cell lymphoma and the leg-type lymphoma. In a minority of cases, the infiltrates are an expression of stage 4 disease of established extracutaneous B-cell lymphoma. We describe 3 patients with an aggressive form of B-cell lymphoma secondarily involving the skin. Two of the patients were in the ninth decade of life, whereas 1 patient was 34 years of age. In the elderly patients, there was an antecedent and/or concurrent history of follicular lymphoma, whereas in the younger patient, the tumor was a de novo presentation of this aggressive form of lymphoma. The elderly patients succumbed to their disease within less than a year from the time of diagnosis, whereas 1 patient is alive but with persistent and progressive disease despite chemotherapeutic intervention. The infiltrates in all 3 cases were diffuse and composed of large malignant hematopoietic cells that exhibited a round nucleus with a finely dispersed chromatin. Phenotypically, the tumor cells were Bcl-2 and CD10 positive, whereas Bcl-6 and Mum-1 showed variable positivity. One case showed combined Mum-1 positivity along with an acute lymphoblastic lymphoma phenotype, including the absence of CD20 expression. In each case, there was a c-MYC and BCL2/IGH rearrangement diagnostic of double-hit lymphoma. In one case, there was an additional BCL6 rearrangement, defining what is in essence triple-hit lymphoma. In conclusion, double-hit lymphoma is an aggressive form of B-cell neoplasia resistant to standard chemotherapy regimens, which in many but not all cases represents tumor progression in the setting of a lower grade B-cell malignancy.

The genetics of aggression: Where are we now?

PubMed

Asherson, Philip; Cormand, Bru

2016-07-01

Aggression, an overt behaviour with the intention to inflict damage, is a physiological trait with important roles throughout evolution, both in defence and predation. However, when expressed in humans in the wrong context, aggression leads to social maladjustment and crime. This special issue is about the genetic and neurobiological basis for aggression. Most of the 12 works presented here have been prepared by members of five international consortia established under the auspice of the FP7 and H2020 programs of the European Union to investigate different aspects of aggression and related behavioural phenotypes, including delineation of subtypes, aetiological mechanisms, neurobiology, neuroimaging, biomarkers, animal models and development and assessment of new treatments. Research on human aggression has largely focused on the societal causes of violent behaviour with relatively little focus on the underlying neuroscientific basis. However, interesting findings are emerging which suggest that by identifying distinct pathways to aggression, better targeting of social, psychological and medical treatments, can lead to improved outcomes for individuals and society. This issue represents a state of the art review of current neurobiological understanding of human aggression and a starting point for concerted efforts to move the field towards the development of new strategies for prevention and treatment. © 2016 Wiley Periodicals, Inc. © 2016 Wiley Periodicals, Inc.

Use of haloperidol and risperidone in highly aggressive Swiss Webster mice by applying the model of spontaneous aggression (MSA).

PubMed

Fragoso, Viviane Muniz da Silva; Hoppe, Luanda Yanaan; de Araújo-Jorge, Tânia Cremonini; de Azevedo, Marcos José; Campos, Jerônimo Diego de Souza; Cortez, Célia Martins; de Oliveira, Gabriel Melo

2016-03-15

Aggression is defined as the act in which an individual intentionally harms or injures another of their own species. Antipsychotics are a form of treatment used in psychiatric routine. They have been used for decades in treatment of patients with aggressive behavior. Haloperidol and risperidone promote the control of psychiatric symptoms, through their respective mechanisms of action. Experimental models are obtained by behavioral, genetic, and pharmacological manipulations, and use a reduced number of animals. In this context, we applied the model of spontaneous aggression (MSA), originating the presence of highly aggressive mice (AgR) when reassembled in adulthood. We administered haloperidol and risperidone in escalating doses, for ten consecutive days. Using positive and negative control groups, we evaluated the effectiveness of these drugs and the reversal of the aggressive behavior, performing the tail suspension test (TST) and open field test (OFT) on 10th day of treatment and 10 days after its discontinuation. The results showed that both antipsychotic drugs were effective in AgR and reversed the aggressive phenotype, reducing the number of attacks by AgR and the extent of lesions in the subordinate mice (AgD) exposed to the pattern of aggressive behavior (PAB) of the aggressors. This conclusion is based on the reduction in the animals' motor and exploratory activity, and on the reversal of patterns of aggressive behavior. The association between the MSA and experiments with other therapeutic protocols and different antipsychotics can be an important methodology in the study of aggressive behavior in psychiatric patients. Copyright © 2015 Elsevier B.V. All rights reserved.

The etiology of the association between child antisocial behavior and maternal negativity varies across aggressive and non-aggressive rule-breaking forms of antisocial behavior

PubMed Central

Klahr, Ashlea M.; Klump, Kelly L.; Burt, S. Alexandra

2014-01-01

There is a robust association between negative parenting and child antisocial behavior problems. However, the etiology of this association remains unclear. Extant literature has reported strikingly different conclusions across studies, with some highlighting genetic mediation and others highlighting environmental mediation. One possible reason for these discrepancies across studies may be the failure to differentiate between aggressive and non-aggressive (rule-breaking) dimensions of childhood antisocial behavior, given their notably different etiologies and developmental trajectories (Burt, 2012). The current study sought to examine the phenotypic and etiologic associations of maternal negativity with aggressive and rule-breaking antisocial behavior, respectively. Participants included 824 mothers and their twin children between the ages of 6 and 10. Our results highlighted clear etiologic distinctions in the associations of aggression and rule-breaking with maternal negativity. Aggression was associated with maternal negativity via both genetic and environmental factors, whereas the association between non-aggressive rule-breaking and maternal negativity was entirely environmental in origin. These findings provide additional support for the presence of meaningful distinctions between aggressive and non-aggressive forms of antisocial behavior, and highlight the complex relationship between parenting and child outcome. PMID:24906982

Sensory modulation intervention and behaviour support modification for the treatment of severe aggression in Huntington's disease. A single case experimental design.

PubMed

Fisher, Caroline A; Brown, Anahita

2017-09-01

Aggression is common in Huntington's disease. However, at present there are no standard guidelines for managing aggression in Huntington's sufferers due to a lack of empirical research. This paper presents a case study of the treatment of very high levels of aggression with sensory modulation and behaviour support intervention in a Huntington's sufferer. The client exhibited a range of aggressive behaviours, including physical aggression to people, furniture and objects, and verbal aggression. Following an eight week baseline phase, five weeks of sensory modulation intervention were employed. A behaviour support plan was then implemented as an adjunct to the sensory intervention, with aggressive behaviour systematically audited for a further 11 weeks. The results indicate a significant reduction in reported levels of aggression during the combined sensory modulation and behaviour support phase, compared to both the baseline and the sensory modulation therapy alone phases. This case study highlights the efficacy non-pharmacological interventions may have for reducing aggression in HD.

Association of Immunological Cell Profiles with Specific Clinical Phenotypes of Scleroderma Disease

PubMed Central

Calzada, David; Mayayo, Teodoro; González-Rodríguez, María Luisa; Rabasco, Antonio María; Lahoz, Carlos

2014-01-01

This study aimed to search the correlation among immunological profiles and clinical phenotypes of scleroderma in well-characterized groups of scleroderma patients, comparing forty-nine scleroderma patients stratified according to specific clinical phenotypes with forty-nine healthy controls. Five immunological cell subpopulations (B, CD4+ and CD8+ T-cells, NK, and monocytes) and their respective stages of apoptosis and activation were analyzed by flow cytometry, in samples of peripheral blood mononuclear cells (PBMCs). Analyses of results were stratified according to disease stage, time since the diagnosis, and visceral damage (pulmonary fibrosis, pulmonary hypertension, and cardiac affliction) and by time of treatment with corticosteroids. An increase in the percentages of monocytes and a decrease in the B cells were mainly related to the disease progression. A general apoptosis decrease was found in all phenotypes studied, except in localized scleroderma. An increase of B and NK cells activation was found in patients diagnosed more than 10 years ago. Specific cell populations like monocytes, NK, and B cells were associated with the type of affected organ. This study shows how, in a heterogeneous disease, proper patient's stratification according to clinical phenotypes allows finding specific cellular profiles. Our data may lead to improvements in the knowledge of prognosis factors and to aid in the analysis of future specific therapies. PMID:24818126

Aggressive periodontitis: case definition and diagnostic criteria.

PubMed

Albandar, Jasim M

2014-06-01

Aggressive periodontitis is a destructive disease characterized by the following: the involvement of multiple teeth with a distinctive pattern of periodontal tissue loss; a high rate of disease progression; an early age of onset; and the absence of systemic diseases. In some patients periodontal tissue loss may commence before puberty, whereas in most patients the age of onset is during or somewhat after the circumpubertal period. Besides infection with specific microorganisms, a host predisposition seems to play a key role in the pathogenesis of aggressive periodontitis, as evidenced by the familial aggregation of the disease. In this article we review the historical background of the diagnostic criteria of aggressive periodontitis, present a contemporary case definition and describe the clinical parameters of the disease. At present, the diagnosis of aggressive periodontitis is achieved using case history, clinical examination and radiographic evaluation. The data gathered using these methods are prone to relatively high measurement errors. Besides, this diagnostic approach measures past disease history and may not reliably measure existing disease activity or accurately predict future tissue loss. A diagnosis is often made years after the onset of the disease, partly because current assessment methods detect established disease more readily and reliably than they detect incipient or initial lesions where the tissue loss is minimal and usually below the detection threshold of present examination methods. Future advancements in understanding the pathogenesis of this disease may contribute to an earlier diagnosis. Insofar, future case definitions may involve the identification of key etiologic and risk factors, combined with high-precision methodologies that enable the early detection of initial lesions. This may significantly enhance the predictive value of these tests and detect cases of aggressive periodontitis before significant tissue loss develops. © 2014

Changes in Crohn's disease phenotype over time in the Chinese population: validation of the Montreal classification system.

PubMed

Chow, Dorothy K L; Leong, Rupert W L; Lai, Larry H; Wong, Grace L H; Leung, Wai-Keung; Chan, Francis K L; Sung, Joseph J Y

2008-04-01

Phenotypic evolution of Crohn's disease occurs in whites but has never been described in other populations. The Montreal classification may describe phenotypes more precisely. The aim of this study was to validate the Montreal classification through a longitudinal sensitivity analysis in detecting phenotypic variation compared to the Vienna classification. This was a retrospective longitudinal study of consecutive Chinese Crohn's disease patients. All cases were classified by the Montreal classification and the Vienna classification for behavior and location. The evolution of these characteristics and the need for surgery were evaluated. A total of 109 patients were recruited (median follow-up: 4 years, range: 6 months-18 years). Crohn's disease behavior changed 3 years after diagnosis (P = 0.025), with an increase in stricturing and penetrating phenotypes, as determined by the Montreal classification, but was only detected by the Vienna classification after 5 years (P = 0.015). Disease location remained stable on follow-up in both classifications. Thirty-four patients (31%) underwent major surgery during the follow-up period with the stricturing [P = 0.002; hazard ratio (HR): 3.3; 95% CI: 1.5-7.0] and penetrating (P = 0.03; HR: 5.8; 95% CI: 1.2-28.2) phenotypes according to the Montreal classification associated with the need for major surgery. In contrast, colonic disease was protective against a major operation (P = 0.02; HR: 0.3; 95% CI: 0.08-0.8). This is the first study demonstrating phenotypic evolution of Crohn's disease in a nonwhite population. The Montreal classification is more sensitive to behavior phenotypic changes than is the Vienna classification after excluding perianal disease from the penetrating disease category and was useful in predicting course and the need for surgery.

The role of monogenic disease in children with very early onset inflammatory bowel disease.

PubMed

Kelsen, Judith R; Baldassano, Robert N

2017-10-01

Inflammatory bowel disease (IBD) is a multifactorial disease caused by dysregulated immune responses to commensal or pathogenic intestinal microbes, resulting in chronic intestinal inflammation. Patients diagnosed with IBD occurring before the age of 5 are a unique population, known as very early onset (VEO)-IBD and can be phenotypically and genetically distinct from older-onset IBD. We aim to review the clinical presentation of children with VEO-IBD and recent discoveries that point to genomic drivers of disease that may impact our therapeutic decisions. VEO-IBD is increasing in incidence and is associated with more severe disease, aggressive progression and poor response to most conventional therapies. This article will review the advances in sequencing technology that have led to identification of novel gene variants associated with disease and potentially new targeted therapeutic options. Children with VEO-IBD may present with a different phenotype and more severe disease than older children and adults. Identification of the causal gene or pathways, these children may allow for true precision medicine with targeted therapy and improved disease course.

Genome sequencing reveals loci under artificial selection that underlie disease phenotypes in the laboratory rat.

PubMed

Atanur, Santosh S; Diaz, Ana Garcia; Maratou, Klio; Sarkis, Allison; Rotival, Maxime; Game, Laurence; Tschannen, Michael R; Kaisaki, Pamela J; Otto, Georg W; Ma, Man Chun John; Keane, Thomas M; Hummel, Oliver; Saar, Kathrin; Chen, Wei; Guryev, Victor; Gopalakrishnan, Kathirvel; Garrett, Michael R; Joe, Bina; Citterio, Lorena; Bianchi, Giuseppe; McBride, Martin; Dominiczak, Anna; Adams, David J; Serikawa, Tadao; Flicek, Paul; Cuppen, Edwin; Hubner, Norbert; Petretto, Enrico; Gauguier, Dominique; Kwitek, Anne; Jacob, Howard; Aitman, Timothy J

2013-08-01

Large numbers of inbred laboratory rat strains have been developed for a range of complex disease phenotypes. To gain insights into the evolutionary pressures underlying selection for these phenotypes, we sequenced the genomes of 27 rat strains, including 11 models of hypertension, diabetes, and insulin resistance, along with their respective control strains. Altogether, we identified more than 13 million single-nucleotide variants, indels, and structural variants across these rat strains. Analysis of strain-specific selective sweeps and gene clusters implicated genes and pathways involved in cation transport, angiotensin production, and regulators of oxidative stress in the development of cardiovascular disease phenotypes in rats. Many of the rat loci that we identified overlap with previously mapped loci for related traits in humans, indicating the presence of shared pathways underlying these phenotypes in rats and humans. These data represent a step change in resources available for evolutionary analysis of complex traits in disease models. Copyright © 2013 The Authors. Published by Elsevier Inc. All rights reserved.

Genome Sequencing Reveals Loci under Artificial Selection that Underlie Disease Phenotypes in the Laboratory Rat

PubMed Central

Atanur, Santosh S.; Diaz, Ana Garcia; Maratou, Klio; Sarkis, Allison; Rotival, Maxime; Game, Laurence; Tschannen, Michael R.; Kaisaki, Pamela J.; Otto, Georg W.; Ma, Man Chun John; Keane, Thomas M.; Hummel, Oliver; Saar, Kathrin; Chen, Wei; Guryev, Victor; Gopalakrishnan, Kathirvel; Garrett, Michael R.; Joe, Bina; Citterio, Lorena; Bianchi, Giuseppe; McBride, Martin; Dominiczak, Anna; Adams, David J.; Serikawa, Tadao; Flicek, Paul; Cuppen, Edwin; Hubner, Norbert; Petretto, Enrico; Gauguier, Dominique; Kwitek, Anne; Jacob, Howard; Aitman, Timothy J.

2013-01-01

Summary Large numbers of inbred laboratory rat strains have been developed for a range of complex disease phenotypes. To gain insights into the evolutionary pressures underlying selection for these phenotypes, we sequenced the genomes of 27 rat strains, including 11 models of hypertension, diabetes, and insulin resistance, along with their respective control strains. Altogether, we identified more than 13 million single-nucleotide variants, indels, and structural variants across these rat strains. Analysis of strain-specific selective sweeps and gene clusters implicated genes and pathways involved in cation transport, angiotensin production, and regulators of oxidative stress in the development of cardiovascular disease phenotypes in rats. Many of the rat loci that we identified overlap with previously mapped loci for related traits in humans, indicating the presence of shared pathways underlying these phenotypes in rats and humans. These data represent a step change in resources available for evolutionary analysis of complex traits in disease models. PaperClip PMID:23890820

Higher serum concentrations of vimentin and DAKP1 are associated with aggressive breast tumour phenotypes in Ghanaian women.

PubMed

Arko-Boham, Benjamin; Lomotey, Justice Tanihu; Tetteh, Emmanuel Nomo; Tagoe, Emmanuel Ayitey; Aryee, Nii Ayite; Owusu, Ewurama Ampadu; Okai, Isaac; Blay, Richard Michael; Clegg-Lamptey, Joe-Nat

2017-01-01

.393, p  < 0.05). DAPK1 serum levels weakly correlated with cancer duration ( r  = 0.098, p  = 0.27) and tumour size ( r  = 0.40, p  < 0.05). Serum concentration of Vimentin and DAPK1 are elevated in Ghanaian breast cancer patients. This may be partly responsible for aggressive nature of the disease among the population. Vimentin and DAPK1 should be explored further as potential breast cancer biomarkers in Africans.

Annotating Diseases Using Human Phenotype Ontology Improves Prediction of Disease-Associated Long Non-coding RNAs.

PubMed

Le, Duc-Hau; Dao, Lan T M

2018-05-23

Recently, many long non-coding RNAs (lncRNAs) have been identified and their biological function has been characterized; however, our understanding of their underlying molecular mechanisms related to disease is still limited. To overcome the limitation in experimentally identifying disease-lncRNA associations, computational methods have been proposed as a powerful tool to predict such associations. These methods are usually based on the similarities between diseases or lncRNAs since it was reported that similar diseases are associated with functionally similar lncRNAs. Therefore, prediction performance is highly dependent on how well the similarities can be captured. Previous studies have calculated the similarity between two diseases by mapping exactly each disease to a single Disease Ontology (DO) term, and then use a semantic similarity measure to calculate the similarity between them. However, the problem of this approach is that a disease can be described by more than one DO terms. Until now, there is no annotation database of DO terms for diseases except for genes. In contrast, Human Phenotype Ontology (HPO) is designed to fully annotate human disease phenotypes. Therefore, in this study, we constructed disease similarity networks/matrices using HPO instead of DO. Then, we used these networks/matrices as inputs of two representative machine learning-based and network-based ranking algorithms, that is, regularized least square and heterogeneous graph-based inference, respectively. The results showed that the prediction performance of the two algorithms on HPO-based is better than that on DO-based networks/matrices. In addition, our method can predict 11 novel cancer-associated lncRNAs, which are supported by literature evidence. Copyright © 2018 Elsevier Ltd. All rights reserved.

Macrophage phenotype is associated with disease severity in preterm infants with chronic lung disease.

PubMed

Prince, Lynne R; Maxwell, Nicola C; Gill, Sharonjit K; Dockrell, David H; Sabroe, Ian; McGreal, Eamon P; Kotecha, Sailesh; Whyte, Moira K

2014-01-01

The etiology of persistent lung inflammation in preterm infants with chronic lung disease of prematurity (CLD) is poorly characterized, hampering efforts to stratify prognosis and treatment. Airway macrophages are important innate immune cells with roles in both the induction and resolution of tissue inflammation. To investigate airway innate immune cellular phenotypes in preterm infants with respiratory distress syndrome (RDS) or CLD. Bronchoalveolar lavage (BAL) fluid was obtained from term and preterm infants requiring mechanical ventilation. BAL cells were phenotyped by flow cytometry. Preterm birth was associated with an increase in the proportion of non-classical CD14(+)/CD16(+) monocytes on the day of delivery (58.9 ± 5.8% of total mononuclear cells in preterm vs 33.0 ± 6.1% in term infants, p = 0.02). Infants with RDS were born with significantly more CD36(+) macrophages compared with the CLD group (70.3 ± 5.3% in RDS vs 37.6 ± 8.9% in control, p = 0.02). At day 3, infants born at a low gestational age are more likely to have greater numbers of CD14(+) mononuclear phagocytes in the airway (p = 0.03), but fewer of these cells are functionally polarized as assessed by HLA-DR (p = 0.05) or CD36 (p = 0.05) positivity, suggesting increased recruitment of monocytes or a failure to mature these cells in the lung. These findings suggest that macrophage polarization may be affected by gestational maturity, that more immature macrophage phenotypes may be associated with the progression of RDS to CLD and that phenotyping mononuclear cells in BAL could predict disease outcome.

Phenotypic concordance in familial inflammatory bowel disease (IBD). Results of a nationwide IBD Spanish database.

PubMed

Cabré, Eduard; Mañosa, Míriam; García-Sánchez, Valle; Gutiérrez, Ana; Ricart, Elena; Esteve, Maria; Guardiola, Jordi; Aguas, Mariam; Merino, Olga; Ponferrada, Angel; Gisbert, Javier P; Garcia-Planella, Esther; Ceña, Gloria; Cabriada, José L; Montoro, Miguel; Domènech, Eugeni

2014-07-01

Disease outcome has been found to be poorer in familial inflammatory bowel disease (IBD) than in sporadic forms, but assessment of phenotypic concordance in familial IBD provided controversial results. We assessed the concordance for disease type and phenotypic features in IBD families. Patients with familial IBD were identified from the IBD Spanish database ENEIDA. Families in whom at least two members were in the database were selected for concordance analysis (κ index). Concordance for type of IBD [Crohn's disease (CD) vs. ulcerative colitis (UC)], as well as for disease extent, localization and behaviour, perianal disease, extraintestinal manifestations, and indicators of severe disease (i.e., need for immunosuppressors, biological agents, and surgery) for those pairs concordant for IBD type, were analyzed. 798 out of 11,905 IBD patients (7%) in ENEIDA had familial history of IBD. Complete data of 107 families (231 patients and 144 consanguineous pairs) were available for concordance analyses. The youngest members of the pairs were diagnosed with IBD at a significantly younger age (p<0.001) than the oldest ones. Seventy-six percent of pairs matched up for the IBD type (κ=0.58; 95%CI: 0.42-0.73, moderate concordance). There was no relevant concordance for any of the phenotypic items assessed in both diseases. Familial IBD is associated with diagnostic anticipation in younger individuals. Familial history does not allow predicting any phenotypic feature other than IBD type. Copyright © 2013 European Crohn's and Colitis Organisation. Published by Elsevier B.V. All rights reserved.

Modifier locus mapping of a transgenic F2 mouse population identifies CCDC115 as a novel aggressive prostate cancer modifier gene in humans.

PubMed

Winter, Jean M; Curry, Natasha L; Gildea, Derek M; Williams, Kendra A; Lee, Minnkyong; Hu, Ying; Crawford, Nigel P S

2018-06-11

It is well known that development of prostate cancer (PC) can be attributed to somatic mutations of the genome, acquired within proto-oncogenes or tumor-suppressor genes. What is less well understood is how germline variation contributes to disease aggressiveness in PC patients. To map germline modifiers of aggressive neuroendocrine PC, we generated a genetically diverse F2 intercross population using the transgenic TRAMP mouse model and the wild-derived WSB/EiJ (WSB) strain. The relevance of germline modifiers of aggressive PC identified in these mice was extensively correlated in human PC datasets and functionally validated in cell lines. Aggressive PC traits were quantified in a population of 30 week old (TRAMP x WSB) F2 mice (n = 307). Correlation of germline genotype with aggressive disease phenotype revealed seven modifier loci that were significantly associated with aggressive disease. RNA-seq were analyzed using cis-eQTL and trait correlation analyses to identify candidate genes within each of these loci. Analysis of 92 (TRAMP x WSB) F2 prostates revealed 25 candidate genes that harbored both a significant cis-eQTL and mRNA expression correlations with an aggressive PC trait. We further delineated these candidate genes based on their clinical relevance, by interrogating human PC GWAS and PC tumor gene expression datasets. We identified four genes (CCDC115, DNAJC10, RNF149, and STYXL1), which encompassed all of the following characteristics: 1) one or more germline variants associated with aggressive PC traits; 2) differential mRNA levels associated with aggressive PC traits; and 3) differential mRNA expression between normal and tumor tissue. Functional validation studies of these four genes using the human LNCaP prostate adenocarcinoma cell line revealed ectopic overexpression of CCDC115 can significantly impede cell growth in vitro and tumor growth in vivo. Furthermore, CCDC115 human prostate tumor expression was associated with better survival

Genomic and Biological Characterization of Aggressive and Docile Strains of LCMV Rescued from a Plasmid-Based Reverse Genetics System

PubMed Central

Chen, Minjie; Lan, Shuiyun; Ou, Rong; Price, Graeme E.; Jiang, Hong; de la Torre, Juan Carlos; Moskophidis, Demetrius

2008-01-01

Arenaviruses include several causative agents of hemorrhagic fever disease in humans. In addition, the prototypic arenavirus lymphocytic choriomeningitis virus (LCMV) is a superb model for the study of virus-host interactions, including the basis of viral persistence and associated diseases. The molecular mechanisms concerning the regulation and specific role of viral proteins in modulating arenavirus-host cell interactions associated either with an acute or persistent infection and associated disease remain little understood. Here we report the genomic and biological characterization of LCMV strains Docile (persistent) and Aggressive (not persistent) recovered from cloned cDNA via reverse genetics. Our results confirmed that the cloned viruses accurately recreated the in vivo phenotypes associated with the corresponding natural Docile and Aggressive viral isolates. In addition, we provide evidence that the ability of the Docile strain to persist is determined by the nature of both S and L RNA segments. Thus, our findings provide the foundation for studies aimed at gaining a detailed understanding of viral determinants of LCMV persistence in its natural host that may aid in the development of vaccines to prevent or treat the diseases caused by arenaviruses in humans. PMID:18474558

Pancreatic Autoantibodies Against CUZD1 and GP2 Are Associated with Distinct Clinical Phenotypes of Crohn's Disease.

PubMed

Michaels, Maike Anna; Jendrek, Sebastian Torben; Korf, Tobias; Nitzsche, Thomas; Teegen, Bianca; Komorowski, Lars; Derer, Stefanie; Schröder, Torsten; Baer, Florian; Lehnert, Henrik; Büning, Jürgen; Fellerman, Klaus; Sina, Christian

2015-12-01

Inflammatory bowel disease (IBD) is characterized by a broad spectrum of clinical phenotypes with different outcomes. In the last decades, several IBD-associated autoantibodies have been identified and investigated for their diagnostic relevance. Autoantibodies against the pancreatic glycoproteins (PAB) CUB and zona pellucida-like domains-containing protein 1 (CUZD1), and glycoprotein 2 (GP2) have been demonstrated to possess high specificity for the diagnosis of IBD. Although several studies have shown significant interrelations of anti-GP2 positivity with disease phenotype, associations of clinical phenotypes with anti-CUZD1 are still unknown. The aim was to identify the association of clinical phenotypes with anti-CUZD1 and anti-GP2 in a well-defined German IBD cohort. Patients with IBD (224 patients with Crohn's disease and 136 patients with ulcerative colitis), who were tested for anti-GP2 and anti-CUZD1 immunoglobulin G and immunoglobulin A by indirect immunofluorescence on transfected cells between 2005 and 2013, were included. Serotype and specified phenotypic data were collected in retrospect and statistically analyzed. Both anti-GP2 (P < 0.001) and anti-CUZD1 (P < 0.001) were significantly more prevalent in patients with Crohn's disease than in ulcerative colitis. PAB positivity was associated with ileocolonic disease (P = 0.002), perianal disease (P = 0.011), immunosuppressive treatment (P = 0.036), and ASCA positivity (P = 0.036). Anti-CUZD1 positivity was associated with ileocolonic (P = 0.016) and perianal disease (P = 0.002), whereas anti-GP2 positivity was positively associated with stricturing behavior (P = 0.016). We found distinct clinical phenotypes to be associated with PAB positivity. Therefore, determination of PABs and their subgroup analysis might identify patients with complicated disease behavior. However, the clinical relevance of our findings should be further evaluated in prospective cohorts.

The Effect of Parkinson Disease Tremor Phenotype on Cepstral Peak Prominence and Transglottal Airflow in Vowels and Speech.

PubMed

Burk, Brittany R; Watts, Christopher R

2018-02-19

The physiological manifestations of Parkinson disease are heterogeneous, as evidenced by disease subtypes. Dysphonia has been well documented as an early and progressively significant impairment associated with the disease. The purpose of this study was to investigate how acoustic and aerodynamic measures of vocal function were affected by Parkinson tremor subtype (phenotype) in an effort to better understand the heterogeneity of voice impairment severity in Parkinson disease. This is a prospective case-control study. Thirty-two speakers with Parkinson disease assigned to tremor and nontremor phenotypes and 10 healthy controls were recruited. Sustained vowels and connected speech were recorded from each speaker. Acoustic measures of cepstral peak prominence (CPP) and aerodynamic measures of transglottal airflow (TAF) were calculated from the recorded acoustic and aerodynamic waveforms. Speakers with a nontremor dominant phenotype exhibited significantly (P < 0.05) lower CPP and higher TAF in vowels compared with the tremor dominant phenotype and control speakers, who were not different from each other. No significant group differences were observed for CPP or TAF in connected speech. When producing vowels, participants with nontremor dominant phenotype exhibited reduced phonation periodicity and elevated TAF compared with tremor dominant and control participants. This finding is consistent with differential limb-motor and cognitive impairments between tremor and nontremor phenotypes reported in the extant literature. Results suggest that sustained vowel production may be sensitive to phonatory control as a function of Parkinson tremor phenotype in mild to moderate stages of the disease. Copyright © 2018 The Voice Foundation. Published by Elsevier Inc. All rights reserved.

Phenotype/genotype correlations in Gaucher disease type 1: Clinical and therapeutic implications

DOE Office of Scientific and Technical Information (OSTI.GOV)

Sibille, A.; Eng, C.M.; Kim, S.J.

1993-06-01

Gaucher disease is the most frequent lysosomal storage disease and the most prevalent genetic disease among Ashkenazi Jews. Gaucher disease type 1 is characterized by marked variability of the phenotype and by the absence of neuronopathic involvement. To test the hypothesis that this phenotypic variability was due to genetic compounds of several different mutant alleles, 161 symptomatic patients with Gaucher disease type 1 (> 90% Ashkenazi Jewish) were analyzed for clinical involvement, and their genotypes were determined. Qualitative and quantitative measures of disease involvement included age at onset of the disease manifestations, hepatic and splenic volumes, age at splenectomy, andmore » severity of bony disease. High statistically significant differences (P < .005) were found in each clinical parameter in patients with the N370S/N370S genotype compared with those patients with the N370S/84GG, N370S/L444P, and N370/ genotypes. The symptomatic N370S homozygotes had onset of their disease two to three decades later than patients with the other genotypes. In addition, patients with the latter genotypes have much more severely involved livers, spleens, and bones and had a higher incidence of splenectomy at an earlier age. These predictive genotype analyses provide the basis for genetic care delivery and therapeutic recommendations in patients affected with Gaucher disease type 1. 38 refs., 1 fig., 4 tabs.« less

Alzheimer’s Disease Neuroimaging Initiative biomarkers as quantitative phenotypes: Genetics core aims, progress, and plans

PubMed Central

Saykin, Andrew J.; Shen, Li; Foroud, Tatiana M.; Potkin, Steven G.; Swaminathan, Shanker; Kim, Sungeun; Risacher, Shannon L.; Nho, Kwangsik; Huentelman, Matthew J.; Craig, David W.; Thompson, Paul M.; Stein, Jason L.; Moore, Jason H.; Farrer, Lindsay A.; Green, Robert C.; Bertram, Lars; Jack, Clifford R.; Weiner, Michael W.

2010-01-01

The role of the Alzheimer’s Disease Neuroimaging Initiative Genetics Core is to facilitate the investigation of genetic influences on disease onset and trajectory as reflected in structural, functional, and molecular imaging changes; fluid biomarkers; and cognitive status. Major goals include (1) blood sample processing, genotyping, and dissemination, (2) genome-wide association studies (GWAS) of longitudinal phenotypic data, and (3) providing a central resource, point of contact and planning group for genetics within Alzheimer’s Disease Neuroimaging Initiative. Genome-wide array data have been publicly released and updated, and several neuroimaging GWAS have recently been reported examining baseline magnetic resonance imaging measures as quantitative phenotypes. Other preliminary investigations include copy number variation in mild cognitive impairment and Alzheimer’s disease and GWAS of baseline cerebrospinal fluid biomarkers and longitudinal changes on magnetic resonance imaging. Blood collection for RNA studies is a new direction. Genetic studies of longitudinal phenotypes hold promise for elucidating disease mechanisms and risk, development of therapeutic strategies, and refining selection criteria for clinical trials. PMID:20451875

Disease Model Discovery from 3,328 Gene Knockouts by The International Mouse Phenotyping Consortium

PubMed Central

Meehan, Terrence F.; Conte, Nathalie; West, David B.; Jacobsen, Julius O.; Mason, Jeremy; Warren, Jonathan; Chen, Chao-Kung; Tudose, Ilinca; Relac, Mike; Matthews, Peter; Karp, Natasha; Santos, Luis; Fiegel, Tanja; Ring, Natalie; Westerberg, Henrik; Greenaway, Simon; Sneddon, Duncan; Morgan, Hugh; Codner, Gemma F; Stewart, Michelle E; Brown, James; Horner, Neil; Haendel, Melissa; Washington, Nicole; Mungall, Christopher J.; Reynolds, Corey L; Gallegos, Juan; Gailus-Durner, Valerie; Sorg, Tania; Pavlovic, Guillaume; Bower, Lynette R; Moore, Mark; Morse, Iva; Gao, Xiang; Tocchini-Valentini, Glauco P; Obata, Yuichi; Cho, Soo Young; Seong, Je Kyung; Seavitt, John; Beaudet, Arthur L.; Dickinson, Mary E.; Herault, Yann; Wurst, Wolfgang; de Angelis, Martin Hrabe; Lloyd, K.C. Kent; Flenniken, Ann M; Nutter, Lauryl MJ; Newbigging, Susan; McKerlie, Colin; Justice, Monica J.; Murray, Stephen A.; Svenson, Karen L.; Braun, Robert E.; White, Jacqueline K.; Bradley, Allan; Flicek, Paul; Wells, Sara; Skarnes, William C.; Adams, David J.; Parkinson, Helen; Mallon, Ann-Marie; Brown, Steve D.M.; Smedley, Damian

2017-01-01

Although next generation sequencing has revolutionised the ability to associate variants with human diseases, diagnostic rates and development of new therapies are still limited by our lack of knowledge of function and pathobiological mechanism for most genes. To address this challenge, the International Mouse Phenotyping Consortium (IMPC) is creating a genome- and phenome-wide catalogue of gene function by characterizing new knockout mouse strains across diverse biological systems through a broad set of standardised phenotyping tests, with all mice made readily available to the biomedical community. Analysing the first 3328 genes reveals models for 360 diseases including the first for type C Bernard-Soulier, Bardet-Biedl-5 and Gordon Holmes syndromes. 90% of our phenotype annotations are novel, providing the first functional evidence for 1092 genes and candidates in unsolved diseases such as Arrhythmogenic Right Ventricular Dysplasia 3. Finally, we describe our role in variant functional validation with the 100,000 Genomes and other projects. PMID:28650483

Individual responsiveness to shock and colony-level aggression in honey bees: evidence for a genetic component

PubMed Central

Avalos, Arian; Rodríguez-Cruz, Yoselyn; Giray, Tugrul

2015-01-01

The phenotype of the social group is related to phenotypes of individuals that form that society. We examined how honey bee colony aggressiveness relates to individual response of male drones and foraging workers. Although the natural focus in colony aggression has been on the worker caste, the sterile females engaged in colony maintenance and defense, males carry the same genes. We measured aggressiveness scores of colonies and examined components of individual aggressive behavior in workers and haploid sons of workers from the same colony. We describe for the first time, that males, although they have no stinger, do bend their abdomen (abdominal flexion) in a posture similar to stinging behavior of workers in response to electric shock. Individual worker sting response and movement rates in response to shock were significantly correlated with colony scores. In the case of drones, sons of workers from the same colonies, abdominal flexion significantly correlated but their movement rates did not correlate with colony aggressiveness. Furthermore, the number of workers responding at increasing levels of voltage exhibits a threshold-like response, whereas the drones respond in increasing proportion to shock. We conclude that there are common and caste-specific components to aggressive behavior in honey bees. We discuss implications of these results on social and behavioral regulation and genetics of aggressive response. PMID:25729126

Wilson’s disease in Lebanon and regional countries: Homozygosity and hepatic phenotype predominance

PubMed Central

Barada, Kassem; El Haddad, Aline; Katerji, Meghri; Jomaa, Mustapha; Usta, Julnar

2017-01-01

AIM To determine the phenotypes and predominant disease-causing mutations in Lebanese patients with Wilson’s disease, as compared to regional non-European data. METHODS The clinical profile of 36 patients diagnosed in Lebanon was studied and their mutations were determined by molecular testing. All patients underwent full physical exam, including ophthalmologic slit-lamp examination ultrasound imaging of the liver, as well as measurement of serum ceruloplasmin and 24-h urinary-Cu levels. In addition, genetic screening using PCR followed by sequencing to determine disease-causing mutations and polymorphisms in the ATP7B gene was carried on extracted DNA from patients and immediate family members. Our phenotypic-genotypic findings were then compared to reported mutations in Wilson’s disease patients from regional Arab and non-European countries. RESULTS Patients belonged to extended consanguineous families. The majority were homozygous for the disease-causing mutation, with no predominant mutation identified. The most common mutation, detected in 4 out of 13 families, involved the ATP hinge region and was present in patients from Lebanon, Egypt, Iran and Turkey. Otherwise, mutations in Lebanese patients and those of the region were scattered over 17 exons of ATP7B. While the homozygous exon 12 mutation Trp939Cys was only detected in patients from Lebanon but none from the regional countries, the worldwide common mutation H1069Q was not present in the Lebanese and was rare in the region. Pure hepatic phenotype was predominant in patients from both Lebanon and the region (25%-65%). Furthermore, the majority of patients, including those who were asymptomatic, had evidence of some hepatic dysfunction. Pure neurologic phenotype was rare. CONCLUSION Findings do not support presence of a founder effect. Clinical and genetic screening is recommended for family members with index patients and unexplained hepatic dysfunction. PMID:29085216

Disease phenotype of a ferret CFTR-knockout model of cystic fibrosis

PubMed Central

Sun, Xingshen; Sui, Hongshu; Fisher, John T.; Yan, Ziying; Liu, Xiaoming; Cho, Hyung-Ju; Joo, Nam Soo; Zhang, Yulong; Zhou, Weihong; Yi, Yaling; Kinyon, Joann M.; Lei-Butters, Diana C.; Griffin, Michelle A.; Naumann, Paul; Luo, Meihui; Ascher, Jill; Wang, Kai; Frana, Timothy; Wine, Jeffrey J.; Meyerholz, David K.; Engelhardt, John F.

2010-01-01

Cystic fibrosis (CF) is a recessive disease that affects multiple organs. It is caused by mutations in CFTR. Animal modeling of this disease has been challenging, with species- and strain-specific differences in organ biology and CFTR function influencing the emergence of disease pathology. Here, we report the phenotype of a CFTR-knockout ferret model of CF. Neonatal CFTR-knockout ferrets demonstrated many of the characteristics of human CF disease, including defective airway chloride transport and submucosal gland fluid secretion; variably penetrant meconium ileus (MI); pancreatic, liver, and vas deferens disease; and a predisposition to lung infection in the early postnatal period. Severe malabsorption by the gastrointestinal (GI) tract was the primary cause of death in CFTR-knockout kits that escaped MI. Elevated liver function tests in CFTR-knockout kits were corrected by oral administration of ursodeoxycholic acid, and the addition of an oral proton-pump inhibitor improved weight gain and survival. To overcome the limitations imposed by the severe intestinal phenotype, we cloned 4 gut-corrected transgenic CFTR-knockout kits that expressed ferret CFTR specifically in the intestine. One clone passed feces normally and demonstrated no detectable ferret CFTR expression in the lung or liver. The animals described in this study are likely to be useful tools for dissecting CF disease pathogenesis and developing treatments. PMID:20739752

Disease phenotype of a ferret CFTR-knockout model of cystic fibrosis.

PubMed

Sun, Xingshen; Sui, Hongshu; Fisher, John T; Yan, Ziying; Liu, Xiaoming; Cho, Hyung-Ju; Joo, Nam Soo; Zhang, Yulong; Zhou, Weihong; Yi, Yaling; Kinyon, Joann M; Lei-Butters, Diana C; Griffin, Michelle A; Naumann, Paul; Luo, Meihui; Ascher, Jill; Wang, Kai; Frana, Timothy; Wine, Jeffrey J; Meyerholz, David K; Engelhardt, John F

2010-09-01

Cystic fibrosis (CF) is a recessive disease that affects multiple organs. It is caused by mutations in CFTR. Animal modeling of this disease has been challenging, with species- and strain-specific differences in organ biology and CFTR function influencing the emergence of disease pathology. Here, we report the phenotype of a CFTR-knockout ferret model of CF. Neonatal CFTR-knockout ferrets demonstrated many of the characteristics of human CF disease, including defective airway chloride transport and submucosal gland fluid secretion; variably penetrant meconium ileus (MI); pancreatic, liver, and vas deferens disease; and a predisposition to lung infection in the early postnatal period. Severe malabsorption by the gastrointestinal (GI) tract was the primary cause of death in CFTR-knockout kits that escaped MI. Elevated liver function tests in CFTR-knockout kits were corrected by oral administration of ursodeoxycholic acid, and the addition of an oral proton-pump inhibitor improved weight gain and survival. To overcome the limitations imposed by the severe intestinal phenotype, we cloned 4 gut-corrected transgenic CFTR-knockout kits that expressed ferret CFTR specifically in the intestine. One clone passed feces normally and demonstrated no detectable ferret CFTR expression in the lung or liver. The animals described in this study are likely to be useful tools for dissecting CF disease pathogenesis and developing treatments.

Cassava brown streak disease in Rwanda, the associated viruses and disease phenotypes.

PubMed

Munganyinka, E; Ateka, E M; Kihurani, A W; Kanyange, M C; Tairo, F; Sseruwagi, P; Ndunguru, J

2018-02-01

Cassava brown streak disease (CBSD) was first observed on cassava ( Manihot esculenta ) in Rwanda in 2009. In 2014 eight major cassava-growing districts in the country were surveyed to determine the distribution and variability of symptom phenotypes associated with CBSD, and the genetic diversity of cassava brown streak viruses. Distribution of the CBSD symptom phenotypes and their combinations varied greatly between districts, cultivars and their associated viruses. The symptoms on leaf alone recorded the highest (32.2%) incidence, followed by roots (25.7%), leaf + stem (20.3%), leaf + root (10.4%), leaf + stem + root (5.2%), stem + root (3.7%), and stem (2.5%) symptoms. Analysis by RT-PCR showed that single infections of Ugandan cassava brown streak virus (UCBSV) were most common (74.2% of total infections) and associated with all the seven phenotypes studied. Single infections of Cassava brown streak virus (CBSV) were predominant (15.3% of total infections) in CBSD-affected plants showing symptoms on stems alone. Mixed infections (CBSV + UCBSV) comprised 10.5% of total infections and predominated in the combinations of leaf + stem + root phenotypes. Phylogenetic analysis and the estimates of evolutionary divergence, using partial sequences (210 nt) of the coat protein gene, revealed that in Rwanda there is one type of CBSV and an indication of diverse UCBSV. This study is the first to report the occurrence and distribution of both CBSV and UCBSV based on molecular techniques in Rwanda.

Photoperiod and aggression induce changes in ventral gland compounds exclusively in male Siberian hamsters.

PubMed

Rendon, Nikki M; Soini, Helena A; Scotti, Melissa-Ann L; Weigel, Ellen R; Novotny, Milos V; Demas, Gregory E

2016-05-01

Chemical communication is a critical component of social behavior as it facilitates social encounters, allows for evaluation of the social partner, defines territories and resources, and advertises information such as sex and physiological state of an animal. Odors provide a key source of information about the social environment to rodents; however, studies identifying chemical compounds have thus far focused primarily on few species, particularly the house mouse. Moreover, considerably less attention has been focused on how environmental factors, reproductive phenotype, and behavioral context alter these compounds outside of reproduction. We examined the effects of photoperiod, sex, and social context on chemical communication in the seasonally breeding Siberian hamster. We sampled ventral gland secretions in both male and female hamsters before and after an aggressive encounter and identified changes in a range of volatile compounds. Next, we investigated how photoperiod, reproductive phenotype, and aggression altered ventral gland volatile compound composition across the sexes. Males exhibited a more diverse chemical composition, more sex-specific volatiles, and showed higher levels of excretion compared to females. Individual volatiles were also differentially excreted across photoperiod and reproductive phenotype, as well as differentially altered in response to an aggressive encounter. Female volatile compound composition, in contrast, did not differ across photoperiods or in response to aggression. Collectively, these data contribute to a greater understanding of context-dependent changes in chemical communication in a seasonally breeding rodent. Copyright © 2016 Elsevier Inc. All rights reserved.

Heritability of boldness and aggressiveness in the zebrafish.

PubMed

Ariyomo, Tolulope O; Carter, Mauricio; Watt, Penelope J

2013-03-01

Behavioural traits that are consistent over time and in different contexts are often referred to as personality traits. These traits influence fitness because they play a major role in foraging, reproduction and survival, and so it is assumed that they have little or no additive genetic variance and, consequently, low heritability because, theoretically, they are under strong selection. Boldness and aggressiveness are two personality traits that have been shown to affect fitness. By crossing single males to multiple females, we estimated the heritability of boldness and aggressiveness in the zebrafish, Danio rerio. The additive genetic variance was statistically significant for both traits and the heritability estimates (95 % confidence intervals) for boldness and aggressiveness were 0.76 (0.49, 0.90) and 0.36 (0.10, 0.72) respectively. Furthermore, there were significant maternal effects accounting for 18 and 9 % of the proportion of phenotypic variance in boldness and aggressiveness respectively. This study shows that there is a significant level of genetic variation in this population that would allow these traits to evolve in response to selection.

Gene expression and variation in social aggression by queens of the harvester ant Pogonomyrmex californicus.

PubMed

Helmkampf, Martin; Mikheyev, Alexander S; Kang, Yun; Fewell, Jennifer; Gadau, Jürgen

2016-08-01

A key requirement for social cooperation is the mitigation and/or social regulation of aggression towards other group members. Populations of the harvester ant Pogonomyrmex californicus show the alternate social phenotypes of queens founding nests alone (haplometrosis) or in groups of unrelated yet cooperative individuals (pleometrosis). Pleometrotic queens display an associated reduction in aggression. To understand the proximate drivers behind this variation, we placed foundresses of the two populations into social environments with queens from the same or the alternate population, and measured their behaviour and head gene expression profiles. A proportion of queens from both populations behaved aggressively, but haplometrotic queens were significantly more likely to perform aggressive acts, and conflict escalated more frequently in pairs of haplometrotic queens. Whole-head RNA sequencing revealed variation in gene expression patterns, with the two populations showing moderate differentiation in overall transcriptional profile, suggesting that genetic differences underlie the two founding strategies. The largest detected difference, however, was associated with aggression, regardless of queen founding type. Several modules of coregulated genes, involved in metabolism, immune system and neuronal function, were found to be upregulated in highly aggressive queens. Conversely, nonaggressive queens exhibited a striking pattern of upregulation in chemosensory genes. Our results highlight that the social phenotypes of cooperative vs. solitary nest founding tap into a set of gene regulatory networks that seem to govern aggression level. We also present a number of highly connected hub genes associated with aggression, providing opportunity to further study the genetic underpinnings of social conflict and tolerance. © 2016 John Wiley & Sons Ltd.

Increased aggressive and affiliative display behavior in intrauterine growth restricted (IUGR) baboons

PubMed Central

Huber, Hillary F; Ford, Susan M; Bartlett, Thad Q; Nathanielsz, Peter W

2016-01-01

Background We hypothesized intrauterine growth restricted offspring (IUGR) demonstrate higher rates of aggression and higher dominance ranks than control (CTR) offspring with normal weight at term; if aggressive behavior is advantageous during resource scarcity, developmental programming may lead to an association between aggression and IUGR. Methods We studied 22 group-housed baboons (ages 3-5 years). CTR (male n=8, female n=5) mothers ate ad libitum. IUGR (male n=4, female n=5) mothers were fed 70% feed eaten by CTR mothers during pregnancy and lactation. Results IUGR showed higher rates of aggressive displays (p<0.01) and friendly displays (p<0.02). Dominance ranks and physical aggression rates did not differ between groups. Conclusions High rates of IUGR aggressive display might reflect developmental programming of behavioral phenotypes enhancing fitness. Friendly displays may reflect reconciliation. Potential mechanisms include neurodevelopment and learning. Exploration of IUGR as a risk factor for behavioral patterns is important for developing diagnostic and therapeutic strategies. PMID:25891005

Non-alcoholic fatty liver disease phenotypes in patients with inflammatory bowel disease.

PubMed

Sartini, Alessandro; Gitto, Stefano; Bianchini, Marcello; Verga, Maria Chiara; Di Girolamo, Maria; Bertani, Angela; Del Buono, Mariagrazia; Schepis, Filippo; Lei, Barbara; De Maria, Nicola; Villa, Erica

2018-01-24

Non-alcoholic fatty liver disease (NAFLD) can be detected in up to 33.6% of inflammatory bowel disease (IBD) patients, often in absence of metabolic risk factors. Nevertheless, most of previous studies on such issue were conducted within the IBD population only. The primary aim of this study was to compare clinical and metabolic features of NAFLD in patients with and without IBD (w/o IBD) and to identify specific NAFLD phenotypes within the IBD population. Among 223 NAFLD patients, 78 patients with IBD were younger compared to 145 without (w/o) IBD, were less likely to have altered liver enzymes, had lower mean body weight, smaller waist circumference and lower body mass index (BMI); at the same time, MetS was more prevalent among patients w/o IBD (56.6 vs. 23.1%, p < 0.001). Within IBD population, patients with severe IBD showed more often severe steatosis (S3) at ultrasound (US) (32.1 vs. 16.6%, p = 0.01), compared to mild-to-moderate disease. Independent risk factors for S3 US steatosis in IBD patients at the multivariate logistic regression analysis were: more than 1 IBD relapse per year during disease history (OR 17.3, 95% CI 3.6-84), surgery for IBD (OR 15.1, 95% CI 3.1-73.7) and more extensive intestinal involvement (OR 19.4, 95% CI 3.4-110.9); the ongoing anti-Tumor Necrosis Factor alpha (antiTNFα) therapy was the only independent factor which protect toward the presence of altered liver enzymes (OR 0.15, 95% CI 0-0.8, p = 0.02). In conclusion, NAFLD in IBD patients is different from that in patients w/o IBD, who seem to develop different NAFLD phenotypes according to intestinal disease clinical course. More severe IBD seem to predict the presence of more severe steatosis. Therapy with antiTNFα antibodies could prevent alteration of liver enzymes in such population.

Distinct prion-like strains of amyloid beta implicated in phenotypic diversity of Alzheimer's disease.

PubMed

Cohen, Mark; Appleby, Brian; Safar, Jiri G

2016-01-01

Vast evidence on human prions demonstrates that variable disease phenotypes, rates of propagation, and targeting of distinct brain structures are determined by unique conformers (strains) of pathogenic prion protein (PrP(Sc)). Recent progress in the development of advanced biophysical tools that inventory structural characteristics of amyloid beta (Aβ) in the brain cortex of phenotypically diverse Alzheimer's disease (AD) patients, revealed unique spectrum of oligomeric particles in the cortex of rapidly progressive cases, implicating these structures in variable rates of propagation in the brain, and in distict disease manifestation. Since only ∼30% of phenotypic diversity of AD can be explained by polymorphisms in risk genes, these and transgenic bioassay data argue that structurally distinct Aβ particles play a major role in the diverse pathogenesis of AD, and may behave as distinct prion-like strains encoding diverse phenotypes. From these observations and our growing understanding of prions, there is a critical need for new strain-specific diagnostic strategies for misfolded proteins causing these elusive disorders. Since targeted drug therapy can induce mutation and evolution of prions into new strains, effective treatments of AD will require drugs that enhance clearance of pathogenic conformers, reduce the precursor protein, or inhibit the conversion of precursors into prion-like states.

'Leukodystrophy-like' phenotype in children with myelin oligodendrocyte glycoprotein antibody-associated disease.

PubMed

Hacohen, Yael; Rossor, Thomas; Mankad, Kshitij; Chong, Wk 'Kling'; Lux, Andrew; Wassmer, Evangeline; Lim, Ming; Barkhof, Frederik; Ciccarelli, Olga; Hemingway, Cheryl

2018-04-01

To review the demographics and clinical and paraclinical parameters of children with myelin oligodendrocyte glycoprotein (MOG) antibody-associated relapsing disease. In this UK-based, multicentre study, 31 children with MOG antibody-associated relapsing disease were studied retrospectively. Of the 31 children studied, 14 presented with acute disseminated encephalomyelitis (ADEM); they were younger (mean 4.1y) than the remainder (mean 8.5y) who presented with optic neuritis and/or transverse myelitis (p<0.001). Similarly, children who had an abnormal brain magnetic resonance imaging (MRI) at onset (n=20) were younger than patients with normal MRI at onset (p=0.001) or at follow-up (p<0.001). 'Leukodystrophy-like' MRI patterns of confluent largely symmetrical lesions was seen during the course of the disease in 7 out of 14 children with a diagnosis of ADEM, and was only seen in children younger than 7 years of age. Their disability after a 3-year follow-up was mild to moderate, and most patients continued to relapse, despite disease-modifying treatments. MOG antibody should be tested in children presenting with relapsing neurological disorders associated with confluent, bilateral white matter changes, and distinct enhancement pattern. Children with MOG antibody-associated disease present with age-related differences in phenotypes, with a severe leukoencephalopathy phenotype in the very young and normal intracranial MRI in the older children. This finding suggests a susceptibility of the very young and myelinating brain to MOG antibody-mediated mechanisms of damage. Myelin oligodendrocyte glycoprotein (MOG) antibody-associated demyelination manifest with an age-related phenotype. Children with MOG antibody and 'leukodystrophy-like' imaging patterns tend to have poor response to second-line immunotherapy. © 2017 Mac Keith Press.

Latent Cognitive Phenotypes in De Novo Parkinson's Disease: A Person-Centered Approach.

PubMed

LaBelle, Denise R; Walsh, Ryan R; Banks, Sarah J

2017-08-01

Cognitive impairment is an important aspect of Parkinson's disease (PD), but there is considerable heterogeneity in its presentation. This investigation aims to identify and characterize latent cognitive phenotypes in early PD. Latent class analysis, a data-driven, person-centered, cluster analysis was performed on cognitive data from the Parkinson's Progressive Markers Initiative baseline visit. This analytic method facilitates identification of naturally occurring endophenotypes. Resulting classes were compared across biomarker, symptom, and demographic data. Six cognitive phenotypes were identified. Three demonstrated consistent performance across indicators, representing poor ("Weak-Overall"), average ("Typical-Overall"), and strong ("Strong-Overall") cognition. The remaining classes demonstrated unique patterns of cognition, characterized by "Strong-Memory," "Weak-Visuospatial," and "Amnestic" profiles. The Amnestic class evidenced greater tremor severity and anosmia, but was unassociated with biomarkers linked with Alzheimer's disease. The Weak-Overall class was older and reported more non-motor features associated with cognitive decline, including anxiety, depression, autonomic dysfunction, anosmia, and REM sleep behaviors. The Strong-Overall class was younger, more female, and reported less dysautonomia and anosmia. Classes were unrelated to disease duration, functional independence, or available biomarkers. Latent cognitive phenotypes with focal patterns of impairment were observed in recently diagnosed individuals with PD. Cognitive profiles were found to be independent of traditional biomarkers and motoric indices of disease progression. Only globally impaired class was associated with previously reported indicators of cognitive decline, suggesting this group may drive the effects reported in studies using variable-based analysis. Longitudinal and neuroanatomical characterization of classes will yield further insight into the evolution of cognitive

Similar Progression of Morphological and Metabolic Phenotype in R6/2 Mice with Different CAG Repeats Revealed by In Vivo Magnetic Resonance Imaging and Spectroscopy.

PubMed

Sawiak, Stephen J; Wood, Nigel I; Morton, A Jennifer

2016-10-01

Huntington's disease (HD) is caused by an unstable polyglutamine (CAG) repeat in the HD gene, whereby a CAG repeat length greater than ∼36 leads to the disease. In HD patients, longer repeats correlate with more severe disease and earlier death. This is also seen in R6/2 mice carrying repeat lengths up to ∼200. Paradoxically, R6/2 mice with repeat lengths >300 have a less aggressive phenotype and longer lifespan than those with shorter repeats. The mechanism underlying this phenomenon is unknown. To investigate the consequences of longer repeat lengths on structural changes in the brains of R6/2 mice, especially with regard to progressive atrophy. We used longitudinal in vivo magnetic resonance imaging (MRI) and spectroscopy (MRS) to compare pathological changes in two strains of R6/2 mice, one with a rapidly progressing disease (250 CAG repeats), and the other with a less aggressive phenotype (350 CAG repeats). We found significant progressive brain atrophy in both 250 and 350 CAG repeat mice, as well as changes in metabolites (glutamine/glutamate, choline and aspartate). Although similar in magnitude, atrophy in the brains of 350 CAG R6/2 mice progressed more slowly than that seen in 250 CAG mice, in line with the milder phenotype and longer lifespan. Interestingly, significant atrophy was detectable in 350 CAG mice as early as 8-12 weeks of age, although behavioural abnormalities in these mice are not apparent before 25-30 weeks. This finding fits well with human data from the PREDICT-HD and TRACK-HD project, where reductions in brain volume were found 10 years in advance of the onset of symptoms. The similar brain atrophy with a mismatch between onset of brain atrophy and behavioural phenotype in HD mice with 350 repeats will make this mouse particularly useful for modelling early stages of HD pathology.

Effect of phenotype on health care costs in Crohn's disease: A European study using the Montreal classification.

PubMed

Odes, Selwyn; Vardi, Hillel; Friger, Michael; Wolters, Frank; Hoie, Ole; Moum, Bjørn; Bernklev, Tomm; Yona, Hagit; Russel, Maurice; Munkholm, Pia; Langholz, Ebbe; Riis, Lene; Politi, Patrizia; Bondini, Paolo; Tsianos, Epameinondas; Katsanos, Kostas; Clofent, Juan; Vermeire, Severine; Freitas, João; Mouzas, Iannis; Limonard, Charles; O'Morain, Colm; Monteiro, Estela; Fornaciari, Giovanni; Vatn, Morten; Stockbrugger, Reinhold

2007-12-01

Crohn's disease (CD) is a chronic inflammation of the gastrointestinal tract associated with life-long high health care costs. We aimed to determine the effect of disease phenotype on cost. Clinical and economic data of a community-based CD cohort with 10-year follow-up were analyzed retrospectively in relation to Montreal classification phenotypes. In 418 patients, mean total costs of health care for the behavior phenotypes were: nonstricturing-nonpenetrating 1690, stricturing 2081, penetrating 3133 and penetrating-with-perianal-fistula 3356 €/patient-phenotype-year (P<0.001), and mean costs of surgical hospitalization 215, 751, 1293 and 1275 €/patient-phenotype-year respectively (P<0.001). Penetrating-with-perianal-fistula patients incurred significantly greater expenses than penetrating patients for total care, diagnosis and drugs, but not surgical hospitalization. Total costs were similar in the location phenotypes: ileum 1893, colon 1748, ileo-colonic 2010 and upper gastrointestinal tract 1758 €/patient-phenotype-year, but surgical hospitalization costs differed significantly, 558, 209, 492 and 542 €/patient-phenotype-year respectively (P<0.001). By multivariate analysis, the behavior phenotype significantly impacted total, medical and surgical hospitalization costs, whereas the location phenotype affected only surgical costs. Younger age at diagnosis predicted greater surgical expenses. Behavior is the dominant phenotype driving health care cost. Use of the Montreal classification permits detection of cost differences caused by perianal fistula.

Phenotype variability and allelic heterogeneity in KMT2B-Associated disease.

PubMed

Kawarai, Toshitaka; Miyamoto, Ryosuke; Nakagawa, Eiji; Koichihara, Reiko; Sakamoto, Takashi; Mure, Hideo; Morigaki, Ryoma; Koizumi, Hidetaka; Oki, Ryosuke; Montecchiani, Celeste; Caltagirone, Carlo; Orlacchio, Antonio; Hattori, Ayako; Mashimo, Hideaki; Izumi, Yuishin; Mezaki, Takahiro; Kumada, Satoko; Taniguchi, Makoto; Yokochi, Fusako; Saitoh, Shinji; Goto, Satoshi; Kaji, Ryuji

2018-04-05

Mutations in Lysine-Specific Histone Methyltransferase 2B gene (KMT2B) have been reported to be associated with complex early-onset dystonia. Almost all reported KMT2B mutations occurred de novo in the paternal germline or in the early development of the patient. We describe clinico-genetic features on four Japanese patients with novel de novo mutations and demonstrate the phenotypic spectrum of KMT2B mutations. We performed genetic studies, including trio-based whole exome sequencing (WES), in a cohort of Japanese patients with a seemingly sporadic early-onset generalized combined dystonia. Potential effects by the identified nucleotide variations were evaluated biologically. Genotype-phenotype correlations were also investigated. Four patients had de novo heterozygous mutations in KMT2B, c.309delG, c.1656dupC, c.3325_3326insC, and c.5636delG. Biological analysis of KMT2B mRNA levels showed a reduced expression of mutant transcript frame. All patients presented with motor milestone delay, microcephaly, mild psychomotor impairment, childhood-onset generalized dystonia and superimposed choreoathetosis or myoclonus. One patient cannot stand due to axial hypotonia associated with cerebellar dysfunction. Three patients had bilateral globus pallidal deep brain stimulation (DBS) with excellent or partial response. We further demonstrate the allelic heterogeneity and phenotypic variations of KMT2B-associated disease. Haploinsufficiency is one of molecular pathomechanisms underlying the disease. Cardinal clinical features include combined dystonia accompanying mild psychomotor disability. Cerebellum would be affected in KMT2B-associated disease. Copyright © 2018 Elsevier Ltd. All rights reserved.

Can we Predict Disease Course with Clinical Factors?

PubMed

Vegh, Zsuzsanna; Kurti, Zsuzsanna; Golovics, Petra A; Lakatos, Peter L

2018-01-01

The disease phenotype at diagnosis and the disease course of Crohn's disease (CD) and ulcerative colitis (UC) show remarkable heterogeneity across patients. This review aims to summarize the currently available evidence on clinical and some environmental predictive factors, which clinicians should evaluate in the everyday practice together with other laboratory and imaging data to prevent disease progression, enable a more personalized therapy, and avoid negative disease outcomes. In recent population-based epidemiological and referral cohort studies, the evolution of disease phenotype of CD and UC varied significantly. Most CD and severe UC patients still require hospitalization or surgery/colectomy during follow-up. A change in the natural history of inflammatory bowel diseases (IBD) with improved outcomes in parallel with tailored positioning of aggressive immunomodulator and biological therapy has been suspected. According to the currently available literature, it is of major importance to refer IBD cases at risk for adverse disease outcomes as early during the disease course as possible. Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.org.

Sequential social experiences interact to modulate aggression but not brain gene expression in the honey bee (Apis mellifera).

PubMed

Rittschof, Clare C

2017-01-01

In highly structured societies, individuals behave flexibly and cooperatively in order to achieve a particular group-level outcome. However, even in social species, environmental inputs can have long lasting effects on individual behavior, and variable experiences can even result in consistent individual differences and constrained behavioral flexibility. Despite the fact that such constraints on behavior could have implications for behavioral optimization at the social group level, few studies have explored how social experiences accumulate over time, and the mechanistic basis of these effects. In the current study, I evaluate how sequential social experiences affect individual and group level aggressive phenotypes, and individual brain gene expression, in the highly social honey bee ( Apis mellifera ). To do this, I combine a whole colony chronic predator disturbance treatment with a lab-based manipulation of social group composition. Compared to the undisturbed control, chronically disturbed individuals show lower aggression levels overall, but also enhanced behavioral flexibility in the second, lab-based social context. Disturbed bees display aggression levels that decline with increasing numbers of more aggressive, undisturbed group members. However, group level aggressive phenotypes are similar regardless of the behavioral tendencies of the individuals that make up the group, suggesting a combination of underlying behavioral tendency and negative social feedback influences the aggressive behaviors displayed, particularly in the case of disturbed individuals. An analysis of brain gene expression showed that aggression related biomarker genes reflect an individual's disturbance history, but not subsequent social group experience or behavioral outcomes. In highly social animals with collective behavioral phenotypes, social context may mask underlying variation in individual behavioral tendencies. Moreover, gene expression patterns may reflect

Frailty and sarcopenia as the basis for the phenotypic manifestation of chronic diseases in older adults.

PubMed

Angulo, Javier; El Assar, Mariam; Rodríguez-Mañas, Leocadio

2016-08-01

Frailty is a functional status that precedes disability and is characterized by decreased functional reserve and increased vulnerability. In addition to disability, the frailty phenotype predicts falls, institutionalization, hospitalization and mortality. Frailty is the consequence of the interaction between the aging process and some chronic diseases and conditions that compromise functional systems and finally produce sarcopenia. Many of the clinical manifestations of frailty are explained by sarcopenia which is closely related to poor physical performance. Reduced regenerative capacity, malperfusion, oxidative stress, mitochondrial dysfunction and inflammation compose the sarcopenic skeletal muscle alterations associated to the frailty phenotype. Inflammation appears as a common determinant for chronic diseases, sarcopenia and frailty. The strategies to prevent the frailty phenotype include an adequate amount of physical activity and exercise as well as pharmacological interventions such as myostatin inhibitors and specific androgen receptor modulators. Cell response to stress pathways such as Nrf2, sirtuins and klotho could be considered as future therapeutic interventions for the management of frailty phenotype and aging-related chronic diseases. Copyright © 2016 Elsevier Ltd. All rights reserved.

Genotype-phenotype variations in five Spanish families with Norrie disease or X-linked FEVR.

PubMed

Riveiro-Alvarez, Rosa; Trujillo-Tiebas, Maria José; Gimenez-Pardo, Ascension; Garcia-Hoyos, Maria; Cantalapiedra, Diego; Lorda-Sanchez, Isabel; Rodriguez de Alba, Marta; Ramos, Carmen; Ayuso, Carmen

2005-09-02

Norrie disease (OMIM 310600) is a rare X-linked disorder characterized by congenital blindness in males. Approximately 40 to 50% of the cases develop deafness and mental retardation. X-linked familial exudative vitreoretinopathy (XL-FEVR) is a hereditary ocular disorder characterized by a failure of peripheral retinal vascularization. Both X-linked disorders are due to mutations in the NDP gene, which encodes a 133 amino acid protein called Norrin, but autosomal recessive (AR) and autosomal dominant (AD) forms of FEVR have also been described. In this study, we report the molecular findings and the related phenotype in five Spanish families affected with Norrie disease or XL-FEVR due to mutations of the NDP gene. The study was conducted in 45 subjects from five Spanish families. These families were clinically diagnosed with Norrie disease or similar conditions. The three exons of the NDP gene were analyzed by automatic DNA sequencing. Haplotype analyses were also performed. Two new nonsense mutations, apart from other mutations previously described in the NDP gene, were found in those patients affected with ND or X-linked FEVR. An important genotype-phenotype variation was found in relation to the different mutations of the NDP gene. In fact, the same mutation may be responsible for different phenotypes. We speculate that there might be other molecular factors that interact in the retina with Norrin, which contribute to the resultant phenotypes.

Genotypic and phenotypic predictors of inflammation in patients with chronic kidney disease.

PubMed

Luttropp, Karin; Debowska, Malgorzata; Lukaszuk, Tomasz; Bobrowski, Leon; Carrero, Juan Jesus; Qureshi, Abdul Rashid; Stenvinkel, Peter; Lindholm, Bengt; Waniewski, Jacek; Nordfors, Louise

2016-12-01

In complex diseases such as chronic kidney disease (CKD), the risk of clinical complications is determined by interactions between phenotypic and genotypic factors. However, clinical epidemiological studies rarely attempt to analyse the combined effect of large numbers of phenotype and genotype features. We have recently shown that the relaxed linear separability (RLS) model of feature selection can address such complex issues. Here, it is applied to identify risk factors for inflammation in CKD. The RLS model was applied in 225 CKD stage 5 patients sampled in conjunction with dialysis initiation. Fifty-seven anthropometric or biochemical measurements and 79 genetic polymorphisms were entered into the model. The model was asked to identify phenotypes and genotypes that, when combined, could separate inflamed from non-inflamed patients. Inflammation was defined as a high-sensitivity C-reactive protein concentration above the median (5 mg/L). Among the 60 genotypic and phenotypic features predicting inflammation, 31 were genetic. Among the 10 strongest predictors of inflammation, 8 were single nucleotide polymorphisms located in the NAMPT, CIITA, BMP2 and PIK3CB genes, whereas fibrinogen and bone mineral density were the only phenotypic biomarkers. These results indicate a larger involvement of hereditary factors in inflammation than might have been expected and suggest that inclusion of genotype features in risk assessment studies is critical. The RLS model demonstrates that inflammation in CKD is determined by an extensive panel of factors and may prove to be a suitable tool that could enable a much-needed multifactorial approach as opposed to the commonly utilized single-factor analysis. © The Author 2016. Published by Oxford University Press on behalf of ERA-EDTA. All rights reserved.

Medullary Thyroid Carcinoma in MEN2A: ATA Moderate- or High-Risk RET Mutations Do Not Predict Disease Aggressiveness.

PubMed

Voss, Rachel K; Feng, Lei; Lee, Jeffrey E; Perrier, Nancy D; Graham, Paul H; Hyde, Samuel M; Nieves-Munoz, Frances; Cabanillas, Maria E; Waguespack, Steven G; Cote, Gilbert J; Gagel, Robert F; Grubbs, Elizabeth G

2017-08-01

High-risk RET mutations (codon 634) are associated with earlier development of medullary thyroid carcinoma (MTC) and presumed increased aggressiveness compared with moderate-risk RET mutations. To determine whether high-risk RET mutations are more aggressive. Retrospective cohort study using institutional multiple endocrine neoplasia type 2 registry. Tertiary cancer care center. Patients with MTC and moderate- or high-risk germline RET mutation. None (observational study). Proxies for aggressiveness were overall survival (OS) and time to distant metastatic disease (DMD). A total of 127 moderate-risk and 135 high-risk patients were included (n = 262). Median age at diagnosis was 42.3 years (range, 6.4 to 86.4 years; mean, 41.6 years) for moderate-risk mutations and 23.0 years (range, 3.7 to 66.8 years; mean, 25.6 years) for high-risk mutations (P < 0.0001). Moderate-risk patients had more T3/T4 tumors at diagnosis (P = 0.03), but there was no significant difference for N or M stage and no significant difference in OS (P = 0.40). From multivariable analysis for OS, increasing age [hazard ratio (HR), 1.05/y; 95% confidence interval (CI), 1.03 to 1.08], T3/T4 tumor (HR, 2.73; 95% CI, 1.22 to 6.11), and M1 status at diagnosis (HR, 3.93; 95% CI, 1.61 to 9.59) were significantly associated with worse OS but high-risk mutation was not (P = 0.40). No significant difference was observed for development of DMD (P = 0.33). From multivariable analysis for DMD, only N1 status at diagnosis was significant (HR, 2.10; 95% CI, 1.03 to 4.27). Patients with high- and moderate-risk RET mutations had similar OS and development of DMD after MTC diagnosis and therefore similarly aggressive clinical courses. High-risk connotes increased disease aggressiveness; thus, future guidelines should consider RET mutation classification by disease onset (early vs late) rather than by risk (high vs moderate). Copyright © 2017 Endocrine Society

Cardiac Phenotype of Prehypertrophic Fabry Disease.

PubMed

Nordin, Sabrina; Kozor, Rebecca; Baig, Shanat; Abdel-Gadir, Amna; Medina-Menacho, Katia; Rosmini, Stefania; Captur, Gabriella; Tchan, Michel; Geberhiwot, Tarekegn; Murphy, Elaine; Lachmann, Robin; Ramaswami, Uma; Edwards, Nicola C; Hughes, Derralynn; Steeds, Richard P; Moon, James C

2018-06-01

Fabry disease (FD) is a rare and treatable X-linked lysosomal storage disorder. Cardiac involvement determines outcomes; therefore, detecting early changes is important. Native T1 by cardiovascular magnetic resonance is low, reflecting sphingolipid storage. Early phenotype development is familiar in hypertrophic cardiomyopathy but unexplored in FD. We explored the prehypertrophic cardiac phenotype of FD and the role of storage. A prospective, international multicenter observational study of 100 left ventricular hypertrophy-negative FD patients (mean age: 39±15 years; 19% male) and 35 age- and sex-matched healthy volunteers (mean age: 40±14 years; 25% male) who underwent cardiovascular magnetic resonance, including native T1 and late gadolinium enhancement, and 12-lead ECG. In FD, 41% had a low native T1 using a single septal region of interest, but this increased to 59% using a second slice because early native T1 lowering was patchy. ECG abnormalities were present in 41% and twice as common with low native T1 (53% versus 24%; P =0.005). When native T1 was low, left ventricular maximum wall thickness, indexed mass, and ejection fraction were higher (maximum wall thickness 9±1.5 versus 8±1.4 mm, P <0.005; indexed left ventricular mass 63±10 versus 58±9 g/m 2 , P <0.05; and left ventricular ejection fraction 73±8% versus 69±7%, P <0.01). Late gadolinium enhancement was more likely when native T1 was low (27% versus 6%; P =0.01). FD had higher maximal apical fractal dimensions compared with healthy volunteers (1.27±0.06 versus 1.24±0.04; P <0.005) and longer anterior mitral valve leaflets (23±2 mm versus 21±3 mm; P <0.005). There is a detectable prehypertrophic phenotype in FD consisting of storage (low native T1), structural, functional, and ECG changes. © 2018 The Authors.

RB loss contributes to aggressive tumor phenotypes in MYC-driven triple negative breast cancer

PubMed Central

Knudsen, Erik S; McClendon, A Kathleen; Franco, Jorge; Ertel, Adam; Fortina, Paolo; Witkiewicz, Agnieszka K

2015-01-01

Triple negative breast cancer (TNBC) is characterized by multiple genetic events occurring in concert to drive pathogenic features of the disease. Here we interrogated the coordinate impact of p53, RB, and MYC in a genetic model of TNBC, in parallel with the analysis of clinical specimens. Primary mouse mammary epithelial cells (mMEC) with defined genetic features were used to delineate the combined action of RB and/or p53 in the genesis of TNBC. In this context, the deletion of either RB or p53 alone and in combination increased the proliferation of mMEC; however, the cells did not have the capacity to invade in matrigel. Gene expression profiling revealed that loss of each tumor suppressor has effects related to proliferation, but RB loss in particular leads to alterations in gene expression associated with the epithelial-to-mesenchymal transition. The overexpression of MYC in combination with p53 loss or combined RB/p53 loss drove rapid cell growth. While the effects of MYC overexpression had a dominant impact on gene expression, loss of RB further enhanced the deregulation of a gene expression signature associated with invasion. Specific RB loss lead to enhanced invasion in boyden chambers assays and gave rise to tumors with minimal epithelial characteristics relative to RB-proficient models. Therapeutic screening revealed that RB-deficient cells were particularly resistant to agents targeting PI3K and MEK pathway. Consistent with the aggressive behavior of the preclinical models of MYC overexpression and RB loss, human TNBC tumors that express high levels of MYC and are devoid of RB have a particularly poor outcome. Together these results underscore the potency of tumor suppressor pathways in specifying the biology of breast cancer. Further, they demonstrate that MYC overexpression in concert with RB can promote a particularly aggressive form of TNBC. PMID:25602521

CpG island methylation phenotype (CIMP) in oral cancer: associated with a marked inflammatory response and less aggressive tumour biology.

PubMed

Shaw, Richard J; Hall, Gillian L; Lowe, Derek; Bowers, Naomi L; Liloglou, Triantafillos; Field, John K; Woolgar, Julia A; Risk, Janet M

2007-10-01

Studies in several tumour sites highlight the significance of the CpG island methylation phenotype (CIMP), with distinct features of histology, biological aggression and outcome. We utilise pyrosequencing techniques of quantitative methylation analysis to investigate the presence of CIMP in oral squamous cell carcinoma (OSCC) for the first time, and evaluate its correlation with allelic imbalance, pathology and clinical behaviour. Tumour tissue, control tissue and PBLs were obtained from 74 patients with oral squamous cell carcinoma. Pyrosequencing was used to analyse methylation patterns in 75-200 bp regions of the CpG rich gene promoters of 10 genes with a broad range of cellular functions. Allelic imbalance was investigated using a multiplexed panel of 11 microsatellite markers. Corresponding variables, histopathological staging and grading were correlated with these genetic and epigenetic aberrations. A cluster of tumours with a greater degree of promoter methylation than would be predicted by chance alone (P=0.001) were designated CIMP+ve. This group had less aggressive tumour biology in terms of tumour thickness (p=0.015) and nodal metastasis (P=0.012), this being apparently independent of tumour diameter. Further, it seems that these CIMP+ve tumours excited a greater host inflammatory response (P=0.019). The exact mechanisms underlying CIMP remain obscure but the association with a greater inflammatory host response supports existing theories relating these features in other tumour sites. As CIMP has significant associations with other well documented prognostic indicators, it may prove beneficial to include methylation analyses in molecular risk modelling of tumours.

House-to-house, community-wide chemoprophylaxis for meningococcal disease: an aggressive approach to disease prevention.

PubMed Central

Chester, T J; Jacobson, J A; Caviness, E L; Wolf, F S

1977-01-01

During an outbreak of meningococcal disease in a rural community in southwest Alabama in 1975-76, we undertook an aggressive campaign of house-to-house, community-wide chemoprophylaxis distribution. Over a three-day period 1,045 households were visited and 4,454 persons received medication. The 1970 census lists 967 households with 4,067 persons residing in the community. To evaluate compliance we cultured for meningococcal carriers before and after the chemoprophylaxis campaign. All of the previously discovered carriers were negative three weeks after the drug distribution. The cost of the campaign ($26,520) was very small compared to the possible benefit achieved. The methods of planning and executing this campaign are described in detail. PMID:410314

Experimental Functional Analysis of Aggression in Children with Angelman Syndrome

ERIC Educational Resources Information Center

Strachan, Rachel; Shaw, Rebecca; Burrow, Caroline; Horsler, Kate; Allen, Debbie; Oliver, Chris

2009-01-01

Background: Kinship theory suggests that genomic imprinting could account for phenotypic behaviors that increase (in the case of Angelman syndrome) or decrease (for Prader-Willi syndrome) the drive to access social resources (adult contact) depending on the imprinting parent-of-origin. Difficult to manage behaviors, such as aggression that is…

Mild expression differences of MECP2 influencing aggressive social behavior.

PubMed

Tantra, Martesa; Hammer, Christian; Kästner, Anne; Dahm, Liane; Begemann, Martin; Bodda, Chiranjeevi; Hammerschmidt, Kurt; Giegling, Ina; Stepniak, Beata; Castillo Venzor, Aracely; Konte, Bettina; Erbaba, Begun; Hartmann, Annette; Tarami, Asieh; Schulz-Schaeffer, Walter; Rujescu, Dan; Mannan, Ashraf U; Ehrenreich, Hannelore

2014-05-01

The X-chromosomal MECP2/Mecp2 gene encodes methyl-CpG-binding protein 2, a transcriptional activator and repressor regulating many other genes. We discovered in male FVB/N mice that mild (~50%) transgenic overexpression of Mecp2 enhances aggression. Surprisingly, when the same transgene was expressed in C57BL/6N mice, transgenics showed reduced aggression and social interaction. This suggests that Mecp2 modulates aggressive social behavior. To test this hypothesis in humans, we performed a phenotype-based genetic association study (PGAS) in >1000 schizophrenic individuals. We found MECP2 SNPs rs2239464 (G/A) and rs2734647 (C/T; 3'UTR) associated with aggression, with the G and C carriers, respectively, being more aggressive. This finding was replicated in an independent schizophrenia cohort. Allele-specific MECP2 mRNA expression differs in peripheral blood mononuclear cells by ~50% (rs2734647: C > T). Notably, the brain-expressed, species-conserved miR-511 binds to MECP2 3'UTR only in T carriers, thereby suppressing gene expression. To conclude, subtle MECP2/Mecp2 expression alterations impact aggression. While the mouse data provides evidence of an interaction between genetic background and mild Mecp2 overexpression, the human data convey means by which genetic variation affects MECP2 expression and behavior.

Phenotype and Clinical Course of Inflammatory Bowel Disease with Co-Existent Celiac Disease.

PubMed

Tse, Chung Sang; Deepak, Parakkal; De La Fuente, Jaime; Bledsoe, Adam C; Larson, Joseph J; Murray, Joseph A; Papadakis, Konstantinos A

2018-05-07

Inflammatory bowel diseases, principally Crohn's disease and ulcerative colitis, and celiac disease are among the most common immune-mediated gastrointestinal diseases. We aim to elucidate the clinical course and outcomes of patients with concomitant inflammatory bowel disease and celiac disease, a unique population that remains scarcely studied to date. A retrospective matched case-control study of adults with coexistent inflammatory bowel disease and celiac disease was performed at a tertiary referral institution in North America. Logistic regression and Kaplan-Meier curves compared disease characteristics and clinical outcomes of the two groups. A total of 342 inflammatory bowel disease patients were included in this study, of which 114 had coexistent celiac disease and 228 did not. Patients with coexistent inflammatory bowel disease and celiac disease had higher rates of primary sclerosing cholangitis (19.3% vs 5.7%; odds ratio, 4.4; 95% confidence interval, 2.1-9.4; p<0.001), extensive ulcerative colitis (78.1% vs 59.0%; odds ratio, 2.8; 95% confidence interval 1.5-5.5, p=0.002), and family history of celiac disease (10.5% vs 3.5%; odds ratio 3.2; 95% confidence interval 1.3-8.2; p=0.01), compared to patients without concomitant celiac disease. Patients with inflammatory bowel disease with concomitant celiac disease have unique phenotypic features compared to non-celiac inflammatory bowel disease, with higher risks for colitis-related hospitalizations, extensive colitis, and primary sclerosing cholangitis. Increased recognition of coexistent IBD and celiac disease can prompt clinicians to investigate for concomitant disease sooner, particularly in patients with seemingly refractory disease.

A Systematic Review of the Huntington Disease-Like 2 Phenotype.

PubMed

Anderson, David G; Walker, Ruth H; Connor, Myles; Carr, Jonathan; Margolis, Russell L; Krause, Amanda

2017-01-01

Huntington Disease-like 2 (HDL2) is a neurodegenerative disorder similar to Huntington Disease (HD) in its clinical phenotype, genetic characteristics, neuropathology and longitudinal progression. Proposed specific differences include an exclusive African ancestry, lack of eye movement abnormalities, increased Parkinsonism, and acanthocytes in HDL2. The objective was to determine the similarities and differences between HD and HDL2 by establishing the clinical phenotype of HDL2 with the published cases. A literature review of all clinically described cases of HDL2 until the end of 2016 was performed and a descriptive analysis was carried out. Sixty-nine new cases were described between 2001 and 2016. All cases had likely African ancestry, and most were found in South Africa and the USA. Many features were found to be similar to HD, including a strong negative correlation between repeat length and age of onset. Chorea was noted in 48/57 cases (84%). Dementia was reported in 74% patients, and Parkinsonism in 37%. Psychiatric features were reported in 44 out of 47 cases. Patients with chorea had lower expanded repeat lengths compared to patients without chorea. Eye movements were described in 19 cases, 8 were abnormal. Acanthocytes were detected in 4 of the 13 patients tested. Nineteen out of 20 MRIs were reported as abnormal with findings similar to HD. This review clarifies some aspects of the HDL2 phenotype and highlights others which require further investigation. Features that are unique to HDL2 have been documented in a minority of subjects and require prospective validation.

HMGB1 targeting by ethyl pyruvate suppresses malignant phenotype of human mesothelioma.

PubMed

Pellegrini, Laura; Xue, Jiaming; Larson, David; Pastorino, Sandra; Jube, Sandro; Forest, Kelly H; Saad-Jube, Zeyana Salim; Napolitano, Andrea; Pagano, Ian; Negi, Vishal S; Bianchi, Marco E; Morris, Paul; Pass, Harvey I; Gaudino, Giovanni; Carbone, Michele; Yang, Haining

2017-04-04

Human malignant mesothelioma (MM) is an aggressive cancer linked to asbestos and erionite exposure. We previously reported that High-Mobility Group Box-1 protein (HMGB1), a prototypic damage-associated molecular pattern, drives MM development and sustains MM progression. Moreover, we demonstrated that targeting HMGB1 inhibited MM cell growth and motility in vitro, reduced tumor growth in vivo, and prolonged survival of MM-bearing mice. Ethyl pyruvate (EP), the ethyl ester of pyruvic acid, has been shown to be an effective HMGB1 inhibitor in inflammation-related diseases and several cancers. Here, we studied the effect of EP on the malignant phenotype of MM cells in tissue culture and on tumor growth in vivo using an orthotopic MM xenograft model. We found that EP impairs HMGB1 secretion by MM cells leading to reduced RAGE expression and NF-κB activation. As a consequence, EP impaired cell motility, cell proliferation, and anchorage-independent growth of MM cells. Moreover, EP reduced HMGB1 serum levels in mice and inhibited the growth of MM xenografts.Our results indicate that EP effectively hampers the malignant phenotype of MM, offering a novel potential therapeutic approach to patients afflicted with this dismal disease.

Comparative evaluation of serum C-reactive protein levels in chronic and aggressive periodontitis patients and association with periodontal disease severity.

PubMed

Goyal, Lata; Bey, Afshan; Gupta, N D; Sharma, Vivek Kumar

2014-10-01

C-reactive protein (CRP) is an acute-phase reactant and has been proved to be a significant predictor of future cardiovascular events. Recent studies have demonstrated a correlation between periodontitis and elevated CRP levels. However, most of the studies have focused on chronic periodontitis and very few studies are done in patients with aggressive periodontitis. The aim of this study was to determine and compare the relative levels of serum CRP in aggressive and chronic periodontitis patients. A total of 75 systemically healthy subjects were divided into three groups: Group I, nonperiodontitis subjects; group II, chronic generalized periodontitis patients and group III, generalized aggressive periodontitis patients. All participants were subjected to quantitative CRP analysis using enzyme-linked immunosorbent assay. Mean CRP levels were significantly greater in both group II and III as compared to group I and group III having greater level than group II. Furthermore, CRP levels positively correlated with the amount of periodontal destruction as measured by probing depth and clinical attachment loss. The present study indicates a positive correlation between CRP and periodontal disease severity with particular concern in younger individuals that could be a possible underlying pathway in the association between periodontal disease and the observed higher risk for cardiovascular disease in periodontitis patients.

Psychophysiological correlates of aggression and violence: an integrative review.

PubMed

Patrick, Christopher J

2008-08-12

This paper reviews existing psychophysiological studies of aggression and violent behaviour including research employing autonomic, electrocortical and neuroimaging measures. Robust physiological correlates of persistent aggressive behaviour evident in this literature include low baseline heart rate, enhanced autonomic reactivity to stressful or aversive stimuli, enhanced EEG slow wave activity, reduced P300 brain potential response and indications from structural and functional neuroimaging studies of dysfunction in frontocortical and limbic brain regions that mediate emotional processing and regulation. The findings are interpreted within a conceptual framework that draws on two integrative models in the literature. The first is a recently developed hierarchical model of impulse control (externalizing) problems, in which various disinhibitory syndromes including aggressive and addictive behaviours of different kinds are seen as arising from common as well as distinctive aetiologic factors. This model represents an approach to organizing these various interrelated phenotypes and investigating their common and distinctive aetiologic substrates. The other is a neurobiological model that posits impairments in affective regulatory circuits in the brain as a key mechanism for impulsive aggressive behaviour. This model provides a perspective for integrating findings from studies employing different measures that have implicated varying brain structures and physiological systems in violent and aggressive behaviour.

Rheumatoid Arthritis-Associated Interstitial Lung Disease and Idiopathic Pulmonary Fibrosis: Shared Mechanistic and Phenotypic Traits Suggest Overlapping Disease Mechanisms.

PubMed

Paulin, Francisco; Doyle, Tracy J; Fletcher, Elaine A; Ascherman, Dana P; Rosas, Ivan O

2015-01-01

The prevalence of clinically evident interstitial lung disease in patients with rheumatoid arthritis is approximately 10%. An additional 33% of undiagnosed patients have interstitial lung abnormalities that can be detected with high-resolution computed tomography. Rheumatoid arthritis-interstitial lung disease patients have three times the risk of death compared to those with rheumatoid arthritis occurring in the absence of interstitial lung disease, and the mortality related to interstitial lung disease is rising. Rheumatoid arthritis-interstitial lung disease is most commonly classified as the usual interstitial pneumonia pattern, overlapping mechanistically and phenotypically with idiopathic pulmonary fibrosis, but can occur in a non-usual interstitial pneumonia pattern, mainly nonspecific interstitial pneumonia. Based on this, we propose two possible pathways to explain the coexistence of rheumatoid arthritis and interstitial lung disease: (i) Rheumatoid arthritis-interstitial lung disease with a non-usual interstitial pneumonia pattern may come about when an immune response against citrullinated peptides taking place in another site (e.g. the joints) subsequently affects the lungs; (ii) Rheumatoid arthritis-interstitial lung disease with a usual interstitial pneumonia pattern may represent a disease process in which idiopathic pulmonary fibrosis-like pathology triggers an immune response against citrullinated proteins that promotes articular disease indicative of rheumatoid arthritis. More studies focused on elucidating the basic mechanisms leading to different sub-phenotypes of rheumatoid arthritis-interstitial lung disease and the overlap with idiopathic pulmonary fibrosis are necessary to improve our understanding of the disease process and to define new therapeutic targets.

The Zebrafish Model Organism Database: new support for human disease models, mutation details, gene expression phenotypes and searching

PubMed Central

Howe, Douglas G.; Bradford, Yvonne M.; Eagle, Anne; Fashena, David; Frazer, Ken; Kalita, Patrick; Mani, Prita; Martin, Ryan; Moxon, Sierra Taylor; Paddock, Holly; Pich, Christian; Ramachandran, Sridhar; Ruzicka, Leyla; Schaper, Kevin; Shao, Xiang; Singer, Amy; Toro, Sabrina; Van Slyke, Ceri; Westerfield, Monte

2017-01-01

The Zebrafish Model Organism Database (ZFIN; http://zfin.org) is the central resource for zebrafish (Danio rerio) genetic, genomic, phenotypic and developmental data. ZFIN curators provide expert manual curation and integration of comprehensive data involving zebrafish genes, mutants, transgenic constructs and lines, phenotypes, genotypes, gene expressions, morpholinos, TALENs, CRISPRs, antibodies, anatomical structures, models of human disease and publications. We integrate curated, directly submitted, and collaboratively generated data, making these available to zebrafish research community. Among the vertebrate model organisms, zebrafish are superbly suited for rapid generation of sequence-targeted mutant lines, characterization of phenotypes including gene expression patterns, and generation of human disease models. The recent rapid adoption of zebrafish as human disease models is making management of these data particularly important to both the research and clinical communities. Here, we describe recent enhancements to ZFIN including use of the zebrafish experimental conditions ontology, ‘Fish’ records in the ZFIN database, support for gene expression phenotypes, models of human disease, mutation details at the DNA, RNA and protein levels, and updates to the ZFIN single box search. PMID:27899582

The Human Phenotype Ontology in 2017

PubMed Central

Köhler, Sebastian; Vasilevsky, Nicole A.; Engelstad, Mark; Foster, Erin; McMurry, Julie; Aymé, Ségolène; Baynam, Gareth; Bello, Susan M.; Boerkoel, Cornelius F.; Boycott, Kym M.; Brudno, Michael; Buske, Orion J.; Chinnery, Patrick F.; Cipriani, Valentina; Connell, Laureen E.; Dawkins, Hugh J.S.; DeMare, Laura E.; Devereau, Andrew D.; de Vries, Bert B.A.; Firth, Helen V.; Freson, Kathleen; Greene, Daniel; Hamosh, Ada; Helbig, Ingo; Hum, Courtney; Jähn, Johanna A.; James, Roger; Krause, Roland; F. Laulederkind, Stanley J.; Lochmüller, Hanns; Lyon, Gholson J.; Ogishima, Soichi; Olry, Annie; Ouwehand, Willem H.; Pontikos, Nikolas; Rath, Ana; Schaefer, Franz; Scott, Richard H.; Segal, Michael; Sergouniotis, Panagiotis I.; Sever, Richard; Smith, Cynthia L.; Straub, Volker; Thompson, Rachel; Turner, Catherine; Turro, Ernest; Veltman, Marijcke W.M.; Vulliamy, Tom; Yu, Jing; von Ziegenweidt, Julie; Zankl, Andreas; Züchner, Stephan; Zemojtel, Tomasz; Jacobsen, Julius O.B.; Groza, Tudor; Smedley, Damian; Mungall, Christopher J.; Haendel, Melissa; Robinson, Peter N.

2017-01-01

Deep phenotyping has been defined as the precise and comprehensive analysis of phenotypic abnormalities in which the individual components of the phenotype are observed and described. The three components of the Human Phenotype Ontology (HPO; www.human-phenotype-ontology.org) project are the phenotype vocabulary, disease-phenotype annotations and the algorithms that operate on these. These components are being used for computational deep phenotyping and precision medicine as well as integration of clinical data into translational research. The HPO is being increasingly adopted as a standard for phenotypic abnormalities by diverse groups such as international rare disease organizations, registries, clinical labs, biomedical resources, and clinical software tools and will thereby contribute toward nascent efforts at global data exchange for identifying disease etiologies. This update article reviews the progress of the HPO project since the debut Nucleic Acids Research database article in 2014, including specific areas of expansion such as common (complex) disease, new algorithms for phenotype driven genomic discovery and diagnostics, integration of cross-species mapping efforts with the Mammalian Phenotype Ontology, an improved quality control pipeline, and the addition of patient-friendly terminology. PMID:27899602

The Human Phenotype Ontology in 2017

DOE PAGES

Köhler, Sebastian; Vasilevsky, Nicole A.; Engelstad, Mark; ...

2016-11-24

Deep phenotyping has been defined as the precise and comprehensive analysis of phenotypic abnormalities in which the individual components of the phenotype are observed and described. The three components of the Human PhenotypeOntology (HPO; www.human-phenotype-ontology.org) project are the phenotype vocabulary, disease-phenotype annotations and the algorithms that operate on these. These components are being used for computational deep phenotyping and precision medicine as well as integration of clinical data into translational research. The HPO is being increasingly adopted as a standard for phenotypic abnormalities by diverse groups such as international rare disease organizations, registries, clinical labs, biomedical resources, and clinical softwaremore » tools and will thereby contribute toward nascent efforts at global data exchange for identifying disease etiologies. This update article reviews the progress of the HPO project since the debut Nucleic Acids Research database article in 2014, including specific areas of expansion such as common (complex) disease, new algorithms for phenotype driven genomic discovery and diagnostics, integration of cross-species mapping efforts with the Mammalian Phenotype Ontology, an improved quality control pipeline, and the addition of patient-friendly terminology.« less

Recapitulation of spinal motor neuron-specific disease phenotypes in a human cell model of spinal muscular atrophy

PubMed Central

Wang, Zhi-Bo; Zhang, Xiaoqing; Li, Xue-Jun

2013-01-01

Establishing human cell models of spinal muscular atrophy (SMA) to mimic motor neuron-specific phenotypes holds the key to understanding the pathogenesis of this devastating disease. Here, we developed a closely representative cell model of SMA by knocking down the disease-determining gene, survival motor neuron (SMN), in human embryonic stem cells (hESCs). Our study with this cell model demonstrated that knocking down of SMN does not interfere with neural induction or the initial specification of spinal motor neurons. Notably, the axonal outgrowth of spinal motor neurons was significantly impaired and these disease-mimicking neurons subsequently degenerated. Furthermore, these disease phenotypes were caused by SMN-full length (SMN-FL) but not SMN-Δ7 (lacking exon 7) knockdown, and were specific to spinal motor neurons. Restoring the expression of SMN-FL completely ameliorated all of the disease phenotypes, including specific axonal defects and motor neuron loss. Finally, knockdown of SMN-FL led to excessive mitochondrial oxidative stress in human motor neuron progenitors. The involvement of oxidative stress in the degeneration of spinal motor neurons in the SMA cell model was further confirmed by the administration of N-acetylcysteine, a potent antioxidant, which prevented disease-related apoptosis and subsequent motor neuron death. Thus, we report here the successful establishment of an hESC-based SMA model, which exhibits disease gene isoform specificity, cell type specificity, and phenotype reversibility. Our model provides a unique paradigm for studying how motor neurons specifically degenerate and highlights the potential importance of antioxidants for the treatment of SMA. PMID:23208423

The hypertriglyceridemic-waist phenotype and the risk of coronary artery disease: results from the EPIC-Norfolk Prospective Population Study

PubMed Central

Arsenault, Benoit J.; Lemieux, Isabelle; Després, Jean-Pierre; Wareham, Nicholas J.; Kastelein, John J.P.; Khaw, Kay-Tee; Boekholdt, S. Matthijs

2010-01-01

Background Screening for increased waist circumference and hypertriglyceridemia (the hypertriglyceridemic-waist phenotype) has been proposed as an inexpensive approach to identify patients with excess intra-abdominal adiposity and associated metabolic abnormalities. We examined the relationship between the hypertriglyceridemic-waist phenotype to the risk of coronary artery disease in apparently healthy individuals. Methods A total of 21 787 participants aged 45–79 years were followed for a mean of 9.8 (standard deviation 1.7) years. Coronary artery disease developed in 2109 of them during follow-up. The hypertriglyceridemic-waist phenotype was defined as a waist circumference of 90 cm or more and a triglyceride level of 2.0 mmol/L or more in men, and a waist circumference of 85 cm or more and a triglyceride level of 1.5 mmol/L or more in women. Results Compared with participants who had a waist circumference and triglyceride level below the threshold, those with the hypertriglyceridemic-waist phenotype had higher blood pressure indices, higher levels of apolipoprotein B and C-reactive protein, lower levels of high-density lipoprotein cholesterol and apolipoprotein A-I, and smaller low-density lipoprotein particles. Among men, those with the hypertriglyceridemic-waist phenotype had an unadjusted hazard ratio for future coronary artery disease of 2.40 (95% confidence interval [CI] 2.02–2.87) compared with men who did not have the phenotype. Women with the phenotype had an unadjusted hazard ratio of 3.84 (95% CI 3.20–4.62) compared with women who did not have the phenotype. Interpretation Among participants from a European cohort representative of a contemporary Western population, the hypertriglyceridemic-waist phenotype was associated with a deteriorated cardiometabolic risk profile and an increased risk for coronary artery disease. PMID:20643837

Tryptophan via serotonin/kynurenine pathways abnormalities in a large cohort of aggressive inmates: markers for aggression.

PubMed

Comai, Stefano; Bertazzo, Antonella; Vachon, Jeanne; Daigle, Marc; Toupin, Jean; Côté, Gilles; Turecki, Gustavo; Gobbi, Gabriella

2016-10-03

Aggressive behavior is one of the most challenging symptoms in psychiatry, and biological markers for aggression lack of large sample validations. Serotonin (5-HT) and other neuroactive compounds deriving from Tryptophan (Trp), including kynurenine (Kyn), have not yet been investigated in large cohorts of aggressive individuals to validate their potential as biomarkers of aggression. In 361 male inmates we measured serum levels of Trp, 5-hydroxytryptophan, 5-HT, Kyn, the ratios 5-HT/Trp∗1000 and Kyn/Trp∗1000, and performed Structured Clinical Interview for DSM-IV Axis-I and -II Disorders (SCID-I and -II), global assessment of functioning (GAF), and scales for aggressive behavior, impulsivity, adult attention-deficit/hyperactivity disorder (ADHD), and intelligent quotient (IQ). Aggressive compared to non-aggressive inmates exhibited lower Trp and Kyn serum levels but higher levels of 5-HT and 5-HT/Trp∗1000, higher levels of impulsivity and ADHD indices, lower IQ and GAF, higher prevalence of mood disorders, drug abuse/dependence, and borderline, conduct and antisocial behaviors. Interestingly, Kyn/Trp∗1000 was positively correlated to the number of severe aggressive acts (r=0.593, P<0.001). After adjusting for confounding factors, logistic regression analysis indicated that 5-HT/Trp∗1000, antisocial behavior, and GAF were predictors of aggressive behavior. The model combining these three predictors had an area under the ROC curve of 0.851 (95% CI 0.806-0.895). This study indicates that while circulating Trp is reduced in aggressive individuals, the combination of biological (5-HT/Trp ratio) and psychopathological (antisocial behavior and GAF) markers discriminates between aggressive and non-aggressive behavior suggesting the potential of a multi-marker approach in psychiatry given the heterogenic nature of mental diseases. Copyright © 2016 Elsevier Inc. All rights reserved.

Pre-clinical cognitive phenotypes for Alzheimer disease: a latent profile approach.

PubMed

Hayden, Kathleen M; Kuchibhatla, Maragatha; Romero, Heather R; Plassman, Brenda L; Burke, James R; Browndyke, Jeffrey N; Welsh-Bohmer, Kathleen A

2014-11-01

Cognitive profiles for pre-clinical Alzheimer disease (AD) can be used to identify groups of individuals at risk for disease and better characterize pre-clinical disease. Profiles or patterns of performance as pre-clinical phenotypes may be more useful than individual test scores or measures of global decline. To evaluate patterns of cognitive performance in cognitively normal individuals to derive latent profiles associated with later onset of disease using a combination of factor analysis and latent profile analysis. The National Alzheimer Coordinating Centers collect data, including a battery of neuropsychological tests, from participants at 29 National Institute on Aging-funded Alzheimer Disease Centers across the United States. Prior factor analyses of this battery demonstrated a four-factor structure comprising memory, attention, language, and executive function. Factor scores from these analyses were used in a latent profile approach to characterize cognition among a group of cognitively normal participants (N = 3,911). Associations between latent profiles and disease outcomes an average of 3 years later were evaluated with multinomial regression models. Similar analyses were used to determine predictors of profile membership. Four groups were identified; each with distinct characteristics and significantly associated with later disease outcomes. Two groups were significantly associated with development of cognitive impairment. In post hoc analyses, both the Trail Making Test Part B, and a contrast score (Delayed Recall - Trails B), significantly predicted group membership and later cognitive impairment. Latent profile analysis is a useful method to evaluate patterns of cognition in large samples for the identification of preclinical AD phenotypes; comparable results, however, can be achieved with very sensitive tests and contrast scores. Copyright © 2014 American Association for Geriatric Psychiatry. Published by Elsevier Inc. All rights reserved.

Alzheimer's Disease Phenotypes and Genotypes Associated with Mutations in Presenilin 2

ERIC Educational Resources Information Center

Jayadev, Suman; Leverenz, James B.; Steinbart, Ellen; Stahl, Justin; Klunk, William; Yu, Cheng-En; Bird, Thomas D.

2010-01-01

Mutations in presenilin 2 are rare causes of early onset familial Alzheimer's disease. Eighteen presenilin 2 mutations have been reported, although not all have been confirmed pathogenic. Much remains to be learned about the range of phenotypes associated with these mutations. We have analysed our unique collection of 146 affected cases in 11…

Serum anti-glycan antibodies in paediatric-onset Crohn's disease: association with disease phenotype and diagnostic accuracy.

PubMed

Sładek, Małgorzata; Wasilewska, Agata; Swiat, Agnieszka; Cmiel, Adam

2014-01-01

Antibodies reacting with various microbial epitopes have been described in inflammatory bowel disease (IBD) and are associated with a specific diagnosis and clinical presentation. To evaluate the profile of new anti-glycan antibodies, their potential association with disease phenotype and diagnostic accuracy in paediatric Crohn's disease (CD). Blood samples from 134 paediatric IBD patients (109 CD, 25 ulcerative colitis (UC)) and 67 controls were blindly analysed for anti-Saccharomyces cerevisiae (ASCA), anti-chitobioside carbohydrate (ACCA), anti-laminaribioside carbohydrate (ALCA), and anti-mannobioside carbohydrate (AMCA) antibodies using commercially available assays. The serological response to glycans was correlated with clinical disease characteristics. At least one of the tested anti-glycan antibodies was present in 75% of CD patients. Despite the high frequency of reactivity to glycan epitopes, a limited overlap of serological markers was observed. In total, 49% of ASCA-negative patients presented with one of the following: ACCA, ALCA, or AMCA. The occurrence of one antibody from the anti-glycan panel was independently associated with complicated disease phenotype and ileocolonic disease location. A higher level of immune response as assessed by the quartile sum scores for ACCA, ALCA, and AMCA was linked with older age at diagnosis (10-17 years) and ileocolonic disease location. The ASCA had the greatest accuracy for diagnosis and differentiation of CD. Qualitative and quantitative serologicalal response to glycan epitopes was associated with distinct clinical presentation in paediatric CD patients. This raises the possibility for the use of these markers to differentiate subgroups of CD patients with more sever clinical presentation. The ASCA was the most accurate serological marker for CD; however, testing for the new anti-glycan antibodies may constitute an adjunctive tool in a specific group of patients to aid in the differentiation of CD with absent

Upper gastrointestinal tract phenotype of Crohn's disease is associated with early surgery and further hospitalization.

PubMed

Chow, Dorothy K L; Sung, Joseph J Y; Wu, Justin C Y; Tsoi, Kelvin K F; Leong, Rupert W L; Chan, Francis K L

2009-04-01

According to the Montreal Classification, upper gastrointestinal tract phenotype L4 is uncommon in Caucasian patients with Crohn's disease (CD) but carries excess risk of recurrence. We studied the clinical course of CD in Chinese patients presenting with the L4 phenotype and factors predicting its occurrence upon longitudinal follow-up. This prospective cohort study included 132 Chinese CD patients (median age at diagnosis, 30.0 years, range: 14.0-77.0 years) who were followed for 770 person-years. Demographic data including disease behavior and location, details of surgery, and hospitalization were collected. The Kaplan-Meier method was used to estimate the probabilities of further hospitalization and major surgery followed by Cox proportional hazards regression to determine if clinical variables independently predicted the endpoints. The L4 phenotype was found in 30 (22.7%) patients at presentation. There were significantly more stricturing (46.7% versus 18.6%) and penetrating (30.0% versus 3.9%) phenotypes in the L4 group than in the non-L4 group (P < 0.0001). The 3-year cumulative probability of further hospitalization was 86.9% (95% confidence interval [CI]: 73.8%-100.0%) in the L4 group as compared with 49.3% (95% CI: 39.3%-59.3%) in the non-L4 group (log-rank test, P < 0.0001). The L4 phenotype independently predicted further hospitalization (adjusted hazards ratio [HR]: 2.1; 95% CI: 1.3-3.5). The cumulative probability of major surgery was significantly higher in the L4 than in the non-L4 group (P < 0.0001). Eighteen (17.6%) patients developed the L4 phenotype on follow-up and the stricturing phenotype predicted its occurrence (adjusted HR: 5.5; 95% CI: 2.2-14.0). Chinese CD patients more often had the L4 phenotype, which predicted the need of subsequent hospitalization.

CXCR6, a newly defined biomarker of tissue-specific stem cell asymmetric self-renewal, identifies more aggressive human melanoma cancer stem cells.

PubMed

Taghizadeh, Rouzbeh; Noh, Minsoo; Huh, Yang Hoon; Ciusani, Emilio; Sigalotti, Luca; Maio, Michele; Arosio, Beatrice; Nicotra, Maria R; Natali, PierGiorgio; Sherley, James L; La Porta, Caterina A M

2010-12-22

A fundamental problem in cancer research is identifying the cell type that is capable of sustaining neoplastic growth and its origin from normal tissue cells. Recent investigations of a variety of tumor types have shown that phenotypically identifiable and isolable subfractions of cells possess the tumor-forming ability. In the present paper, using two lineage-related human melanoma cell lines, primary melanoma line IGR39 and its metastatic derivative line IGR37, two main observations are reported. The first one is the first phenotypic evidence to support the origin of melanoma cancer stem cells (CSCs) from mutated tissue-specific stem cells; and the second one is the identification of a more aggressive subpopulation of CSCs in melanoma that are CXCR6+. We defined CXCR6 as a new biomarker for tissue-specific stem cell asymmetric self-renewal. Thus, the relationship between melanoma formation and ABCG2 and CXCR6 expression was investigated. Consistent with their non-metastatic character, unsorted IGR39 cells formed significantly smaller tumors than unsorted IGR37 cells. In addition, ABCG2+ cells produced tumors that had a 2-fold greater mass than tumors produced by unsorted cells or ABCG2- cells. CXCR6+ cells produced more aggressive tumors. CXCR6 identifies a more discrete subpopulation of cultured human melanoma cells with a more aggressive MCSC phenotype than cells selected on the basis of the ABCG2+ phenotype alone. The association of a more aggressive tumor phenotype with asymmetric self-renewal phenotype reveals a previously unrecognized aspect of tumor cell physiology. Namely, the retention of some tissue-specific stem cell attributes, like the ability to asymmetrically self-renew, impacts the natural history of human tumor development. Knowledge of this new aspect of tumor development and progression may provide new targets for cancer prevention and treatment.

Mild expression differences of MECP2 influencing aggressive social behavior

PubMed Central

Tantra, Martesa; Hammer, Christian; Kästner, Anne; Dahm, Liane; Begemann, Martin; Bodda, Chiranjeevi; Hammerschmidt, Kurt; Giegling, Ina; Stepniak, Beata; Castillo Venzor, Aracely; Konte, Bettina; Erbaba, Begun; Hartmann, Annette; Tarami, Asieh; Schulz-Schaeffer, Walter; Rujescu, Dan; Mannan, Ashraf U; Ehrenreich, Hannelore

2014-01-01

The X-chromosomal MECP2/Mecp2 gene encodes methyl-CpG-binding protein 2, a transcriptional activator and repressor regulating many other genes. We discovered in male FVB/N mice that mild (∼50%) transgenic overexpression of Mecp2 enhances aggression. Surprisingly, when the same transgene was expressed in C57BL/6N mice, transgenics showed reduced aggression and social interaction. This suggests that Mecp2 modulates aggressive social behavior. To test this hypothesis in humans, we performed a phenotype-based genetic association study (PGAS) in >1000 schizophrenic individuals. We found MECP2 SNPs rs2239464 (G/A) and rs2734647 (C/T; 3′UTR) associated with aggression, with the G and C carriers, respectively, being more aggressive. This finding was replicated in an independent schizophrenia cohort. Allele-specific MECP2mRNA expression differs in peripheral blood mononuclear cells by ∼50% (rs2734647: C > T). Notably, the brain-expressed, species-conserved miR-511 binds to MECP2 3′UTR only in T carriers, thereby suppressing gene expression. To conclude, subtle MECP2/Mecp2 expression alterations impact aggression. While the mouse data provides evidence of an interaction between genetic background and mild Mecp2 overexpression, the human data convey means by which genetic variation affects MECP2 expression and behavior. PMID:24648499

Genetically defined fear-induced aggression: Focus on BDNF and its receptors.

PubMed

Ilchibaeva, Tatiana V; Tsybko, Anton S; Kozhemyakina, Rimma V; Kondaurova, Elena M; Popova, Nina K; Naumenko, Vladimir S

2018-05-02

Brain-derived neurotrophic factor (BDNF), its precursor proBDNF, BDNF pro-peptide, BDNF mRNA levels, as well as TrkB and p75 NTR receptors mRNA and protein levels, were studied in the brain of rats, selectively bred for more than 85 generations for either the high level or the lack of fear-induced aggressive behavior. Furthermore, we have found that rats of aggressive strain demonstrated both high level of aggression toward humans and increased amplitude of acoustic startle response compared to rats selectively bred for the lack of fear-induced aggression. Significant increase in the BDNF mRNA, mature BDNF and proBDNF protein levels in the raphe nuclei (RN), hippocampus (Hc), nucleus accumbens (NAcc), amygdala, striatum and hypothalamus (Ht) of aggressive rats was revealed. The BDNF/proBDNF ratio was significantly reduced in the Hc and NAcc of highly aggressive rats suggesting prevalence of the proBDNF in these structures. In the Hc and frontal cortex (FC) of aggressive rats, the level of the full-length TrkB (TrkB-FL) receptor form was decreased, whereas the truncated TrkB (TrkB-T) protein level was increased in the RN, FC, substantia nigra and Ht. The TrkB-FL/TrkB-T ratio was significantly decreased in highly aggressive rats suggesting TrkB-T is predominant in highly aggressive rats. The p75 NTR expression was slightly changed in majority of studied brain structures of aggressive rats. The data indicate the BDNF system in the brain of aggressive and nonaggressive animals is extremely different at all levels, from transcription to reception, suggesting significant role of BDNF system in the development of highly aggressive phenotype. Copyright © 2018 Elsevier B.V. All rights reserved.

Patterns of magnetic resonance imaging abnormalities in symptomatic patients with Krabbe disease correspond to phenotype.

PubMed

Abdelhalim, Ahmed N; Alberico, Ronald A; Barczykowski, Amy L; Duffner, Patricia K

2014-02-01

Initial magnetic resonance imaging studies of individuals with Krabbe disease were analyzed to determine whether the pattern of abnormalities corresponded to the phenotype. This was a retrospective, nonblinded study. Families/patients diagnosed with Krabbe disease submitted medical records and magnetic resonance imaging discs for central review. Institutional review board approval/informed consents were obtained. Sixty-four magnetic resonance imaging scans were reviewed by two neuroradiologists and a child neurologist according to phenotype: early infantile (onset 0-6 months) = 39 patients; late infantile (onset 7-12 months) = 10 patients; later onset (onset 13 months-10 years) = 11 patients; adolescent (onset 11-20 years) = one patient; and adult (21 years or greater) = three patients. Local interpretations were compared with central review. Magnetic resonance imaging abnormalities differed among phenotypes. Early infantile patients had a predominance of increased intensity in the dentate/cerebellar white matter as well as changes in the deep cerebral white matter. Later onset patients did not demonstrate involvement in the dentate/cerebellar white matter but had extensive involvement of the deep cerebral white matter, parieto-occipital region, and posterior corpus callosum. Late infantile patients exhibited a mixed pattern; 40% had dentate/cerebellar white matter involvement while all had involvement of the deep cerebral white matter. Adolescent/adult patients demonstrated isolated corticospinal tract involvement. Local and central reviews primarily differed in interpretation of the early infantile phenotype. Analysis of magnetic resonance imaging in a large cohort of symptomatic patients with Krabbe disease demonstrated imaging abnormalities correspond to specific phenotypes. Knowledge of these patterns along with typical clinical signs/symptoms should promote earlier diagnosis and facilitate treatment. Copyright © 2014 Elsevier Inc. All rights reserved.

Comparative evaluation of serum C-reactive protein levels in chronic and aggressive periodontitis patients and association with periodontal disease severity

PubMed Central

Goyal, Lata; Bey, Afshan; Gupta, N. D.; Sharma, Vivek Kumar

2014-01-01

Objective: C-reactive protein (CRP) is an acute-phase reactant and has been proved to be a significant predictor of future cardiovascular events. Recent studies have demonstrated a correlation between periodontitis and elevated CRP levels. However, most of the studies have focused on chronic periodontitis and very few studies are done in patients with aggressive periodontitis. The aim of this study was to determine and compare the relative levels of serum CRP in aggressive and chronic periodontitis patients. Materials and Methods: A total of 75 systemically healthy subjects were divided into three groups: Group I, nonperiodontitis subjects; group II, chronic generalized periodontitis patients and group III, generalized aggressive periodontitis patients. All participants were subjected to quantitative CRP analysis using enzyme-linked immunosorbent assay. Results: Mean CRP levels were significantly greater in both group II and III as compared to group I and group III having greater level than group II. Furthermore, CRP levels positively correlated with the amount of periodontal destruction as measured by probing depth and clinical attachment loss. Conclusion: The present study indicates a positive correlation between CRP and periodontal disease severity with particular concern in younger individuals that could be a possible underlying pathway in the association between periodontal disease and the observed higher risk for cardiovascular disease in periodontitis patients. PMID:25395764

Gaucher disease: molecular heterogeneity and phenotype-genotype correlations.

PubMed

Theophilus, B; Latham, T; Grabowski, G A; Smith, F I

1989-08-01

Gaucher disease (GD) is the most prevalent lysosomal storage disease. This autosomal recessive trait results from the defective activity of acid beta-glucosidase (beta-Glc). Four different exonic point mutations have been identified as causal alleles for GD. To facilitate screening for these alleles, assays were developed using allele-specific oligonucleotide hybridization to amplified genomic DNA sequences. Specifically, intron bases flanking exons 5, 9, and 10 were determined, and conditions for PCR amplification of these exons were obtained. Two different procedures were developed to distinguish signals obtained from the structural beta-Glc gene exons and those from the pseudogene. These procedures were used to determine the distribution of all known GD alleles in a population of 44 affected patients of varying phenotypes and ethnicity. The high frequency of one of the exon 9 mutations in Ashkenazi Jewish GD type 1 patients was confirmed, and, in addition, this mutation was present in ethnically diverse non-Jewish type 1 GD patients. Homozygotes (N = 5) for this allele were midly affected older individuals, and this mutant allele was not found in any patient with neuronopathic disease. The exon 10 mutation was confirmed as the predominant allele in types 2 and 3 GD. However, several type 1 GD patients, including one of Ashkenazi-Jewish heritage, also were heterozygous for this allele. The presence of this allele in type 1 patients did not correlate with the severity of clinical symptoms. The second exon 9 mutation and the exon 5 mutation were rare, since they occurred only heterozygously either in one type 2 GD patient or in two related Ashkenazi-Jewish GD patients, respectively. Although most GD patients (38 of 44) had at least one of the known mutant alleles, 57% were heterozygotes for only one of these mutations. Fourteen percent of patients were negative for all mutations. A total of 73% of GD patients had at least one unknown allele. The varying clinical

Obstructive Sleep Apnea Phenotypes and Markers of Vascular Disease: A Review

PubMed Central

Ramos, Alberto R.; Figueredo, Pedro; Shafazand, Shirin; Chediak, Alejandro D.; Abreu, Alexandre R.; Dib, Salim I.; Torre, Carlos; Wallace, Douglas M.

2017-01-01

Obstructive sleep apnea (OSA) is a chronic and heterogeneous disorder that leads to early mortality, stroke, and cardiovascular disease (CVD). OSA is defined by the apnea–hypopnea index, which is an index of OSA severity that combines apneas (pauses in breathing) and hypopneas (partial obstructions in breathing) associated with hypoxemia. Yet, other sleep metrics (i.e., oxygen nadir, arousal frequency), along with clinical symptoms and molecular markers could be better predictors of stroke and CVD outcomes in OSA. The recent focus on personalized medical care introduces the possibility of a unique approach to the treatment of OSA based on its phenotypes, defined by pathophysiological mechanisms and/or clinical presentation. We summarized what is known about OSA and its phenotypes, and review the literature on factors or intermediate markers that could increase stroke risk and CVD in patients with OSA. The OSA phenotypes where divided across three different domains (1) clinical symptoms (i.e., daytime sleepiness), (2) genetic/molecular markers, and (3) experimental data-driven approach (e.g., cluster analysis). Finally, we further highlight gaps in the literature framing a research agenda. PMID:29259576

Brain-derived neurotrophic factor (BDNF) and its precursor (proBDNF) in genetically defined fear-induced aggression.

PubMed

Ilchibaeva, Tatiana V; Kondaurova, Elena M; Tsybko, Anton S; Kozhemyakina, Rimma V; Popova, Nina K; Naumenko, Vladimir S

2015-09-01

The brain-derived neurotrophic factor (BDNF), its precursor (proBDNF) and BDNF mRNA levels were studied in the brain of wild rats selectively bred for more than 70 generations for either high level or for the lack of affective aggressiveness towards man. Significant increase of BDNF mRNA level in the frontal cortex and increase of BDNF level in the hippocampus of aggressive rats was revealed. In the midbrain and hippocampus of aggressive rats proBDNF level was increased, whereas BDNF/proBDNF ratio was reduced suggesting the prevalence and increased influence of proBDNF in highly aggressive rats. In the frontal cortex, proBDNF level in aggressive rats was decreased. Thus, considerable structure-specific differences in BDNF and proBDNF levels as well as in BDNF gene expression between highly aggressive and nonaggressive rats were shown. The data suggested the implication of BDNF and its precursor proBDNF in the mechanism of aggressiveness and in the creation of either aggressive or nonaggressive phenotype. Copyright © 2015 Elsevier B.V. All rights reserved.

In silico analysis of a disease-causing mutation in PCDH15 gene in a consanguineous Pakistani family with Usher phenotype.

PubMed

Saleha, Shamim; Ajmal, Muhammad; Jamil, Muhammad; Nasir, Muhammad; Hameed, Abdul

2016-01-01

To map Usher phenotype in a consanguineous Pakistani family and identify disease-associated mutation in a causative gene to establish phenotype-genotype correlation. A consanguineous Pakistani family in which Usher phenotype was segregating as an autosomal recessive trait was ascertained. On the basis of results of clinical investigations of affected members of this family disease was diagnosed as Usher syndrome (USH). To identify the locus responsible for the Usher phenotype in this family, genomic DNA from blood sample of each individual was genotyped using microsatellite Short Tandem Repeat (STR) markers for the known Usher syndrome loci. Then direct sequencing was performed to find out disease associated mutations in the candidate gene. By genetic linkage analysis, the USH phenotype of this family was mapped to PCDH15 locus on chromosome 10q21.1. Three different point mutations in exon 11 of PCDH15 were identified and one of them, c.1304A>C was found to be segregating with the disease phenotype in Pakistani family with Usher phenotype. This, c.1304A>C transversion mutation predicts an amino-acid substitution of aspartic acid with an alanine at residue number 435 (p.D435A) of its protein product. Moreover, in silico analysis revealed conservation of aspartic acid at position 435 and predicated this change as pathogenic. The identification of c.1304A>C pathogenic mutation in PCDH15 gene and its association with Usher syndrome in a consanguineous Pakistani family is the first example of a missense mutation of PCDH15 causing USH1 phenotype. In previous reports, it was hypothesized that severe mutations such as truncated protein of PCDH15 led to the Usher I phenotype and that missense variants are mainly responsible for non-syndromic hearing impairment.

Brief Report: Aggression and Stereotypic Behavior in Males with Fragile X Syndrome-- Moderating Secondary Genes in a "Single Gene" Disorder

ERIC Educational Resources Information Center

Hessl, David; Tassone, Flora; Cordeiro, Lisa; Koldewyn, Kami; McCormick, Carolyn; Green, Cherie; Wegelin, Jacob; Yuhas, Jennifer; Hagerman, Randi J.

2008-01-01

Although fragile X syndrome (FXS) is a single gene disorder with a well-described phenotype, it is not known why some individuals develop more significant maladaptive behaviors such as aggression or autistic symptoms. Here, we studied two candidate genes known to affect mood and aggression, the serotonin transporter (5-HTTLPR) and monoamine…

[Buffering capacity of the vitreous body in aggressive posterior retinopathy of prematurity].

PubMed

Amkhanitskaia, L I; Sidorenko, E I; Nikolaeva, G V; Kuznetsova, Iu D

2014-01-01

To investigate the role of vitreous body changes in the pathogenesis of aggressive posterior retinopathy of prematurity. The study included 60 children with stage 4-5 retinopathy of prematurity demonstrating either classical or aggressive posterior form of progression. In all cases vitreous samples for laboratory testing were taken during surgery. The study showed that aggressive posterior retinopathy of prematurity is associated with more significant metabolic changes in comparison with classical form of the disease. The degree of biochemical imbalance of the vitreous appeared directly related to the stage of the disease, which was determined by the type and extent of retinal detachment. Volcano-shaped retinal detachment with intensive exudation within the posterior eye segment is considered the most severe variant of aggressive posterior retinopathy of prematurity. Aggressive posterior retinopathy of prematurity is characterized by substantial disturbance of metabolism of the vitreous body, which contributes to exudation and proliferation, thus aggravating the course of the disease and worsening the prognosis.

Systematic Review and Meta-analysis: Phenotype and Clinical Outcomes of Older-onset Inflammatory Bowel Disease.

PubMed

Ananthakrishnan, Ashwin N; Shi, Hai Yun; Tang, Whitney; Law, Cindy C Y; Sung, Joseph J Y; Chan, Francis K L; Ng, Siew C

2016-10-01

Little is known of the clinical outcome of patients with older-onset inflammatory bowel disease [IBD]. We performed a systematic review to determine phenotype and outcomes of older-onset IBD compared with younger-onset subjects. A systematic search of Embase and Medline up to June 2015 identified studies investigating phenotype and outcomes of older-onset [diagnosed at age ≥ 50 years] Crohn's disease [CD] and ulcerative colitis [UC] subjects. Pooled analyses of disease phenotype, medication use, and disease-related surgery were calculated. We analysed findings from 43 studies comprising 8274 older-onset and 34641 younger-onset IBD subjects. Compared with younger-onset patients, older-onset CD patients were more likely to have colonic disease (odds ratio [OR] 2.56, 95% confidence interval [CI] 1.88 - 3.48) and inflammatory behaviour [OR 1.19, 95% CI 1.07 - 1.33], and less likely to have penetrating disease or perianal involvement. More older-onset UC patients had left-sided colitis [OR 1.49, 95% CI 1.18 - 1.88]. Although fewer older-onset IBD patients received immunomodulators [CD: OR 0.44; UC: OR 0.60] or biologicals [CD: OR 0.34; UC: OR 0.41], older-onset CD was similar in the need for surgery [OR 0.70, 95% CI 0.40 - 1.22] whereas more older-onset UC patients underwent surgery [OR 1.36, 95% CI 1.18 - 1.57]. Elderly IBD patients present with less complicated disease, but have similar or higher rates of surgery than non-elderly patients. Whether this reflects a non-benign disease course, physicians' reluctance to employ immunomodulators, or both, merits further study which is essential for improving the care of IBD in the elderly. Copyright © 2016 European Crohn’s and Colitis Organisation (ECCO). Published by Oxford University Press. All rights reserved. For permissions, please email: journals.permissions@oup.com.

Disease modeling and phenotypic drug screening for diabetic cardiomyopathy using human induced pluripotent stem cells.

PubMed

Drawnel, Faye M; Boccardo, Stefano; Prummer, Michael; Delobel, Frédéric; Graff, Alexandra; Weber, Michael; Gérard, Régine; Badi, Laura; Kam-Thong, Tony; Bu, Lei; Jiang, Xin; Hoflack, Jean-Christophe; Kiialainen, Anna; Jeworutzki, Elena; Aoyama, Natsuyo; Carlson, Coby; Burcin, Mark; Gromo, Gianni; Boehringer, Markus; Stahlberg, Henning; Hall, Benjamin J; Magnone, Maria Chiara; Kolaja, Kyle; Chien, Kenneth R; Bailly, Jacques; Iacone, Roberto

2014-11-06

Diabetic cardiomyopathy is a complication of type 2 diabetes, with known contributions of lifestyle and genetics. We develop environmentally and genetically driven in vitro models of the condition using human-induced-pluripotent-stem-cell-derived cardiomyocytes. First, we mimic diabetic clinical chemistry to induce a phenotypic surrogate of diabetic cardiomyopathy, observing structural and functional disarray. Next, we consider genetic effects by deriving cardiomyocytes from two diabetic patients with variable disease progression. The cardiomyopathic phenotype is recapitulated in the patient-specific cells basally, with a severity dependent on their original clinical status. These models are incorporated into successive levels of a screening platform, identifying drugs that preserve cardiomyocyte phenotype in vitro during diabetic stress. In this work, we present a patient-specific induced pluripotent stem cell (iPSC) model of a complex metabolic condition, showing the power of this technique for discovery and testing of therapeutic strategies for a disease with ever-increasing clinical significance. Copyright © 2014 The Authors. Published by Elsevier Inc. All rights reserved.

[Aggressive and prosocial behavior in childhood psychopathology].

PubMed

Vida, Péter; Halász, József; Gádoros, Júlia

2013-01-01

Aggressive/attacking and helpful/emphatic/prosocial behaviors are extremely important in human relationships. Both high levels of aggression and deficits of prosociality play important role in the development and conservation of mental disorders. We review the measurement options and clinical importance of aggressive and prosocial behavior. The typical developmental pathways and the genetic and environmental background of these behaviors are presented. The clinical tools used in the measurement of aggression and prosociality are summarized in the present paper, with specific attention on questionnaires applied in Hungarian practice. The connections between diagnostic categories (conduct disorder, oppositional-defiant disorder, attention deficit and hyperactive disorder, autism spectrum disorders) and the two behaviors are evaluated. In the end, we present those additional research projects that explore the cognitive-emotional background of aggressive or prosocial behavior with clinical relevance either in the diagnosis or in the treatment of child psychiatric diseases.

Distinct pathological phenotypes of Creutzfeldt-Jakob disease in recipients of prion-contaminated growth hormone.

PubMed

Cali, Ignazio; Miller, Cathleen J; Parisi, Joseph E; Geschwind, Michael D; Gambetti, Pierluigi; Schonberger, Lawrence B

2015-06-25

The present study compares the clinical, pathological and molecular features of a United States (US) case of growth hormone (GH)-associated Creutzfeldt-Jakob disease (GH-CJD) (index case) to those of two earlier referred US cases of GH-CJD and one case of dura mater (d)-associated CJD (dCJD). All iatrogenic CJD (iCJD) subjects were methionine (M) homozygous at codon 129 (129MM) of the prion protein (PrP) gene and had scrapie prion protein (PrP(Sc)) type 1 (iCJDMM1). The index subject presented with ataxia, weight loss and changes in the sleep pattern about 38 years after the midpoint of GH treatment. Autopsy examination revealed a neuropathological phenotype reminiscent of both sCJDMV2-K (a sporadic CJD subtype in subjects methionine/valine heterozygous at codon 129 with PrP(Sc) type 2 and the presence of kuru plaques) and variant CJD (vCJD). The two earlier cases of GH-CJDMM1 and the one of dCJDMM1 were associated with neuropathological phenotypes that differed from that of the index case mainly because they lacked PrP plaques. The phenotype of the earlier GH-CJDMM1 cases shared several, but not all, characteristics with sCJDMM1, whereas dCJDMM1 was phenotypically indistinguishable from sCJDMM1. Two distinct groups of dCJDMM1 have also been described in Japan based on clinical features, the presence or absence of PrP plaques and distinct PK-resistant PrP(Sc) (resPrP(Sc)) electrophoretic mobilities. The resPrP(Sc) electrophoretic mobility was, however, identical in our GH-CJDMM1 and dCJDMM1 cases, and matched that of sCJDMM1. Our study shows that receipt of prion-contaminated GH can lead to a prion disease with molecular features (129MM and PrP(Sc) type 2) and phenotypic characteristics that differ from those of sporadic prion disease (sCJDMM1), a difference that may reflect adaptation of "heterologous" prion strains to the 129MM background.

The Human Phenotype Ontology project: linking molecular biology and disease through phenotype data

PubMed Central

Köhler, Sebastian; Doelken, Sandra C.; Mungall, Christopher J.; Bauer, Sebastian; Firth, Helen V.; Bailleul-Forestier, Isabelle; Black, Graeme C. M.; Brown, Danielle L.; Brudno, Michael; Campbell, Jennifer; FitzPatrick, David R.; Eppig, Janan T.; Jackson, Andrew P.; Freson, Kathleen; Girdea, Marta; Helbig, Ingo; Hurst, Jane A.; Jähn, Johanna; Jackson, Laird G.; Kelly, Anne M.; Ledbetter, David H.; Mansour, Sahar; Martin, Christa L.; Moss, Celia; Mumford, Andrew; Ouwehand, Willem H.; Park, Soo-Mi; Riggs, Erin Rooney; Scott, Richard H.; Sisodiya, Sanjay; Vooren, Steven Van; Wapner, Ronald J.; Wilkie, Andrew O. M.; Wright, Caroline F.; Vulto-van Silfhout, Anneke T.; de Leeuw, Nicole; de Vries, Bert B. A.; Washingthon, Nicole L.; Smith, Cynthia L.; Westerfield, Monte; Schofield, Paul; Ruef, Barbara J.; Gkoutos, Georgios V.; Haendel, Melissa; Smedley, Damian; Lewis, Suzanna E.; Robinson, Peter N.

2014-01-01

The Human Phenotype Ontology (HPO) project, available at http://www.human-phenotype-ontology.org, provides a structured, comprehensive and well-defined set of 10,088 classes (terms) describing human phenotypic abnormalities and 13,326 subclass relations between the HPO classes. In addition we have developed logical definitions for 46% of all HPO classes using terms from ontologies for anatomy, cell types, function, embryology, pathology and other domains. This allows interoperability with several resources, especially those containing phenotype information on model organisms such as mouse and zebrafish. Here we describe the updated HPO database, which provides annotations of 7,278 human hereditary syndromes listed in OMIM, Orphanet and DECIPHER to classes of the HPO. Various meta-attributes such as frequency, references and negations are associated with each annotation. Several large-scale projects worldwide utilize the HPO for describing phenotype information in their datasets. We have therefore generated equivalence mappings to other phenotype vocabularies such as LDDB, Orphanet, MedDRA, UMLS and phenoDB, allowing integration of existing datasets and interoperability with multiple biomedical resources. We have created various ways to access the HPO database content using flat files, a MySQL database, and Web-based tools. All data and documentation on the HPO project can be found online. PMID:24217912

Clinical phenotype-based gene prioritization: an initial study using semantic similarity and the human phenotype ontology.

PubMed

Masino, Aaron J; Dechene, Elizabeth T; Dulik, Matthew C; Wilkens, Alisha; Spinner, Nancy B; Krantz, Ian D; Pennington, Jeffrey W; Robinson, Peter N; White, Peter S

2014-07-21

Exome sequencing is a promising method for diagnosing patients with a complex phenotype. However, variant interpretation relative to patient phenotype can be challenging in some scenarios, particularly clinical assessment of rare complex phenotypes. Each patient's sequence reveals many possibly damaging variants that must be individually assessed to establish clear association with patient phenotype. To assist interpretation, we implemented an algorithm that ranks a given set of genes relative to patient phenotype. The algorithm orders genes by the semantic similarity computed between phenotypic descriptors associated with each gene and those describing the patient. Phenotypic descriptor terms are taken from the Human Phenotype Ontology (HPO) and semantic similarity is derived from each term's information content. Model validation was performed via simulation and with clinical data. We simulated 33 Mendelian diseases with 100 patients per disease. We modeled clinical conditions by adding noise and imprecision, i.e. phenotypic terms unrelated to the disease and terms less specific than the actual disease terms. We ranked the causative gene against all 2488 HPO annotated genes. The median causative gene rank was 1 for the optimal and noise cases, 12 for the imprecision case, and 60 for the imprecision with noise case. Additionally, we examined a clinical cohort of subjects with hearing impairment. The disease gene median rank was 22. However, when also considering the patient's exome data and filtering non-exomic and common variants, the median rank improved to 3. Semantic similarity can rank a causative gene highly within a gene list relative to patient phenotype characteristics, provided that imprecision is mitigated. The clinical case results suggest that phenotype rank combined with variant analysis provides significant improvement over the individual approaches. We expect that this combined prioritization approach may increase accuracy and decrease effort for

FAM5C Contributes to Aggressive Periodontitis

PubMed Central

Carvalho, Flavia M.; Tinoco, Eduardo M. B.; Deeley, Kathleen; Duarte, Poliana M.; Faveri, Marcelo; Marques, Marcelo R.; Mendonça, Adriana C.; Wang, Xiaojing; Cuenco, Karen; Menezes, Renato; Garlet, Gustavo P.; Vieira, Alexandre R.

2010-01-01

Aggressive periodontitis is characterized by a rapid and severe periodontal destruction in young systemically healthy subjects. A greater prevalence is reported in Africans and African descendent groups than in Caucasians and Hispanics. We first fine mapped the interval 1q24.2 to 1q31.3 suggested as containing an aggressive periodontitis locus. Three hundred and eighty-nine subjects from 55 pedigrees were studied. Saliva samples were collected from all subjects, and DNA was extracted. Twenty-one single nucleotide polymorphisms were selected and analyzed by standard polymerase chain reaction using TaqMan chemistry. Non-parametric linkage and transmission distortion analyses were performed. Although linkage results were negative, statistically significant association between two markers, rs1935881 and rs1342913, in the FAM5C gene and aggressive periodontitis (p = 0.03) was found. Haplotype analysis showed an association between aggressive periodontitis and the haplotype A-G (rs1935881-rs1342913; p = 0.009). Sequence analysis of FAM5C coding regions did not disclose any mutations, but two variants in conserved intronic regions of FAM5C, rs57694932 and rs10494634, were found. However, these two variants are not associated with aggressive periodontitis. Secondly, we investigated the pattern of FAM5C expression in aggressive periodontitis lesions and its possible correlations with inflammatory/immunological factors and pathogens commonly associated with periodontal diseases. FAM5C mRNA expression was significantly higher in diseased versus healthy sites, and was found to be correlated to the IL-1β, IL-17A, IL-4 and RANKL mRNA levels. No correlations were found between FAM5C levels and the presence and load of red complex periodontopathogens or Aggregatibacter actinomycetemcomitans. This study provides evidence that FAM5C contributes to aggressive periodontitis. PMID:20383335

Hemopexin therapy reverts heme-induced proinflammatory phenotypic switching of macrophages in a mouse model of sickle cell disease.

PubMed

Vinchi, Francesca; Costa da Silva, Milene; Ingoglia, Giada; Petrillo, Sara; Brinkman, Nathan; Zuercher, Adrian; Cerwenka, Adelheid; Tolosano, Emanuela; Muckenthaler, Martina U

2016-01-28

Hemolytic diseases, such as sickle cell anemia and thalassemia, are characterized by enhanced release of hemoglobin and heme into the circulation, heme-iron loading of reticulo-endothelial system macrophages, and chronic inflammation. Here we show that in addition to activating the vascular endothelium, hemoglobin and heme excess alters the macrophage phenotype in sickle cell disease. We demonstrate that exposure of cultured macrophages to hemolytic aged red blood cells, heme, or iron causes their functional phenotypic change toward a proinflammatory state. In addition, hemolysis and macrophage heme/iron accumulation in a mouse model of sickle disease trigger similar proinflammatory phenotypic alterations in hepatic macrophages. On the mechanistic level, this critically depends on reactive oxygen species production and activation of the Toll-like receptor 4 signaling pathway. We further demonstrate that the heme scavenger hemopexin protects reticulo-endothelial macrophages from heme overload in heme-loaded Hx-null mice and reduces production of cytokines and reactive oxygen species. Importantly, in sickle mice, the administration of human exogenous hemopexin attenuates the inflammatory phenotype of macrophages. Taken together, our data suggest that therapeutic administration of hemopexin is beneficial to counteract heme-driven macrophage-mediated inflammation and its pathophysiologic consequences in sickle cell disease. © 2016 by The American Society of Hematology.

Modulation of Fgfr1a signaling in zebrafish reveals a genetic basis for the aggression-boldness syndrome.

PubMed

Norton, William H J; Stumpenhorst, Katharina; Faus-Kessler, Theresa; Folchert, Anja; Rohner, Nicolas; Harris, Matthew P; Callebert, Jacques; Bally-Cuif, Laure

2011-09-28

Behavioral syndromes are suites of two or more behaviors that correlate across environmental contexts. The aggression-boldness syndrome links aggression, boldness, and exploratory activity in a novel environment. Although aggression-boldness has been described in many animals, the mechanism linking its behavioral components is not known. Here we show that mutation of the gene encoding fibroblast growth factor receptor 1a (fgfr1a) simultaneously increases aggression, boldness, and exploration in adult zebrafish. We demonstrate that altered Fgf signaling also results in reduced brain histamine levels in mutants. Pharmacological increase of histamine signaling is sufficient to rescue the behavioral phenotype of fgfr1a mutants. Together, we show that a single genetic locus can underlie the aggression-boldness behavioral syndrome. We also identify one of the neurotransmitter pathways that may mediate clustering of these behaviors.

Unravelling the neurophysiological basis of aggression in a fish model

PubMed Central

2010-01-01

Background Aggression is a near-universal behaviour with substantial influence on and implications for human and animal social systems. The neurophysiological basis of aggression is, however, poorly understood in all species and approaches adopted to study this complex behaviour have often been oversimplified. We applied targeted expression profiling on 40 genes, spanning eight neurological pathways and in four distinct regions of the brain, in combination with behavioural observations and pharmacological manipulations, to screen for regulatory pathways of aggression in the zebrafish (Danio rerio), an animal model in which social rank and aggressiveness tightly correlate. Results Substantial differences occurred in gene expression profiles between dominant and subordinate males associated with phenotypic differences in aggressiveness and, for the chosen gene set, they occurred mainly in the hypothalamus and telencephalon. The patterns of differentially-expressed genes implied multifactorial control of aggression in zebrafish, including the hypothalamo-neurohypophysial-system, serotonin, somatostatin, dopamine, hypothalamo-pituitary-interrenal, hypothalamo-pituitary-gonadal and histamine pathways, and the latter is a novel finding outside mammals. Pharmacological manipulations of various nodes within the hypothalamo-neurohypophysial-system and serotonin pathways supported their functional involvement. We also observed differences in expression profiles in the brains of dominant versus subordinate females that suggested sex-conserved control of aggression. For example, in the HNS pathway, the gene encoding arginine vasotocin (AVT), previously believed specific to male behaviours, was amongst those genes most associated with aggression, and AVT inhibited dominant female aggression, as in males. However, sex-specific differences in the expression profiles also occurred, including differences in aggression-associated tryptophan hydroxylases and estrogen receptors

Age at onset and Parkinson disease phenotype

PubMed Central

Pagano, Gennaro; Ferrara, Nicola; Brooks, David J.

2016-01-01

Objective: To explore clinical phenotype and characteristics of Parkinson disease (PD) at different ages at onset in recently diagnosed patients with untreated PD. Methods: We have analyzed baseline data from the Parkinson's Progression Markers Initiative database. Four hundred twenty-two patients with a diagnosis of PD confirmed by DaTSCAN imaging were divided into 4 groups according to age at onset (onset younger than 50 years, 50–59 years, 60–69 years, and 70 years or older) and investigated for differences in side, type and localization of symptoms, occurrence/severity of motor and nonmotor features, nigrostriatal function, and CSF biomarkers. Results: Older age at onset was associated with a more severe motor and nonmotor phenotype, a greater dopaminergic dysfunction on DaTSCAN, and reduction of CSF α-synuclein and total tau. The most common presentation was the combination of 2 or 3 motor symptoms (bradykinesia, resting tremor, and rigidity) with rigidity being more common in the young-onset group. In about 80% of the patients with localized onset, the arm was the most affected part of the body, with no difference across subgroups. Conclusions: Although the presentation of PD symptoms is similar across age subgroups, the severity of motor and nonmotor features, the impairment of striatal binding, and the levels of CSF biomarkers increase with age at onset. The variability of imaging and nonimaging biomarkers in patients with PD at different ages could hamper the results of future clinical trials. PMID:26865518

Modeling Aggressive Medulloblastoma Using Human Induced Pluripotent Stem Cells

DTIC Science & Technology

2017-09-01

and Myc in turn induces expression of AT1R creating a positive feedback loop and development of aggression tumor phenotype. The therapeutic...strengths are the relevant expertise of the applicant and his collaborating team, the novel paracrine positive feedback loop in EC-tumor cell...to as MYC-driven MB. The molecular mechanisms that drive MYC hyper -activation in MB remain incompletely understood. MB cells in actual tumors interact

Longitudinal relationships between Alzheimer disease progression and psychosis, depressed mood, and agitation/aggression.

PubMed

Zahodne, Laura B; Ornstein, Katherine; Cosentino, Stephanie; Devanand, D P; Stern, Yaakov

2015-02-01

Behavioral and psychological symptoms of dementia (BPSD) are prevalent in Alzheimer disease (AD) and are related to poor outcomes such as nursing home placement. No study has examined the impact of individual BPSD on dependence, a clinically important feature that reflects changing patient needs and their effect on caregivers. The current study characterized independent cross-sectional and longitudinal relationships between three BPSD (psychosis, depressed mood, and agitation/aggression), cognition, and dependence to better understand the interplay between these symptoms over time. The Predictors Study measured changes in BPSD, cognition, and dependence every 6 months in patients with AD. Cross-sectional and longitudinal relationships between individual BPSD, cognition, and dependence over 6 years were characterized by using multivariate latent growth curve modeling. This approach characterizes independent changes in multiple outcome measures over time. Four memory clinics in the United States and Europe. A total of 517 patients with probable AD. Columbia University Scale for Psychopathology, modified Mini-Mental State Examination, and Dependence Scale. Both psychosis and depressed mood at study entry were associated with worse subsequent cognitive decline. Independent of cognitive decline, initial psychosis was associated with worse subsequent increases in dependence. Rates of increase in agitation/aggression separately correlated with rates of declines in both cognition and independence. Although purely observational, our findings support the poor prognosis associated with psychosis and depression in AD. Results also show that agitation/aggression tracks declines in cognition and independence independently over time. Targeted intervention for individual BPSD, particularly psychosis, could have broad effects not only on patient well-being but also on care costs and family burden. Copyright © 2015 American Association for Geriatric Psychiatry. Published by

Alpha-1-antitrypsin phenotypes in adult liver disease patients

PubMed Central

Alempijevic, Tamara; Milutinovic, Aleksandra Sokic; Kovacevic, Nada

2009-01-01

Alpha-1-antitrypsin (AAT) is an important serine protease inhibitor in humans. Hereditary alpha-1-antitrypsin deficiency (AATD) affects lungs and liver. Liver disease caused by AATD in paediatric patients has been previously well documented. However, the association of liver disease with alpha-1-antitrypsin gene polymorphisms in adults is less clear. Therefore, we aimed to study AAT polymorphisms in adults with liver disease. We performed a case-control study. AAT polymorphisms were investigated by isoelectric focusing in 61 patients with liver cirrhosis and 9 patients with hepatocellular carcinoma. The control group consisted of 218 healthy blood donors. A significant deviation of observed and expected frequency of AAT phenotypes from Hardy-Weinberg equilibrium (chi-square = 34.77, df 11, P = 0.000) in the patient group was caused by a higher than expected frequency of Pi ZZ homozygotes (f = 0.0143 and f = 0.0005, respectively, P = 0.000). In addition, Pi M homozygotes were more frequent in patients than in controls (63% and 46%, respectively, P = 0.025). Our study results show that Pi ZZ homozygosity in adults could be associated with severe liver disease. Presence of Pi M homozygosity could be associated with liver disease via some mechanism different from Z allele-induced liver damage through accumulation of AAT polymers. PMID:19961268

Proximal correlates of metabolic phenotypes during 'at-risk' and 'case' stages of the metabolic disease continuum.

PubMed

Haren, M T; Misan, G; Grant, J F; Buckley, J D; Howe, P R C; Taylor, A W; Newbury, J; McDermott, R A

2012-01-16

To examine the social and behavioural correlates of metabolic phenotypes during 'at-risk' and 'case' stages of the metabolic disease continuum. Cross-sectional study of a random population sample. A total of 718 community-dwelling adults (57% female), aged 18-92 years from a regional South Australian city. Total body fat and lean mass and abdominal fat mass were assessed by dual energy x-ray absorptiometry. Fasting venous blood was collected in the morning for assessment of glycated haemoglobin, plasma glucose, serum triglycerides, cholesterol lipoproteins and insulin. Seated blood pressure (BP) was measured. Physical activity and smoking, alcohol and diet (96-item food frequency), sleep duration and frequency of sleep disordered breathing (SDB) symptoms, and family history of cardiometabolic disease, education, lifetime occupation and household income were assessed by questionnaire. Current medications were determined by clinical inventory. 36.5% were pharmacologically managed for a metabolic risk factor or had known diabetes ('cases'), otherwise were classified as the 'at-risk' population. In both 'at-risk' and 'cases', four major metabolic phenotypes were identified using principal components analysis that explained over 77% of the metabolic variance between people: fat mass/insulinemia (FMI); BP; lipidaemia/lean mass (LLM) and glycaemia (GLY). The BP phenotype was uncorrelated with other phenotypes in 'cases', whereas all phenotypes were inter-correlated in the 'at-risk'. Over and above other socioeconomic and behavioural factors, medications were the dominant correlates of all phenotypes in 'cases' and SDB symptom frequency was most strongly associated with FMI, LLM and GLY phenotypes in the 'at-risk'. Previous research has shown FMI, LLM and GLY phenotypes to be most strongly predictive of diabetes development. Reducing SDB symptom frequency and optimising the duration of sleep may be important concomitant interventions to standard diabetes risk reduction

Clinical and Phenotypic Differences in Inflammatory Bowel Disease Among Arab and Jewish Children in Israel.

PubMed

Rinawi, Firas; Assa, Amit; Bashir, Husam; Peleg, Sarit; Shamir, Raanan

2017-08-01

Data on inflammatory bowel disease (IBD) phenotypes among the Arab population in Israel or in the neighboring Arab countries is scarce. We aimed to assess differences in disease phenotype among Arab and Jewish children living in Israel. We performed a retrospective chart review of pediatric IBD cases, which were diagnosed at the Schneider Children's Medical Center and Ha'Emek Medical Center in Israel between 2000 and 2014. Demographic, clinical, and phenotypic variables were compared between Arabs and Jews from Eastern (Sephardic) and Western (Ashkenazi) origin. Seventy-one Arab children with IBD were compared with 165 Ashkenazi and 158 Sephardic Jewish children. Age and gender did not differ between groups. Sephardic and Ashkenazi Jewish Crohn's disease (CD) patients had significantly more stenotic behavior (24 and 26 vs. 5%, p = 0.03) and less fistulzing perianal disease (15 and 11 vs. 31%, p = 0.014) compared with Arab patients. Arab children with ulcerative colitis (UC) had more severe disease at diagnosis compared to Sephardic and Ashkenazi Jews reflected by higher Pediatric UC Activity Index (45 vs. 35 and 35, respectively, p = 0.03). Arab patients had significantly lower proportion of anti-Saccharomyces cerevisiae antibodies positivity (in CD) and perinuclear anti-neutrophil cytoplasmic antibodies positivity (in UC) than both Sephardic and Ashkenazi Jewish children (23 vs. 53 and 65%, p = 0.002 and 35 vs. 60 and 75%, respectively, p = 0.002). Arab and Jewish children with IBD differ in disease characteristics and severity. Whether genetic or environmental factors are the cause for these differences is yet to be determined.

Does Affective Theory of Mind Contribute to Proactive Aggression in Boys with Conduct Problems and Psychopathic Tendencies?

PubMed

Gillespie, Steven M; Kongerslev, Mickey T; Sharp, Carla; Bo, Sune; Abu-Akel, Ahmad M

2018-04-27

Adolescent psychopathic tendencies are associated with phenotypic increases in proactive aggression. However, the extent to which an understanding of others' affective mental states, or affective theory of mind (ToM), contributes to proactive aggression remains unknown. We examined how performance on a well-known test of affective ToM, based on cropped images of the eye region, contributes to reactive and proactive types of aggression in a mixed ethnicity sample of 80 incarcerated adolescent boys. A hierarchical regression model showed that affective ToM predicted proactive aggression over and above the influence of clinically rated psychopathic tendencies. Importantly, affective ToM was unrelated to reactive aggression. Our results suggest that being able to recognize others' affective mental states may be an important factor in aggressing against others for personal gain. These findings have implications for interventions designed to enhance ToM in youth with conduct problems.

Biomarkers of aggression in dementia.

PubMed

Gotovac, Kristina; Nikolac Perković, Matea; Pivac, Nela; Borovečki, Fran

2016-08-01

Dementia is a clinical syndrome defined by progressive global impairment of acquired cognitive abilities. It can be caused by a number of underlying conditions. The most common types of dementia are Alzheimer's disease (AD), frontotemporal dementia (FTD), vascular cognitive impairment (VCI) and dementia with Lewy bodies (DLB). Despite the fact that cognitive impairment is central to the dementia, noncognitive symptoms, most commonly described nowadays as neuropsychiatric symptoms (NPS) exist almost always at certain point of the illness. Aggression as one of the NPS represents danger both for patients and caregivers and the rate of aggression correlates with the loss of independence, cognitive decline and poor outcome. Therefore, biomarkers of aggression in dementia patients would be of a great importance. Studies have shown that different genetic factors, including monoamine signaling and processing, can be associated with various NPS including aggression. There have been significant and multiple neurotransmitter changes identified in the brains of patients with dementia and some of these changes have been involved in the etiology of NPS. Aggression specific changes have also been observed in neuropathological studies. The current consensus is that the best approach for development of such biomarkers may be incorporation of genetics (polymorphisms), neurobiology (neurotransmitters and neuropathology) and neuroimaging techniques. Copyright © 2016 Elsevier Inc. All rights reserved.

IGF-1 intranasal administration rescues Huntington's disease phenotypes in YAC128 mice.

PubMed

Lopes, Carla; Ribeiro, Márcio; Duarte, Ana I; Humbert, Sandrine; Saudou, Frederic; Pereira de Almeida, Luís; Hayden, Michael; Rego, A Cristina

2014-06-01

Huntington's disease (HD) is an autosomal dominant disease caused by an expansion of CAG repeats in the gene encoding for huntingtin. Brain metabolic dysfunction and altered Akt signaling pathways have been associated with disease progression. Nevertheless, conflicting results persist regarding the role of insulin-like growth factor-1 (IGF-1)/Akt pathway in HD. While high plasma levels of IGF-1 correlated with cognitive decline in HD patients, other data showed protective effects of IGF-1 in HD striatal neurons and R6/2 mice. Thus, in the present study, we investigated motor phenotype, peripheral and central metabolic profile, and striatal and cortical signaling pathways in YAC128 mice subjected to intranasal administration of recombinant human IGF-1 (rhIGF-1) for 2 weeks, in order to promote IGF-1 delivery to the brain. We show that IGF-1 supplementation enhances IGF-1 cortical levels and improves motor activity and both peripheral and central metabolic abnormalities in YAC128 mice. Moreover, decreased Akt activation in HD mice brain was ameliorated following IGF-1 administration. Upregulation of Akt following rhIGF-1 treatment occurred concomitantly with increased phosphorylation of mutant huntingtin on Ser421. These data suggest that intranasal administration of rhIGF-1 ameliorates HD-associated glucose metabolic brain abnormalities and mice phenotype.

Assessment of owner-directed aggressive behavioural tendencies of dogs in situations of possession and manipulation.

PubMed

Bálint, Anna; Rieger, Gabriella; Miklósi, Ádám; Pongrácz, Péter

2017-10-01

Excessive aggression is a common behaviour problem in dogs that can have various destructive effects on the affected people and the implicated dog. Aggressive behaviour directed towards the owner or other family members is one of the most frequently occurring aggressive phenotypes. Here, we examine the reliability of a short questionnaire assessing aggressive behaviours by two, contextually different behavioural tests: 'take away bone' and 'roll over'. Based on dogs' behaviour in the tests, we sorted dogs ( N  = 93) in two groups for each test, namely a less and a more disobedient/resistant group. The two principal components obtained in our questionnaire-'obedient' and 'aggressive towards owner'-showed significant differences between the behaviour groups. While dogs in the less disobedient/resistant groups had significantly higher 'obedient' and significantly lower 'aggressive towards owner' scores, dogs in the more disobedient/resistant groups had significantly higher 'aggressive towards owner' and significantly lower 'obedient' scores. Dogs' age, sex and neuter/spay status expressed their effect through interactions. Males, young dogs and intact dogs were less 'obedient' than older ones, while resistant spayed/neutered dogs were more aggressive towards the owner. The questionnaire used is a safe, easy to deploy and time-efficient tool to reliably assess certain owner-directed aggressive tendencies of family dogs.

JPO2/CDCA7L and LEDGF/p75 Are Novel Mediators of PI3K/AKT Signaling and Aggressive Phenotypes in Medulloblastoma.

PubMed

Chan, Tiffany Sin Yu; Hawkins, Cynthia; Krieger, Jonathan R; McGlade, C Jane; Huang, Annie

2016-05-01

Substantial evidence links Myc-PI3K/AKT signaling to the most aggressive subtype of medulloblastoma and this axis in medulloblastoma therapy. In this study, we advance understanding of how Myc-PI3K/AKT signaling contributes to this malignancy, specifically, in identifying the Myc-interacting protein JPO2 and its partner binding protein LEDGF/p75 as critical modulators of PI3K/AKT signaling and metastasis in medulloblastoma. JPO2 overexpression induced metastatic medulloblastoma in vivo through two synergistic feed-forward regulatory circuits involving LEDGF/p75 and AKT that promote metastatic phenotypes in this setting. Overall, our findings highlight two novel prometastatic loci in medulloblastoma and point to the JPO2:LEDGF/p75 protein complex as a potentially new targetable component of PI3K/AKT signaling in medulloblastoma. Cancer Res; 76(9); 2802-12. ©2016 AACR. ©2016 American Association for Cancer Research.

Evolution of disease phenotype in adult and pediatric onset Crohn’s disease in a population-based cohort

PubMed Central

Lovasz, Barbara Dorottya; Lakatos, Laszlo; Horvath, Agnes; Szita, Istvan; Pandur, Tunde; Mandel, Michael; Vegh, Zsuzsanna; Golovics, Petra Anna; Mester, Gabor; Balogh, Mihaly; Molnar, Csaba; Komaromi, Erzsebet; Kiss, Lajos Sandor; Lakatos, Peter Laszlo

2013-01-01

AIM: To investigate the evolution of disease phenotype in adult and pediatric onset Crohn’s disease (CD) populations, diagnosed between 1977 and 2008. METHODS: Data of 506 incident CD patients were analyzed (age at diagnosis: 28.5 years, interquartile range: 22-38 years). Both in- and outpatient records were collected prospectively with a complete clinical follow-up and comprehensively reviewed in the population-based Veszprem province database, which included incident patients diagnosed between January 1, 1977 and December 31, 2008 in adult and pediatric onset CD populations. Disease phenotype according to the Montreal classification and long-term disease course was analysed according to the age at onset in time-dependent univariate and multivariate analysis. RESULTS: Among this population-based cohort, seventy-four (12.8%) pediatric-onset CD patients were identified (diagnosed ≤ 17 years of age). There was no significant difference in the distribution of disease behavior between pediatric (B1: 62%, B2: 15%, B3: 23%) and adult-onset CD patients (B1: 56%, B2: 21%, B3: 23%) at diagnosis, or during follow-up. Overall, the probability of developing complicated disease behaviour was 49.7% and 61.3% in the pediatric and 55.1% and 62.4% in the adult onset patients after 5- and 10-years of follow-up. Similarly, time to change in disease behaviour from non stricturing, non penetrating (B1) to complicated, stricturing or penetrating (B2/B3) disease was not significantly different between pediatric and adult onset CD in a Kaplan-Meier analysis. Calendar year of diagnosis (P = 0.04), ileal location (P < 0.001), perianal disease (P < 0.001), smoking (P = 0.038) and need for steroids (P < 0.001) were associated with presence of, or progression to, complicated disease behavior at diagnosis and during follow-up. A change in disease location was observed in 8.9% of patients and it was associated with smoking status (P = 0.01), but not with age at diagnosis. CONCLUSION: Long

Behavioral Phenotyping and Pathological Indicators of Parkinson's Disease in C. elegans Models

PubMed Central

Maulik, Malabika; Mitra, Swarup; Bult-Ito, Abel; Taylor, Barbara E.; Vayndorf, Elena M.

2017-01-01

Parkinson's disease (PD) is a neurodegenerative disorder with symptoms that progressively worsen with age. Pathologically, PD is characterized by the aggregation of α-synuclein in cells of the substantia nigra in the brain and loss of dopaminergic neurons. This pathology is associated with impaired movement and reduced cognitive function. The etiology of PD can be attributed to a combination of environmental and genetic factors. A popular animal model, the nematode roundworm Caenorhabditis elegans, has been frequently used to study the role of genetic and environmental factors in the molecular pathology and behavioral phenotypes associated with PD. The current review summarizes cellular markers and behavioral phenotypes in transgenic and toxin-induced PD models of C. elegans. PMID:28659967

Localized severe aggressive periodontitis. Disease progression and tooth preservation: a short case report over 14 years.

PubMed

Pelka, Matthias; Petschelt, Anselm

2009-04-01

A case of a 31-year-old female with aggressive periodontitis over 14 years is presented. From 1993 to 2000, no periodontal therapy occurred; disease development and progression could be reconstructed upon radiographic findings. In 2000, full-mouth disinfection therapy and antibiotic therapy was performed, as well as regenerative surgical treatments. Seven years after surgical treatment, stable periodontal conditions and clear bone regeneration in the surgical areas was evident.

Orthodontic Management in Aggressive Periodontitis

PubMed Central

Bhattarai, Bhagabat

2017-01-01

Aggressive periodontitis is a type of periodontitis with early onset and rapid progression and mostly affecting young adults who occupy a large percentage of orthodontic patients. The role of the orthodontist is important in screening the disease, making a provisional diagnosis, and referring it to a periodontist for immediate treatment. The orthodontist should be aware of the disease not only before starting the appliance therapy, but also during and after the active mechanotherapy. The orthodontic treatment plan, biomechanics, and appliance system may need to be modified to deal with the teeth having reduced periodontal support. With proper force application and oral hygiene maintenance, orthodontic tooth movement is possible without any deleterious effect in the tooth with reduced bone support. With proper motivation and interdisciplinary approach, orthodontic treatment is possible in patients with controlled aggressive periodontitis. PMID:28299350

Genome Analyses of an Aggressive and Invasive Lineage of the Irish Potato Famine Pathogen

PubMed Central

Raffaele, Sylvain; Bain, Ruairidh A.; Cooke, Louise R.; Etherington, Graham J.; Deahl, Kenneth L.; Farrer, Rhys A.; Gilroy, Eleanor M.; Goss, Erica M.; Grünwald, Niklaus J.; Hein, Ingo; MacLean, Daniel; McNicol, James W.; Randall, Eva; Oliva, Ricardo F.; Pel, Mathieu A.; Shaw, David S.; Squires, Julie N.; Taylor, Moray C.; Vleeshouwers, Vivianne G. A. A.; Birch, Paul R. J.; Lees, Alison K.; Kamoun, Sophien

2012-01-01

Pest and pathogen losses jeopardise global food security and ever since the 19th century Irish famine, potato late blight has exemplified this threat. The causal oomycete pathogen, Phytophthora infestans, undergoes major population shifts in agricultural systems via the successive emergence and migration of asexual lineages. The phenotypic and genotypic bases of these selective sweeps are largely unknown but management strategies need to adapt to reflect the changing pathogen population. Here, we used molecular markers to document the emergence of a lineage, termed 13_A2, in the European P. infestans population, and its rapid displacement of other lineages to exceed 75% of the pathogen population across Great Britain in less than three years. We show that isolates of the 13_A2 lineage are among the most aggressive on cultivated potatoes, outcompete other aggressive lineages in the field, and overcome previously effective forms of plant host resistance. Genome analyses of a 13_A2 isolate revealed extensive genetic and expression polymorphisms particularly in effector genes. Copy number variations, gene gains and losses, amino-acid replacements and changes in expression patterns of disease effector genes within the 13_A2 isolate likely contribute to enhanced virulence and aggressiveness to drive this population displacement. Importantly, 13_A2 isolates carry intact and in planta induced Avrblb1, Avrblb2 and Avrvnt1 effector genes that trigger resistance in potato lines carrying the corresponding R immune receptor genes Rpi-blb1, Rpi-blb2, and Rpi-vnt1.1. These findings point towards a strategy for deploying genetic resistance to mitigate the impact of the 13_A2 lineage and illustrate how pathogen population monitoring, combined with genome analysis, informs the management of devastating disease epidemics. PMID:23055926

Xeroderma pigmentosum is a definite cause of Huntington's disease-like syndrome.

PubMed

Garcia-Moreno, Hector; Fassihi, Hiva; Sarkany, Robert P E; Phukan, Julie; Warner, Thomas; Lehmann, Alan R; Giunti, Paola

2018-01-01

Xeroderma pigmentosum is characterized by cutaneous, ophthalmological, and neurological features. Although it is typical of childhood, late presentations can mimic different neurodegenerative conditions. We report two families presenting as Huntington's disease-like syndromes. The first case (group G) presented with neuropsychiatric features, cognitive decline and chorea. Typical lentigines were only noticed after the neurological disease started. The second case (group B) presented adult-onset chorea and neuropsychiatric symptoms after an aggressive ocular melanoma. Xeroderma pigmentosum can manifest as a Huntington's Disease-like syndrome. Classic dermatological and oncological features have to be investigated in choreic patients with negative genetic tests for Huntington's disease-like phenotypes.

Maintaining intestinal health: the genetics and immunology of very early onset inflammatory bowel disease.

PubMed

Kelsen, Judith R; Baldassano, Robert N; Artis, David; Sonnenberg, Gregory F

2015-09-01

Inflammatory bowel disease (IBD) is a multifactoral disease caused by dysregulated immune responses to commensal or pathogenic microbes in the intestine, resulting in chronic intestinal inflammation. An emerging population of patients with IBD occurring before the age of 5 represent a unique form of disease, termed Very Early Onset (VEO)-IBD, which is phenotypically- and genetically-distinct from older-onset IBD. VEO-IBD is associated with increased disease severity, aggressive progression and poor responsiveness to most conventional therapies. Further investigation into the causes and pathogenesis of VEO-IBD will help improve treatment strategies, and may lead to a better understanding of the mechanisms that are essential to maintain intestinal health or provoke the development of targeted therapeutic strategies to limit intestinal disease. Here we discuss the phenotypic nature of VEO-IBD, the recent identification of novel gene variants associated with disease, and functional immunologic studies interrogating the contribution of specific genetic variants to the development of chronic intestinal inflammation.

Parents’ Aggressive Influences and Children's Aggressive Problem Solutions with Peers

PubMed Central

Duman, Sarah; Margolin, Gayla

2009-01-01

This study examined children's aggressive and assertive solutions to hypothetical peer scenarios in relation to parents’ responses to similar hypothetical social scenarios and parents’ actual marital aggression. The study included 118 9−10 year old children, and their mothers and fathers. Children's aggressive solutions correlated with same-sex parents’ actual marital aggression. For children with mothers who exhibit low actual marital aggression, mothers’ aggressive solutions to hypothetical situations corresponded with children's tendencies to propose aggressive but not assertive solutions. In a 3-way interaction, fathers’ aggressive solutions to peer scenarios and marital aggression, combined, exacerbated girls’ aggressive problem solving, but had the opposite effect for boys. Discussion addresses the complexity, particularly with respect to parent and child gender combinations, in understanding parents’ aggressive influences on children's peer relationships. PMID:17206880

Haptoglobin Phenotype Modifies Serum Iron Levels and the Effect of Smoking on Parkinson Disease Risk

PubMed Central

Costa-Mallen, Paola; Zabetian, Cyrus P.; Agarwal, Pinky; Hu, Shu-Ching; Yearout, Dora; Samii, Ali; Leverenz, James B.; Roberts, John W.; Checkoway, Harvey

2015-01-01

Introduction Haptoglobin is a hemoglobin-binding protein that exists in three functionally different phenotypes, and haptoglobin phenotype 2-1 has previously been associated with Parkinson disease (PD) risk, with mechanisms not elucidated. Some evidence is emerging that low levels of serum iron may increase PD risk. In this study we investigated whether PD patients have lower serum iron and ferritin than controls, and whether this is dependent on haptoglobin phenotype. We also investigated the effect of Hp phenotype as a modifier of the effect of smoking on PD risk. Methods The study population consisted of 128 PD patients and 226 controls. Serum iron, ferritin, and haptoglobin phenotype were determined, and compared between PD cases and controls. Stratified analysis by haptoglobin phenotype was performed to determine effect of haptoglobin phenotype on serum iron parameter differences between PD cases and controls and to investigate its role in the protective effect of smoking on PD risk. Results PD cases had lower serum iron than controls (83.28 ug/100ml vs 94.00 ug/100 ml, p 0.006), and in particular among subjects with phenotype 2-1. The protective effect of smoking on PD risk resulted stronger in subjects with phenotype 1-1 and 2-2, and weakest among subjects with phenotype 2-1. Ferritin levels were higher in PD cases than controls among subjects of White ethnicity. Conclusions Our results report for the first time that the haptoglobin phenotype may be a contributor of iron levels abnormalities in PD patients. The mechanisms for these haptoglobin-phenotype specific effects will have to be further elucidated. PMID:26228081

The Prevalence and Phenomenology of Self-Injurious and Aggressive Behaviour in Genetic Syndromes

ERIC Educational Resources Information Center

Arron, K.; Oliver, C.; Moss, J.; Berg, K.; Burbidge, C.

2011-01-01

Background: Self-injurious and aggressive behaviours are reported as components of some behavioural phenotypes but there are few studies comparing across syndrome groups. In this study we examined the prevalence of these behaviours and the associated person characteristics in seven genetic syndromes. Methods: Questionnaire data on self-injury and…

Aging Microglia—Phenotypes, Functions and Implications for Age-Related Neurodegenerative Diseases

PubMed Central

Spittau, Björn

2017-01-01

Aging of the central nervous system (CNS) is one of the major risk factors for the development of neurodegenerative pathologies such as Parkinson’s disease (PD) and Alzheimer’s disease (AD). The molecular mechanisms underlying the onset of AD and especially PD are not well understood. However, neuroinflammatory responses mediated by microglia as the resident immune cells of the CNS have been reported for both diseases. The unique nature and developmental origin of microglia causing microglial self-renewal and telomere shortening led to the hypothesis that these CNS-specific innate immune cells become senescent. Age-dependent and senescence-driven impairments of microglia functions and responses have been suggested to play essential roles during onset and progression of neurodegenerative diseases. This review article summarizes the current knowledge of microglia phenotypes and functions in the aging CNS and further discusses the implications of these age-dependent microglia changes for the development and progression of AD and PD as the most common neurodegenerative diseases. PMID:28659790

Toward a Reasoned Classification of Diseases Using Physico-Chemical Based Phenotypes

PubMed Central

Schwartz, Laurent; Lafitte, Olivier; da Veiga Moreira, Jorgelindo

2018-01-01

Background: Diseases and health conditions have been classified according to anatomical site, etiological, and clinical criteria. Physico-chemical mechanisms underlying the biology of diseases, such as the flow of energy through cells and tissues, have been often overlooked in classification systems. Objective: We propose a conceptual framework toward the development of an energy-oriented classification of diseases, based on the principles of physical chemistry. Methods: A review of literature on the physical chemistry of biological interactions in a number of diseases is traced from the point of view of the fluid and solid mechanics, electricity, and chemistry. Results: We found consistent evidence in literature of decreased and/or increased physical and chemical forces intertwined with biological processes of numerous diseases, which allowed the identification of mechanical, electric and chemical phenotypes of diseases. Discussion: Biological mechanisms of diseases need to be evaluated and integrated into more comprehensive theories that should account with principles of physics and chemistry. A hypothetical model is proposed relating the natural history of diseases to mechanical stress, electric field, and chemical equilibria (ATP) changes. The present perspective toward an innovative disease classification may improve drug-repurposing strategies in the future. PMID:29541031

Alterations of the spindle checkpoint pathway in clinicopathologically aggressive CpG island methylator phenotype clear cell renal cell carcinomas.

PubMed

Arai, Eri; Gotoh, Masahiro; Tian, Ying; Sakamoto, Hiromi; Ono, Masaya; Matsuda, Akio; Takahashi, Yoriko; Miyata, Sayaka; Totsuka, Hirohiko; Chiku, Suenori; Komiyama, Motokiyo; Fujimoto, Hiroyuki; Matsumoto, Kenji; Yamada, Tesshi; Yoshida, Teruhiko; Kanai, Yae

2015-12-01

CpG-island methylator phenotype (CIMP)-positive clear cell renal cell carcinomas (RCCs) are characterized by accumulation of DNA hypermethylation of CpG islands, clinicopathological aggressiveness and poor patient outcome. The aim of this study was to clarify the molecular pathways participating in CIMP-positive renal carcinogenesis. Genome (whole-exome and copy number), transcriptome and proteome (two-dimensional image converted analysis of liquid chromatography-mass spectrometry) analyses were performed using tissue specimens of 87 CIMP-negative and 14 CIMP-positive clear cell RCCs and corresponding specimens of non-cancerous renal cortex. Genes encoding microtubule-associated proteins, such as DNAH2, DNAH5, DNAH10, RP1 and HAUS8, showed a 10% or higher incidence of genetic aberrations (non-synonymous single-nucleotide mutations and insertions/deletions) in CIMP-positive RCCs, whereas CIMP-negative RCCs lacked distinct genetic characteristics. MetaCore pathway analysis of CIMP-positive RCCs revealed that alterations of mRNA or protein expression were significantly accumulated in six pathways, all participating in the spindle checkpoint, including the "The metaphase checkpoint (p = 1.427 × 10(-6))," "Role of Anaphase Promoting Complex in cell cycle regulation (p = 7.444 × 10(-6))" and "Spindle assembly and chromosome separation (p = 9.260 × 10(-6))" pathways. Quantitative RT-PCR analysis revealed that mRNA expression levels for genes included in such pathways, i.e., AURKA, AURKB, BIRC5, BUB1, CDC20, NEK2 and SPC25, were significantly higher in CIMP-positive than in CIMP-negative RCCs. All CIMP-positive RCCs showed overexpression of Aurora kinases, AURKA and AURKB, and this overexpression was mainly attributable to increased copy number. These data suggest that abnormalities of the spindle checkpoint pathway participate in CIMP-positive renal carcinogenesis, and that AURKA and AURKB may be potential therapeutic targets in more aggressive CIMP-positive RCCs. �

Alterations of the spindle checkpoint pathway in clinicopathologically aggressive CpG island methylator phenotype clear cell renal cell carcinomas

PubMed Central

Arai, Eri; Gotoh, Masahiro; Tian, Ying; Sakamoto, Hiromi; Ono, Masaya; Matsuda, Akio; Takahashi, Yoriko; Miyata, Sayaka; Totsuka, Hirohiko; Chiku, Suenori; Komiyama, Motokiyo; Fujimoto, Hiroyuki; Matsumoto, Kenji; Yamada, Tesshi; Yoshida, Teruhiko

2015-01-01

CpG‐island methylator phenotype (CIMP)‐positive clear cell renal cell carcinomas (RCCs) are characterized by accumulation of DNA hypermethylation of CpG islands, clinicopathological aggressiveness and poor patient outcome. The aim of this study was to clarify the molecular pathways participating in CIMP‐positive renal carcinogenesis. Genome (whole‐exome and copy number), transcriptome and proteome (two‐dimensional image converted analysis of liquid chromatography‐mass spectrometry) analyses were performed using tissue specimens of 87 CIMP‐negative and 14 CIMP‐positive clear cell RCCs and corresponding specimens of non‐cancerous renal cortex. Genes encoding microtubule‐associated proteins, such as DNAH2, DNAH5, DNAH10, RP1 and HAUS8, showed a 10% or higher incidence of genetic aberrations (non‐synonymous single‐nucleotide mutations and insertions/deletions) in CIMP‐positive RCCs, whereas CIMP‐negative RCCs lacked distinct genetic characteristics. MetaCore pathway analysis of CIMP‐positive RCCs revealed that alterations of mRNA or protein expression were significantly accumulated in six pathways, all participating in the spindle checkpoint, including the “The metaphase checkpoint (p = 1.427 × 10−6),” “Role of Anaphase Promoting Complex in cell cycle regulation (p = 7.444 × 10−6)” and “Spindle assembly and chromosome separation (p = 9.260 × 10−6)” pathways. Quantitative RT‐PCR analysis revealed that mRNA expression levels for genes included in such pathways, i.e., AURKA, AURKB, BIRC5, BUB1, CDC20, NEK2 and SPC25, were significantly higher in CIMP‐positive than in CIMP‐negative RCCs. All CIMP‐positive RCCs showed overexpression of Aurora kinases, AURKA and AURKB, and this overexpression was mainly attributable to increased copy number. These data suggest that abnormalities of the spindle checkpoint pathway participate in CIMP‐positive renal carcinogenesis, and that AURKA and AURKB may be potential

Integration of Multiple Genomic and Phenotype Data to Infer Novel miRNA-Disease Associations

PubMed Central

Zhou, Meng; Cheng, Liang; Yang, Haixiu; Wang, Jing; Sun, Jie; Wang, Zhenzhen

2016-01-01

MicroRNAs (miRNAs) play an important role in the development and progression of human diseases. The identification of disease-associated miRNAs will be helpful for understanding the molecular mechanisms of diseases at the post-transcriptional level. Based on different types of genomic data sources, computational methods for miRNA-disease association prediction have been proposed. However, individual source of genomic data tends to be incomplete and noisy; therefore, the integration of various types of genomic data for inferring reliable miRNA-disease associations is urgently needed. In this study, we present a computational framework, CHNmiRD, for identifying miRNA-disease associations by integrating multiple genomic and phenotype data, including protein-protein interaction data, gene ontology data, experimentally verified miRNA-target relationships, disease phenotype information and known miRNA-disease connections. The performance of CHNmiRD was evaluated by experimentally verified miRNA-disease associations, which achieved an area under the ROC curve (AUC) of 0.834 for 5-fold cross-validation. In particular, CHNmiRD displayed excellent performance for diseases without any known related miRNAs. The results of case studies for three human diseases (glioblastoma, myocardial infarction and type 1 diabetes) showed that all of the top 10 ranked miRNAs having no known associations with these three diseases in existing miRNA-disease databases were directly or indirectly confirmed by our latest literature mining. All these results demonstrated the reliability and efficiency of CHNmiRD, and it is anticipated that CHNmiRD will serve as a powerful bioinformatics method for mining novel disease-related miRNAs and providing a new perspective into molecular mechanisms underlying human diseases at the post-transcriptional level. CHNmiRD is freely available at http://www.bio-bigdata.com/CHNmiRD. PMID:26849207

Integration of Multiple Genomic and Phenotype Data to Infer Novel miRNA-Disease Associations.

PubMed

Shi, Hongbo; Zhang, Guangde; Zhou, Meng; Cheng, Liang; Yang, Haixiu; Wang, Jing; Sun, Jie; Wang, Zhenzhen

2016-01-01

MicroRNAs (miRNAs) play an important role in the development and progression of human diseases. The identification of disease-associated miRNAs will be helpful for understanding the molecular mechanisms of diseases at the post-transcriptional level. Based on different types of genomic data sources, computational methods for miRNA-disease association prediction have been proposed. However, individual source of genomic data tends to be incomplete and noisy; therefore, the integration of various types of genomic data for inferring reliable miRNA-disease associations is urgently needed. In this study, we present a computational framework, CHNmiRD, for identifying miRNA-disease associations by integrating multiple genomic and phenotype data, including protein-protein interaction data, gene ontology data, experimentally verified miRNA-target relationships, disease phenotype information and known miRNA-disease connections. The performance of CHNmiRD was evaluated by experimentally verified miRNA-disease associations, which achieved an area under the ROC curve (AUC) of 0.834 for 5-fold cross-validation. In particular, CHNmiRD displayed excellent performance for diseases without any known related miRNAs. The results of case studies for three human diseases (glioblastoma, myocardial infarction and type 1 diabetes) showed that all of the top 10 ranked miRNAs having no known associations with these three diseases in existing miRNA-disease databases were directly or indirectly confirmed by our latest literature mining. All these results demonstrated the reliability and efficiency of CHNmiRD, and it is anticipated that CHNmiRD will serve as a powerful bioinformatics method for mining novel disease-related miRNAs and providing a new perspective into molecular mechanisms underlying human diseases at the post-transcriptional level. CHNmiRD is freely available at http://www.bio-bigdata.com/CHNmiRD.

The Impact of "Possible Patients" on Phenotyping Algorithms: Electronic Phenotype Algorithms Can Only Be Reproduced by Sharing Detailed Annotation Criteria.

PubMed

Kagawa, Rina; Kawazoe, Yoshimasa; Shinohara, Emiko; Imai, Takeshi; Ohe, Kazuhiko

2017-01-01

Phenotyping is an automated technique for identifying patients diagnosed with a particular disease based on electronic health records (EHRs). To evaluate phenotyping algorithms, which should be reproducible, the annotation of EHRs as a gold standard is critical. However, we have found that the different types of EHRs cannot be definitively annotated into CASEs or CONTROLs. The influence of such "possible patients" on phenotyping algorithms is unknown. To assess these issues, for four chronic diseases, we annotated EHRs by using information not directly referring to the diseases and developed two types of phenotyping algorithms for each disease. We confirmed that each disease included different types of possible patients. The performance of phenotyping algorithms differed depending on whether possible patients were considered as CASEs, and this was independent of the type of algorithms. Our results indicate that researchers must share annotation criteria for classifying the possible patients to reproduce phenotyping algorithms.

Thyroid Hormone Differentially Modulates Warburg Phenotype in Breast Cancer Cells

PubMed Central

Suhane, Sonal; Ramanujan, V Krishnan

2011-01-01

Sustenance of cancer cells in vivo critically depends on a variety of genetic and metabolic adaptations. Aerobic glycolysis or Warburg effect has been a defining biochemical hallmark of transformed cells for more than five decades although a clear molecular basis of this observation is emerging only in recent years. In this study, we present our findings that thyroid hormone exerts its non-genomic and genomic actions in two model human breast cancer cell lines differentially. By laying a clear foundation for experimentally monitoring the Warburg phenotype in living cancer cells, we demonstrate that thyroid hormone-induced modulation of bioenergetic profiles in these two model cell lines depends on the degree of Warburg phenotype that they display. Further we also show that thyroid hormone can sensitize mitochondria in aggressive, triple-negative breast cancer cells favorably to increase the chemotherapeutic efficacy in these cells. Even though the role of thyroid hormone in modulating mitochondrial metabolism has been known, the current study accentuates the critical role it plays in modulating Warburg phenotype in breast cancer cells. The clinical significance of this finding is the possibility to devise strategies for metabolically modulating aggressive triple-negative tumors so as to enhance their chemosensitivity in vivo. PMID:21945435

Adolescents’ Aggression to Parents: Longitudinal Links with Parents’ Physical Aggression

PubMed Central

Margolin, Gayla; Baucom, Brian R.

2014-01-01

Purpose To investigate whether parents’ previous physical aggression (PPA) exhibited during early adolescence is associated with adolescents’ subsequent parent-directed aggression even beyond parents’ concurrent physical aggression (CPA); to investigate whether adolescents’ emotion dysregulation and attitudes condoning child-to-parent aggression moderate associations. Methods Adolescents (N = 93) and their parents participated in a prospective, longitudinal study. Adolescents and parents reported at waves 1–3 on four types of parents’ PPA (mother-to-adolescent, father-to-adolescent, mother-to-father, father-to-mother). Wave 3 assessments also included adolescents’ emotion dysregulation, attitudes condoning aggression, and externalizing behaviors. At waves 4 and 5, adolescents and parents reported on adolescents’ parent-directed physical aggression, property damage, and verbal aggression, and on parents’ CPA Results Parents’ PPA emerged as a significant indicator of adolescents’ parent-directed physical aggression (odds ratio [OR]: 1.25, 95% confidence interval [CI]: 1.0–1.55; p = .047), property damage (OR: 1.29, 95% CI: 1.1–1.5, p = .002), and verbal aggression (OR: 1.35, 95% CI: 1.15–1.6, p < .001) even controlling for adolescents’ sex, externalizing behaviors, and family income. When controlling for parents’ CPA, previous mother-to-adolescent aggression still predicted adolescents’ parent-directed physical aggression (OR: 5.56, 95% CI: 1.82–17.0, p = .003), and father-to-mother aggression predicted adolescents’ parent-directed verbal aggression (OR: 1.86, 95% CI: 1.0–3.3, p = .036). Emotion dysregulation and attitudes condoning aggression did not produce direct or moderated effects. Conclusions Adolescents’ parent-directed aggression deserves greater attention in discourse about lasting, adverse effects of even minor forms of parents’ physical aggression. Future research should investigate parent-directed aggression as

Minimally-aggressive gestational trophoblastic neoplasms.

PubMed

Cole, Laurence A

2012-04-01

We have previously defined a new syndrome "Minimally-aggressive gestational trophoblastic neoplasms" in which choriocarcinoma or persistent hydatidiform mole has a minimal growth rate and becomes chemorefractory. Previously we described a new treatment protocol, waiting for hCG rise to >3000 mIU/ml and disease becomes more advanced, then using combination chemotherapy. Initially we found this treatment successful in 8 of 8 cases, here we find this protocol appropriate in a further 16 cases. Initially we used hyperglycosylated hCG, a limited availability test, to identify this syndrome. Here we propose also using hCG doubling rate to detect this syndrome. Minimally aggressive gestational trophoblastic disease can be detected by chemotherapy resistance or low hyperglycosylated hCG, <40% of total hCG. It can also be identified by hCG doubling rate, with doubling time greater than 2 weeks. Nineteen new cases were identified as having minimally aggressive gestational trophoblastic disease by hyperglycosylated hCG and by hCG doubling test. All were recommended to hold off further chemotherapy until hCG >3000mIU/ml. One case died prior to the start of the study, one case withdrew because of a lung nodule and one withdrew refusing the suggested combination chemotherapy. The remaining 16 women were all successfully treated. A total of 8 plus 16 or 24 of 24 women were successfully treated using the proposed protocol, holding back on chemotherapy until hCG >3000mIU/ml. Copyright © 2011 Elsevier Inc. All rights reserved.

IDH1(R132H) mutation causes a less aggressive phenotype and radiosensitizes human malignant glioma cells independent of the oxygenation status.

PubMed

Kessler, Jacqueline; Güttler, Antje; Wichmann, Henri; Rot, Swetlana; Kappler, Matthias; Bache, Matthias; Vordermark, Dirk

2015-09-01

In malignant glioma the presence of the IDH1 mutation (IDH1(R132H)) is associated with better clinical outcome. However, it is unclear whether IDH1 mutation is associated with a less aggressive phenotype or directly linked to increased sensitivity to radiotherapy. We determined the influence of IDH1(R132H) mutant protein on proliferation and growth in 3D culture, migration, cell survival and radiosensitivity in vitro under normoxia (21% O2) and hypoxia (<1% O2) in a panel of human malignant glioma cell lines (U-251MG, U-343MG, LN-229) with stable overexpression of wild-type (IDH1(wt)) and mutated IDH1 (IDH1(R132H)). Overexpression of IDH1(R132H) in glioma cells resulted in slightly decreased cell proliferation, considerably reduced cell migration and caused differences in growth properties in 3D spheroid cultures. Furthermore, IDH1(R132H)-positive cells consistently demonstrated an increased radiosensitivity in human malignant glioma cells U-251MG (DMF10: 1.52, p<0.01 and 1.42, p<0.01), U-343MG (DMF10: 1.78, p<0.01 and 1.75, p<0.01) and LN-229 (DMF10: 1.41, p<0.05 and 1.68, p<0.01) under normoxia and hypoxia, respectively. Our data indicate that IDH1(R132H) mutation causes both a less aggressive biological behavior and direct radiosensitization of human malignant glioma cells. Targeting IDH1 appears to be an attractive approach in combination with radiotherapy. Copyright © 2015 Elsevier Ireland Ltd. All rights reserved.

Assessment of owner-directed aggressive behavioural tendencies of dogs in situations of possession and manipulation

PubMed Central

Bálint, Anna; Rieger, Gabriella; Miklósi, Ádám

2017-01-01

Excessive aggression is a common behaviour problem in dogs that can have various destructive effects on the affected people and the implicated dog. Aggressive behaviour directed towards the owner or other family members is one of the most frequently occurring aggressive phenotypes. Here, we examine the reliability of a short questionnaire assessing aggressive behaviours by two, contextually different behavioural tests: ‘take away bone’ and ‘roll over’. Based on dogs' behaviour in the tests, we sorted dogs (N = 93) in two groups for each test, namely a less and a more disobedient/resistant group. The two principal components obtained in our questionnaire—‘obedient’ and ‘aggressive towards owner’—showed significant differences between the behaviour groups. While dogs in the less disobedient/resistant groups had significantly higher ‘obedient’ and significantly lower ‘aggressive towards owner’ scores, dogs in the more disobedient/resistant groups had significantly higher ‘aggressive towards owner’ and significantly lower ‘obedient’ scores. Dogs' age, sex and neuter/spay status expressed their effect through interactions. Males, young dogs and intact dogs were less ‘obedient’ than older ones, while resistant spayed/neutered dogs were more aggressive towards the owner. The questionnaire used is a safe, easy to deploy and time-efficient tool to reliably assess certain owner-directed aggressive tendencies of family dogs. PMID:29134099

Systematic detection of polyvascular disease combined with aggressive secondary prevention in patients presenting with severe coronary artery disease: The randomized AMERICA Study.

PubMed

Collet, Jean-Philippe; Cayla, Guillaume; Ennezat, Pierre-Vladimir; Leclercq, Florence; Cuisset, Thomas; Elhadad, Simon; Henry, Patrick; Belle, Loic; Cohen, Ariel; Silvain, Johanne; Barthelemy, Olivier; Beygui, Farzin; Diallo, Abdourahmane; Vicaut, Eric; Montalescot, Gilles

2018-03-01

The prevalence and associated-risk of asymptomatic multisite artery disease (MSAD) in high risk coronary patients are unknown. Whether systematic identification and aggressive management of asymptomatic MSAD is clinically relevant in high risk coronary patients has not been evaluated. We randomly assigned 521 high risk coronary patients defined by the presence of three-vessel coronary disease (n=304) or recent acute coronary syndrome beyond the age of 75years (n=215) to either a strategy of systematic detection of asymptomatic MSAD combined with an aggressive secondary prevention (n=263) or to a more conventional strategy based on treatment of coronary artery disease only with standard of care (n=258). The primary end point was the time to first occurrence of death, any organ failure or ischemic event leading to re-hospitalization through two years of follow-up. The pro-active strategy identified asymptomatic MSAD in 21.7% of patients with few revascularizations (3.6%); the pro-active pharmacological secondary prevention was obtained in >85% of patients and life-style changes in <60% of patients. At 2-year follow-up, the primary end point occurred in 44.9% of patients in the pro-active group and 43.0% of patients in the conventional group (HR 1.03; 95% confidence interval [CI], 0.80 to 1.34]. The rate of major bleeding did not differ significantly between groups (4.6% vs 5.0%; HR, 0.97; 95% CI, 0.40 to 1.91). In high risk coronary patients, there is no apparent benefit of a systematic detection of asymptomatic extra-coronary atherothrombotic disease and intensified treatment over a 2-year follow-up period. (Funded by the Academic Allies in Cardiovascular Trials Initiatives and Organized Networks and Institut de l'Athérothrombose; AMERICA ClinicalTrials.gov number, NCT00445835). Copyright © 2017 Elsevier Ireland Ltd. All rights reserved.

Simultaneous induction of jasmonic acid and disease-responsive genes signifies tolerance of American elm to Dutch elm disease

PubMed Central

Sherif , S. M.; Shukla, M. R.; Murch, S. J.; Bernier, L.; Saxena, P. K.

2016-01-01

Dutch elm disease (DED), caused by three fungal species in the genus Ophiostoma, is the most devastating disease of both native European and North American elm trees. Although many tolerant cultivars have been identified and released, the tolerance mechanisms are not well understood and true resistance has not yet been achieved. Here we show that the expression of disease-responsive genes in reactions leading to tolerance or susceptibility is significantly differentiated within the first 144 hours post-inoculation (hpi). Analysis of the levels of endogenous plant defense molecules such as jasmonic acid (JA) and salicylic acid (SA) in tolerant and susceptible American elm saplings suggested SA and methyl-jasmonate as potential defense response elicitors, which was further confirmed by field observations. However, the tolerant phenotype can be best characterized by a concurrent induction of JA and disease-responsive genes at 96 hpi. Molecular investigations indicated that the expression of fungal genes (i.e. cerato ulmin) was also modulated by endogenous SA and JA and this response was unique among aggressive and non-aggressive fungal strains. The present study not only provides better understanding of tolerance mechanisms to DED, but also represents a first, verified template for examining simultaneous transcriptomic changes during American elm-fungus interactions. PMID:26902398

Ineffective esophageal motility phenotypes following fundoplication in gastroesophageal reflux disease.

PubMed

Mello, M D; Shriver, A R; Li, Y; Patel, A; Gyawali, C P

2016-02-01

Ineffective esophageal motility (IEM) is associated with reflux disease, but its natural history is unclear. We evaluated patients undergoing repeat esophageal high resolution manometry (HRM) for symptomatic presentations after antireflux surgery (ARS) to understand the progression of IEM. Patients with repeat HRM after ARS were included. Ineffective esophageal motility was diagnosed if ≥5 sequences had distal contractile integral (DCI) <450 mmHg cm s. Augmentation of DCI following multiple rapid swallows (MRS) was assessed. The esophagogastric junction (EGJ) was interrogated using the EGJ contractile integral (EGJ-CI). Esophageal motor function was compared between patients with and without IEM. Sixty-eight patients (53.9 ± 1.8 years, 66.2% female) had pre- and post-ARS HRM studies 2.1 ± 0.19 years apart. Esophagogastric junction-CI augmented by a mean of 26.3% following ARS. Four IEM phenotypes were identified: 14.7% had persistent IEM, 8.8% resolved IEM after ARS, 19.1% developed new IEM, and 57.4% had no IEM at any point. Patients with IEM had a lower DCI pre- and post-ARS, lower pre-ARS EGJ CI, and lower pre-ARS-integrated relaxation pressure (p ≤ 0.02 for all comparisons); presenting symptoms and other EGJ metrics were similar (p ≥ 0.08 for all comparisons). The IEM phenotypes could be predicted by MRS DCI response patterns (p = 0.008 across groups); patients with persistent IEM had the least DCI augmentation (p = 0.007 compared to no IEM), while those who resolved IEM had DCI augmentation comparable to no IEM (p = 0.08). Distinct phenotypes of IEM exist among symptomatic reflux patients following ARS. Provocative testing with MRS may help identify these phenotypes pre-ARS. © 2015 John Wiley & Sons Ltd.

Aggression Can be Contagious: Longitudinal Associations between Proactive Aggression and Reactive Aggression Among Young Twins

PubMed Central

Dickson, Daniel J.; Richmond, Ashley; Brendgen, Mara; Vitaro, Frank; Laursen, Brett; Dionne, Ginette; Boivin, Michel

2015-01-01

The present study examined sibling influence over reactive and proactive aggression in a sample of 452 same-sex twins (113 male dyads, 113 female dyads). Between and within siblings influence processes were examined as a function of relative levels of parental coercion and hostility to test the hypothesis that aggression contagion between twins occurs only among dyads who experience parental coerciveness. Teacher reports of reactive and proactive aggression were collected for each twin in kindergarten (M = 6.04 years; SD = 0.27) and in first grade (M = 7.08 years; SD = 0.27). Families were divided into relatively low, average, and relatively high parental coercion-hostility groups on the basis of maternal reports collected when the children were 5 years old. In families with relatively high levels of parental coercion-hostility, there was evidence of between-sibling influence, such that one twin’s reactive aggression at age 6 predicted increases in the other twin’s reactive aggression from ages 6 to 7, and one twin’s proactive aggression at age 6 predicted increases in the other twin’s proactive aggression from ages 6 to 7. There was also evidence of within-sibling influence such that a child’s level of reactive aggression at age 6 predicted increases in the same child’s proactive aggression at age 7, regardless of parental coercion-hostility. The findings provide new information about the etiology of reactive and proactive aggression and individual differences in their developmental interplay. PMID:25683448

Aggression can be contagious: Longitudinal associations between proactive aggression and reactive aggression among young twins.

PubMed

Dickson, Daniel J; Richmond, Ashley D; Brendgen, Mara; Vitaro, Frank; Laursen, Brett; Dionne, Ginette; Boivin, Michel

2015-01-01

The present study examined sibling influence over reactive and proactive aggression in a sample of 452 same-sex twins (113 male dyads, 113 female dyads). Between and within siblings influence processes were examined as a function of relative levels of parental coercion and hostility to test the hypothesis that aggression contagion between twins occurs only among dyads who experience parental coerciveness. Teacher reports of reactive and proactive aggression were collected for each twin in kindergarten (M = 6.04 years; SD = 0.27) and in first grade (M = 7.08 years; SD = 0.27). Families were divided into relatively low, average, and relatively high parental coercion-hostility groups on the basis of maternal reports collected when the children were 5 years old. In families with relatively high levels of parental coercion-hostility, there was evidence of between-sibling influence, such that one twin's reactive aggression at age 6 predicted increases in the other twin's reactive aggression from ages 6 to 7, and one twin's proactive aggression at age 6 predicted increases in the other twin's proactive aggression from ages 6 to 7. There was also evidence of within-sibling influence such that a child's level of reactive aggression at age 6 predicted increases in the same child's proactive aggression at age 7, regardless of parental coercion-hostility. The findings provide new information about the etiology of reactive and proactive aggression and individual differences in their developmental interplay. © 2015 Wiley Periodicals, Inc.

Genetic, Phenotypic, and Interferon Biomarker Status in ADAR1-Related Neurological Disease.

PubMed

Rice, Gillian I; Kitabayashi, Naoki; Barth, Magalie; Briggs, Tracy A; Burton, Annabel C E; Carpanelli, Maria Luisa; Cerisola, Alfredo M; Colson, Cindy; Dale, Russell C; Danti, Federica Rachele; Darin, Niklas; De Azua, Begoña; De Giorgis, Valentina; De Goede, Christian G L; Desguerre, Isabelle; De Laet, Corinne; Eslahi, Atieh; Fahey, Michael C; Fallon, Penny; Fay, Alex; Fazzi, Elisa; Gorman, Mark P; Gowrinathan, Nirmala Rani; Hully, Marie; Kurian, Manju A; Leboucq, Nicolas; Lin, Jean-Pierre S-M; Lines, Matthew A; Mar, Soe S; Maroofian, Reza; Martí-Sanchez, Laura; McCullagh, Gary; Mojarrad, Majid; Narayanan, Vinodh; Orcesi, Simona; Ortigoza-Escobar, Juan Dario; Pérez-Dueñas, Belén; Petit, Florence; Ramsey, Keri M; Rasmussen, Magnhild; Rivier, François; Rodríguez-Pombo, Pilar; Roubertie, Agathe; Stödberg, Tommy I; Toosi, Mehran Beiraghi; Toutain, Annick; Uettwiller, Florence; Ulrick, Nicole; Vanderver, Adeline; Waldman, Amy; Livingston, John H; Crow, Yanick J

2017-06-01

We investigated the genetic, phenotypic, and interferon status of 46 patients from 37 families with neurological disease due to mutations in ADAR1 . The clinicoradiological phenotype encompassed a spectrum of Aicardi-Goutières syndrome, isolated bilateral striatal necrosis, spastic paraparesis with normal neuroimaging, a progressive spastic dystonic motor disorder, and adult-onset psychological difficulties with intracranial calcification. Homozygous missense mutations were recorded in five families. We observed a p.Pro193Ala variant in the heterozygous state in 22 of 23 families with compound heterozygous mutations. We also ascertained 11 cases from nine families with a p.Gly1007Arg dominant-negative mutation, which occurred de novo in four patients, and was inherited in three families in association with marked phenotypic variability. In 50 of 52 samples from 34 patients, we identified a marked upregulation of type I interferon-stimulated gene transcripts in peripheral blood, with a median interferon score of 16.99 (interquartile range [IQR]: 10.64-25.71) compared with controls (median: 0.93, IQR: 0.57-1.30). Thus, mutations in ADAR1 are associated with a variety of clinically distinct neurological phenotypes presenting from early infancy to adulthood, inherited either as an autosomal recessive or dominant trait. Testing for an interferon signature in blood represents a useful biomarker in this context. Georg Thieme Verlag KG Stuttgart · New York.

Aggressive posterior retinopathy of prematurity in Asian Indian babies: spectrum of disease and outcome after laser treatment.

PubMed

Sanghi, Gaurav; Dogra, Mangat R; Das, Pranab; Vinekar, Anand; Gupta, Amod; Dutta, Saurabh

2009-10-01

To analyze the spectrum of aggressive posterior retinopathy of prematurity and outcome after laser treatment. This is a retrospective review of 81 eyes of 44 consecutive infants diagnosed to have aggressive posterior retinopathy of prematurity and treated between September 2005 and March 2007 from a large tertiary care center in North India. Qualitative variables were tested for statistical significance using the chi-square test and independent samples with the student's t-test. Mean birth weight and gestational age were 1,259.66 +/- 310.51 g (range, 660-2,000 g) and 29.75 +/- 2.35 weeks (range, 26-36 weeks), respectively. Twenty-one infants (47.72%) had a birth weight > 1,250 g. Thirty-three (40.74%) eyes had Zone 1, and 48 (59.26%) had posterior Zone 2 disease. All eyes underwent confluent laser photocoagulation at a mean postconceptional age of 34.58 +/- 2.19 weeks (range, 31-40.5 weeks). Mean follow-up was 12.8 months (range, 6-24 months). At the last follow-up visit, 55 (71.4%) of 77 eyes had a favorable outcome. Eighteen eyes (23.4%) had a localized (1-3 clock hours) partial peripheral tractional detachment (Stage 4a), which remained stable at last follow-up. Two eyes (2.6%) developed falciform fold involving the macular area, and 2 (2.6%) developed Stage 5 retinopathy of prematurity. Aggressive posterior retinopathy of prematurity is encountered not only in low birth weight infants, but also in heavier and more mature Asian Indian infants. Early, aggressive confluent laser photocoagulation is necessary to maximize outcomes in these eyes.

Gaucher disease: Pseudoreversion of a disease mutation`s effects--implications for structure/function and genotype/phenotype correlations

DOE Office of Scientific and Technical Information (OSTI.GOV)

Ponce, E.; Mear, J; Grabowski, G.A.

1994-09-01

Numerous mutations ({approximately}45) of the acid {beta}-glucosidase gene have been identified in patients with Gaucher disease. Many of these have been characterized by partial sequencing of cDNAs derived by RT-PCR or PCR of genomic DNA. In addition, genotype/phenotype correlations have been based on screening for known mutations. Thus, only a part of the gene is characterized in any population of affected patients. Several Gaucher disease alleles contain multiple, authentic point mutations that raises concern about conclusions based on only partial genetic characterization. Several wild-type cDNAs for acid {beta}-glucosidase have been sequenced. One contained a cloning artifact encoding R495H. We expressedmore » this cDNA and showed that the R495H enzyme had normal kinetic and stability properties. A disease-associated allele encoding R496H has been found by several groups. The close association and similarities of these two substitutions led us to question the disease casuality of the R496H allele. To evaluate this, we created and/or expressed cDNAs encoding R495, R496 (wild-type), (R495H, R496), (R495, R496H) and (R495H, R496H). The (wild-type) and (R495H, R496) enzymes had indistinguishable properties whereas the (R495, R496H) enzyme was essentially inactive. The introduction of both mutations (R495H, R496H) produced an enzyme whose activity was 25 to 50% of the wild-type. These results indicate that a pseudoreversion to a functional enzyme can occur by introducing a functionally neutral mutation together with a severe mutation. These results have major implications to structure/function and genotype/phenotype correlations in this disease.« less

Interoperability between phenotype and anatomy ontologies.

PubMed

Hoehndorf, Robert; Oellrich, Anika; Rebholz-Schuhmann, Dietrich

2010-12-15

Phenotypic information is important for the analysis of the molecular mechanisms underlying disease. A formal ontological representation of phenotypic information can help to identify, interpret and infer phenotypic traits based on experimental findings. The methods that are currently used to represent data and information about phenotypes fail to make the semantics of the phenotypic trait explicit and do not interoperate with ontologies of anatomy and other domains. Therefore, valuable resources for the analysis of phenotype studies remain unconnected and inaccessible to automated analysis and reasoning. We provide a framework to formalize phenotypic descriptions and make their semantics explicit. Based on this formalization, we provide the means to integrate phenotypic descriptions with ontologies of other domains, in particular anatomy and physiology. We demonstrate how our framework leads to the capability to represent disease phenotypes, perform powerful queries that were not possible before and infer additional knowledge. http://bioonto.de/pmwiki.php/Main/PheneOntology.

Activation of IRF1 in Human Adipocytes Leads to Phenotypes Associated with Metabolic Disease.

PubMed

Friesen, Max; Camahort, Raymond; Lee, Youn-Kyoung; Xia, Fang; Gerszten, Robert E; Rhee, Eugene P; Deo, Rahul C; Cowan, Chad A

2017-05-09

The striking rise of obesity-related metabolic disorders has focused attention on adipocytes as critical mediators of disease phenotypes. To better understand the role played by excess adipose in metabolic dysfunction it is crucial to decipher the transcriptional underpinnings of the low-grade adipose inflammation characteristic of diseases such as type 2 diabetes. Through employing a comparative transcriptomics approach, we identified IRF1 as differentially regulated between primary and in vitro-derived genetically matched adipocytes. This suggests a role as a mediator of adipocyte inflammatory phenotypes, similar to its function in other tissues. Utilizing adipose-derived mesenchymal progenitors we subsequently demonstrated that expression of IRF1 in adipocytes indeed contributes to upregulation of inflammatory processes, both in vitro and in vivo. This highlights IRF1's relevance to obesity-related inflammation and the resultant metabolic dysregulation. Copyright © 2017 The Authors. Published by Elsevier Inc. All rights reserved.

Risk reductions for cardiovascular disease with pravastatin treatment by dyslipidemia phenotype: a post hoc analysis of the MEGA Study.

PubMed

Nishiwaki, Masato; Ikewaki, Katsunori; Ayaori, Makoto; Mizuno, Kyoichi; Ohashi, Yasuo; Ohsuzu, Fumitaka; Ishikawa, Toshitsugu; Nakamura, Haruo

2013-03-01

The beneficial effect of statins for cardiovascular disease (CVD) prevention has been well established. However, the effectiveness among different phenotypes of dyslipidemia has not been confirmed. We evaluated the effect of pravastatin on the incidence of CVD in relation to the phenotype of dyslipidemia. The MEGA Study evaluated the effect of low-dose pravastatin on primary prevention of CVD in 7832 Japanese patients, who were randomized to diet alone or diet plus pravastatin and followed for more than 5 years. These patients were classified into phenotype IIa (n=5589) and IIb (n=2041) based on the electrophoretic pattern for this post hoc analysis. In the diet group there was no significant difference in the incidence of coronary heart disease (CHD), stroke, CVD, and total mortality between the two phenotypes. Phenotype IIb patients, compared to phenotype IIa, had lower levels of high-density lipoprotein cholesterol (HDL-C) and a significantly higher incidence of CVD in relation to a low HDL-C level (<47.5mg/dL; p=0.02). Furthermore, pravastatin decreased the relative risk for each major endpoint in both type IIa and type IIb dyslipidemia. Significant risk reductions were observed for CHD by 38% (p=0.04) and CVD by 31% (p=0.02) in type IIa dyslipidemia but not in phenotype IIb. Pravastatin therapy provided significant risk reductions for CHD and CVD in patients with phenotype IIa dyslipidemia, but not in those with phenotype IIb dyslipidemia. Copyright © 2012 Japanese College of Cardiology. Published by Elsevier Ltd. All rights reserved.

The severe hypercholesterolemia phenotype: clinical diagnosis, management, and emerging therapies.

PubMed

Sniderman, Allan D; Tsimikas, Sotirios; Fazio, Sergio

2014-05-20

The severe hypercholesterolemia phenotype includes all patients with marked elevation of low-density lipoprotein cholesterol (LDL-C) levels. The most common cause is autosomal dominant hypercholesterolemia, an inherited disorder caused by mutations either in LDL receptor, apolipoprotein B (APOB), or proprotein convertase subtilisin kexin type 9 (PCSK9) genes. However, it is now known that many subjects with severe inherited hypercholesterolemia have no defects in these genes. These cases are caused either by mutations in genes yet to be identified or are consequences of polygenic, epigenetic, or acquired defects. Because the clinical consequences of extreme hypercholesterolemia are the same no matter the cause, the focus should be on the identification of subjects with severe hypercholesterolemia, followed by phenotypic screening of family members. Genetic screening is not necessary to diagnose or initiate treatment for the severe hypercholesterolemia phenotype. Management of severe hypercholesterolemia is based on risk factor modification and use of multiple lipid-lowering medications. Lipoprotein apheresis is indicated for coronary artery disease (CAD) patients taking maximally tolerated therapy and with LDL-C levels >200 mg/dl (>300 mg/dl if without CAD). A microsomal triglyceride transfer protein inhibitor and an antisense oligonucleotide against APOB have recently been approved for use in subjects with clinically diagnosed homozygous familial hypercholesterolemia. PCSK9 inhibitors, currently in phase II and III trials, lower LDL-C up to an additional 70% in the setting of maximally tolerated medical therapy and have the potential to reduce LDL-C to <70 mg/dl in most patients. Early identification of affected individuals and aggressive treatment should significantly reduce the burden of cardiovascular disease in society. Copyright © 2014 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.

School Aggression and Dispositional Aggression among Middle School Boys

ERIC Educational Resources Information Center

Ballard, Mary E.; Rattley, Kelvin T.; Fleming, Willie C.; Kidder-Ashley, Pamela

2004-01-01

We examined the relationship between dispositional (trait) aggression and administrative reports of school aggression among 100 adolescent male participants from an urban middle school. Aggression was fairly common among the sample; 58 boys had a record of school aggression, and many of those were repeat offenders. Our hypothesis that those higher…

A hypothalamic circuit for the circadian control of aggression.

PubMed

Todd, William D; Fenselau, Henning; Wang, Joshua L; Zhang, Rong; Machado, Natalia L; Venner, Anne; Broadhurst, Rebecca Y; Kaur, Satvinder; Lynagh, Timothy; Olson, David P; Lowell, Bradford B; Fuller, Patrick M; Saper, Clifford B

2018-05-01

'Sundowning' in dementia and Alzheimer's disease is characterized by early-evening agitation and aggression. While such periodicity suggests a circadian origin, whether the circadian clock directly regulates aggressive behavior is unknown. We demonstrate that a daily rhythm in aggression propensity in male mice is gated by GABAergic subparaventricular zone (SPZ GABA ) neurons, the major postsynaptic targets of the central circadian clock, the suprachiasmatic nucleus. Optogenetic mapping revealed that SPZ GABA neurons receive input from vasoactive intestinal polypeptide suprachiasmatic nucleus neurons and innervate neurons in the ventrolateral part of the ventromedial hypothalamus (VMH), which is known to regulate aggression. Additionally, VMH-projecting dorsal SPZ neurons are more active during early day than early night, and acute chemogenetic inhibition of SPZ GABA transmission phase-dependently increases aggression. Finally, SPZ GABA -recipient central VMH neurons directly innervate ventrolateral VMH neurons, and activation of this intra-VMH circuit drove attack behavior. Altogether, we reveal a functional polysynaptic circuit by which the suprachiasmatic nucleus clock regulates aggression.

Apigenin suppresses the senescence-associated secretory phenotype and paracrine effects on breast cancer cells.

PubMed

Perrott, Kevin M; Wiley, Christopher D; Desprez, Pierre-Yves; Campisi, Judith

2017-04-01

Apigenin (4',5,7,-trihydroxyflavone) is a flavonoid found in certain herbs, fruits, and vegetables. Apigenin can attenuate inflammation, which is associated with many chronic diseases of aging. Senescent cells-stressed cells that accumulate with age in mammals-display a pro-inflammatory senescence-associated secretory phenotype (SASP) that can drive or exacerbate several age-related pathologies, including cancer. Flavonoids, including apigenin, were recently shown to reduce the SASP of a human fibroblast strain induced to senesce by bleomycin. Here, we confirm that apigenin suppresses the SASP in three human fibroblast strains induced to senesce by ionizing radiation, constitutive MAPK (mitogen-activated protein kinase) signaling, oncogenic RAS, or replicative exhaustion. Apigenin suppressed the SASP in part by suppressing IL-1α signaling through IRAK1 and IRAK4, p38-MAPK, and NF-κB. Apigenin was particularly potent at suppressing the expression and secretion of CXCL10 (IP10), a newly identified SASP factor. Further, apigenin-mediated suppression of the SASP substantially reduced the aggressive phenotype of human breast cancer cells, as determined by cell proliferation, extracellular matrix invasion, and epithelial-mesenchymal transition. Our results support the idea that apigenin is a promising natural product for reducing the impact of senescent cells on age-related diseases such as cancer.

Phenotypic & Genotypic Characteristics of Inflammatory Bowel Disease (IBD) in French-Canadians: comparison with a large North American repository

PubMed Central

Bhat, Mamatha; Nguyen, Geoffrey C.; Pare, Pierre; Lahaie, Raymond; Deslandres, Colette; Bernard, Edmond-Jean; Aumais, Guy; Jobin, Gilles; Wild, Gary; Cohen, Albert; Langelier, Diane; Brant, Steven; Dassopoulos, Themistocles; McGovern, Dermot; Torres, Esther; Duerr, Richard; Regueiro, Miguel; Silverberg, Mark S; Steinhart, Hillary; Griffiths, Anne M.; Elkadri, Abdul; Cho, Judy; Proctor, Deborah; Goyette, Philippe; Rioux, John; Bitton, Alain

2009-01-01

BACKGROUND Phenotype characteristics of inflammatory bowel disease (IBD) may differ significantly among ethnic subpopulations. The aim of this study was to characterize the IBD phenotype in French-Canadians, the most prominent founder population in North America. METHODS Using well-characterized phenotype data in the NIDDK-IBD Genetics Consortium repository on IBD patients, we compared phenotypic characteristics of 202 French-Canadians to those of 1287 other Caucasian patients. These included: diagnosis, anatomical location, disease behaviour, extraintestinal manifestations, surgical history, and family history of IBD. RESULTS French-Canadian CD patients were less likely to have stricturing disease (11 vs 21%, P=0.005; OR 0.45, 95% CI: 0.24– 0.85). Using a stringent definition of ethnicity (3 out of 4 grandparents being French-Canadian, as opposed to self-report, n= 148), French-Canadians had a tendency towards developing fistulizing CD (37% vs 28%, p= 0.07), and there was an increased prevalence of sacroiliitis among French-Canadians with IBD (4% vs 2%, p=0.045). Among French-Canadians, the numbers of current smokers in CD (40 vs 25%, p=0.006) and former smokers in UC (35% vs 20%, p=0.03) were significantly higher. The prevalence of one of the three main variant NOD2 SNPs among French-Canadian CD patients was 43.2%. The 3020insC SNP correlated with small bowel disease in French-Canadians (75% versus 0%, P=0.006). CONCLUSION French-Canadians exhibit an IBD phenotype profile distinct from other Caucasian IBD populations, with an accentuated association between smoking status and IBD. This unique profile may have implications regarding the need for a different approach to management of IBD in this population. PMID:19513023

Predicted Mutation Strength of Nontruncating PKD1 Mutations Aids Genotype-Phenotype Correlations in Autosomal Dominant Polycystic Kidney Disease.

PubMed

Heyer, Christina M; Sundsbak, Jamie L; Abebe, Kaleab Z; Chapman, Arlene B; Torres, Vicente E; Grantham, Jared J; Bae, Kyongtae T; Schrier, Robert W; Perrone, Ronald D; Braun, William E; Steinman, Theodore I; Mrug, Michal; Yu, Alan S L; Brosnahan, Godela; Hopp, Katharina; Irazabal, Maria V; Bennett, William M; Flessner, Michael F; Moore, Charity G; Landsittel, Douglas; Harris, Peter C

2016-09-01

Autosomal dominant polycystic kidney disease (ADPKD) often results in ESRD but with a highly variable course. Mutations to PKD1 or PKD2 cause ADPKD; both loci have high levels of allelic heterogeneity. We evaluated genotype-phenotype correlations in 1119 patients (945 families) from the HALT Progression of PKD Study and the Consortium of Radiologic Imaging Study of PKD Study. The population was defined as: 77.7% PKD1, 14.7% PKD2, and 7.6% with no mutation detected (NMD). Phenotypic end points were sex, eGFR, height-adjusted total kidney volume (htTKV), and liver cyst volume. Analysis of the eGFR and htTKV measures showed that the PKD1 group had more severe disease than the PKD2 group, whereas the NMD group had a PKD2-like phenotype. In both the PKD1 and PKD2 populations, men had more severe renal disease, but women had larger liver cyst volumes. Compared with nontruncating PKD1 mutations, truncating PKD1 mutations associated with lower eGFR, but the mutation groups were not differentiated by htTKV. PKD1 nontruncating mutations were evaluated for conservation and chemical change and subdivided into strong (mutation strength group 2 [MSG2]) and weak (MSG3) mutation groups. Analysis of eGFR and htTKV measures showed that patients with MSG3 but not MSG2 mutations had significantly milder disease than patients with truncating cases (MSG1), an association especially evident in extreme decile populations. Overall, we have quantified the contribution of genic and PKD1 allelic effects and sex to the ADPKD phenotype. Intrafamilial correlation analysis showed that other factors shared by families influence htTKV, with these additional genetic/environmental factors significantly affecting the ADPKD phenotype. Copyright © 2016 by the American Society of Nephrology.

CONCEPT ANALYSIS: AGGRESSION

PubMed Central

Liu, Jianghong

2006-01-01

The concept of aggression is important to nursing because further knowledge of aggression can help generate a better theoretical model to drive more effective intervention and prevention approaches. This paper outlines a conceptual analysis of aggression. First, the different forms of aggression are reviewed, including the clinical classification and the stimulus-based classification. Then the manifestations and measurement of aggression are described. Finally, the causes and consequences of aggression are outlined. It is argued that a better understanding of aggression and the causal factors underlying it are essential for learning how to prevent negative aggression in the future. PMID:15371137

Presenting phenotype of paediatric inflammatory bowel disease in Wessex, Southern England 2010-2013.

PubMed

Ashton, J J; Coelho, T; Ennis, S; Batra, A; Afzal, N A; Beattie, R M

2015-08-01

There has been at least a twofold increase in the incidence of paediatric inflammatory bowel disease (PIBD) over the last 20 years; we report the presenting features from 2010 to 2013 and compare with previous data. All patients diagnosed with PIBD at University Hospitals Southampton from 2010 to 2013 were identified from an in-house database. Data were obtained from paper and electronic notes. Height, weight and BMI SDS are presented as median values (95% CI). One hundred and seventy-two patients were included (median age at diagnosis 13.5, 115 male); Crohn's disease (CD) - 107, UC - 50, inflammatory bowel disease unclassified (IBDU) - 15. The most common presenting features of CD were abdominal pain (86%), diarrhoea (78.5%) and weight loss (56.1%); 42.1% of patients had all three. In UC blood in stool (92%), diarrhoea (92%) and abdominal pain (88%) were the most common; all three in 76% of patients. CD presented with ileocolonic disease in 52.5%. UC presented with pancolitis in 64%. There was growth delay in CD: height -0.37 (-0.60 to -0.14); weight -1.09 (-1.35 to -0.83). Growth was maintained in UC: height 0.53 (0.19 to 0.87); weight 0.14 (-0.20 to 0.48). Paediatric inflammatory bowel disease phenotype remains as extensive despite increasing incidence. Although the classical phenotype is common, a reasonable proportion present with atypical features, normal growth and normal blood markers. ©2015 Foundation Acta Paediatrica. Published by John Wiley & Sons Ltd.

A Phenotyping Regimen for Genetically Modified Mice Used to Study Genes Implicated in Human Diseases of Aging.

PubMed

Patterson, Victoria L; Thompson, Brian S; Cherry, Catherine; Wang, Shao-Bin; Chen, Bo; Hoh, Josephine

2016-07-14

Age-related diseases are becoming increasingly prevalent and the burden continues to grow as our population ages. Effective treatments are necessary to lessen the impact of debilitating conditions but remain elusive in many cases. Only by understanding the causes and pathology of diseases associated with aging, can scientists begin to identify potential therapeutic targets and develop strategies for intervention. The most common age-related conditions are neurodegenerative disorders such as Parkinson's disease and blindness. Age-related macular degeneration (AMD) is the leading cause of blindness in the elderly. Genome wide association studies have previously identified loci that are associated with increased susceptibility to this disease and identified two regions of interest: complement factor H (CFH) and the 10q26 locus, where the age-related maculopathy susceptibility 2 (ARMS2) and high-temperature requirement factor A1 (HtrA1) genes are located. CFH acts as a negative regulator of the alternative pathway (AP) of the complement system while HtrA1 is an extracellular serine protease. ARMS2 is located upstream of HtrA1 in the primate genome, although the gene is absent in mice. To study the effects of these genes, humanized knock-in mouse lines of Cfh and ARMS2, knockouts of Cfh, HtrA1, HtrA2, HtrA3 and HtrA4 as well as a conditional neural deletion of HtrA2 were generated. Of all the genetically engineered mice produced only mice lacking HtrA2, either systemically or in neural tissues, displayed clear phenotypes. In order to examine these mice thoroughly and systematically, an initial phenotyping schedule was established, consisting of a series of tests related to two main diseases of interest: AMD and Parkinson's. Genetically modified mice can be subjected to appropriate experiments to identify phenotypes that may be related to the associated diseases in humans. A phenotyping regimen with a mitochondrial focus is presented here alongside representative results

Phenotype variability of infantile-onset multisystem neurologic, endocrine, and pancreatic disease IMNEPD.

PubMed

Picker-Minh, Sylvie; Mignot, Cyril; Doummar, Diane; Hashem, Mais; Faqeih, Eissa; Josset, Patrice; Dubern, Béatrice; Alkuraya, Fowzan S; Kraemer, Nadine; Kaindl, Angela M

2016-04-29

Infantile-onset multisystem neurologic, endocrine, and pancreatic disease (IMNEPD) has been recently linked to biallelic mutation of the peptidyl-tRNA hydrolase 2 gene PTRH2. Two index patients with IMNEPD in the original report had multiple neurological symptoms such as postnatal microcephaly, intellectual disability, developmental delay, sensorineural deafness, cerebellar atrophy, ataxia, and peripheral neuropathy. In addition, distal muscle weakness and abnormalities of thyroid, pancreas, and liver were found. Here, we report five further IMNEPD patients with a different homozygous PTRH2 mutation, broaden the phenotypic spectrum of the disease and differentiate common symptoms and interindividual variability in IMNEPD associated with a unique mutation. We thereby hope to better define IMNEPD and promote recognition and diagnosis of this novel disease entity.

Local oxytocin expression and oxytocin receptor binding in the male rat brain is associated with aggressiveness.

PubMed

Calcagnoli, Federica; de Boer, Sietse F; Beiderbeck, Daniela I; Althaus, Monika; Koolhaas, Jaap M; Neumann, Inga D

2014-03-15

We recently demonstrated in male wild-type Groningen rats that enhancing brain oxytocin (OXT) levels acutely produces marked pro-social explorative and anti-aggressive effects. Moreover, these pharmacologically-induced changes are moderated by the individual's aggressive phenotype, suggesting an inverse relationship between aggressiveness and tonic endogenous OXT signaling properties. Aim of the present study was to verify the hypothesis that variations in OXT expression and/or OXT receptor (OXTR) binding in selected brain regions are associated with different levels or forms of aggression. To this end, male resident wild-type Groningen rats that repeatedly contested and dominated intruder conspecifics were categorized as being low aggressive, highly aggressive or excessively aggressive. Their brains were subsequently collected and quantified for OXT mRNA expression and OXTR binding levels. Our results showed that OXT mRNA expression in the hypothalamic paraventricular nucleus (PVN), but not in the supraoptic nucleus (SON), negatively correlates with the level of offensiveness. In particular, the excessively aggressive group showed a significantly lower OXT mRNA expression in the PVN as compared to both low and highly aggressive groups. Further, the excessively aggressive animals showed the highest OXTR binding in the central amygdala (CeA) and bed nucleus of the stria terminalis (BNST). These findings demonstrate that male rats with excessively high levels and abnormal forms of aggressive behavior have diminished OXT transcription and enhanced OXTR binding capacities in specific nodes of the social behavioral brain circuitry. Copyright © 2014 Elsevier B.V. All rights reserved.

The 19q12 bladder cancer GWAS signal: association with cyclin E function and aggressive disease

PubMed Central

Fu, Yi-Ping; Kohaar, Indu; Moore, Lee E.; Lenz, Petra; Figueroa, Jonine D.; Tang, Wei; Porter-Gill, Patricia; Chatterjee, Nilanjan; Scott-Johnson, Alexandra; Garcia-Closas, Montserrat; Muchmore, Brian; Baris, Dalsu; Paquin, Ashley; Ylaya, Kris; Schwenn, Molly; Apolo, Andrea B.; Karagas, Margaret R.; Tarway, McAnthony; Johnson, Alison; Mumy, Adam; Schned, Alan; Guedez, Liliana; Jones, Michael A.; Kida, Masatoshi; Monawar Hosain, GM; Malats, Nuria; Kogevinas, Manolis; Tardon, Adonina; Serra, Consol; Carrato, Alfredo; Garcia-Closas, Reina; Lloreta, Josep; Wu, Xifeng; Purdue, Mark; Andriole, Gerald L.; Grubb, Robert L.; Black, Amanda; Landi, Maria T.; Caporaso, Neil E.; Vineis, Paolo; Siddiq, Afshan; Bueno-de-Mesquita, H. Bas; Trichopoulos, Dimitrios; Ljungberg, Börje; Severi, Gianluca; Weiderpass, Elisabete; Krogh, Vittorio; Dorronsoro, Miren; Travis, Ruth C.; Tjønneland, Anne; Brennan, Paul; Chang-Claude, Jenny; Riboli, Elio; Prescott, Jennifer; Chen, Constance; De Vivo, Immaculata; Govannucci, Edward; Hunter, David; Kraft, Peter; Lindstrom, Sara; Gapstur, Susan M.; Jacobs, Eric J.; Diver, W. Ryan; Albanes, Demetrius; Weinstein, Stephanie J.; Virtamo, Jarmo; Kooperberg, Charles; Hohensee, Chancellor; Rodabough, Rebecca J.; Cortessis, Victoria K.; Conti, David V.; Gago-Dominguez, Manuela; Stern, Mariana C.; Pike, Malcolm C.; Van Den Berg, David; Yuan, Jian-Min; Haiman, Christopher A.; Cussenot, Olivier; Cancel-Tassin, Geraldine; Roupret, Morgan; Comperat, Eva; Porru, Stefano; Carta, Angela; Pavanello, Sofia; Arici, Cecilia; Mastrangelo, Giuseppe; Grossman, H. Barton; Wang, Zhaoming; Deng, Xiang; Chung, Charles C.; Hutchinson, Amy; Burdette, Laurie; Wheeler, William; Fraumeni, Joseph; Chanock, Stephen J.; Hewitt, Stephen M.; Silverman, Debra T.; Rothman, Nathaniel; Prokunina-Olsson, Ludmila

2014-01-01

A genome-wide association study (GWAS) of bladder cancer identified a genetic marker rs8102137 within the 19q12 region as a novel susceptibility variant. This marker is located upstream of the CCNE1 gene, which encodes cyclin E, a cell cycle protein. We performed genetic fine mapping analysis of the CCNE1 region using data from two bladder cancer GWAS (5,942 cases and 10,857 controls). We found that the original GWAS marker rs8102137 represents a group of 47 linked SNPs (with r2≥0.7) associated with increased bladder cancer risk. From this group we selected a functional promoter variant rs7257330, which showed strong allele-specific binding of nuclear proteins in several cell lines. In both GWAS, rs7257330 was associated only with aggressive bladder cancer, with a combined per-allele odds ratio (OR) =1.18 (95%CI=1.09-1.27, p=4.67×10−5 vs. OR =1.01 (95%CI=0.93-1.10, p=0.79) for non-aggressive disease, with p=0.0015 for case-only analysis. Cyclin E protein expression analyzed in 265 bladder tumors was increased in aggressive tumors (p=0.013) and, independently, with each rs7257330-A risk allele (ptrend=0.024). Over-expression of recombinant cyclin E in cell lines caused significant acceleration of cell cycle. In conclusion, we defined the 19q12 signal as the first GWAS signal specific for aggressive bladder cancer. Molecular mechanisms of this genetic association may be related to cyclin E over-expression and alteration of cell cycle in carriers of CCNE1 risk variants. In combination with established bladder cancer risk factors and other somatic and germline genetic markers, the CCNE1 variants could be useful for inclusion into bladder cancer risk prediction models. PMID:25320178

Sense of control and adolescents' aggression: The role of aggressive cues.

PubMed

Guo, Xucheng; Egan, Vincent; Zhang, Jianxin

2016-12-01

The misperception of aggressive cues is considered a risk factor for inducing adolescent aggression. Poor coping with life stress is also considered a major influence on aggression. The current study examined the relationship between subjective sense of control and adolescent aggression, considering influences upon the perception of these aggressive cues. In Study 1, 60 participants took part in a 2 (sense of control: high sense of control vs. low sense of control) × 2 (aggressive cue: aggressive vs. neutral) between-subjects contextual experiment. The result found that a lower sense of control led to an increase in adolescents' aggression; only in the low-sense-of-control condition did exposure to aggressive cues boost aggression. In Study 2, the catalytic effect of aggressive cues was further explored by an experiment in which 40 adolescents were randomly assigned to a low- or high-sense-of-control condition to test the importance of aggressive cues. The results suggest that adolescents in the low-sense-of-control condition show a higher salience for aggressive cues. © 2016 The Institute of Psychology, Chinese Academy of Sciences and John Wiley & Sons Australia, Ltd.

Subjective aggression during alcohol and cannabis intoxication before and after aggression exposure.

PubMed

De Sousa Fernandes Perna, E B; Theunissen, E L; Kuypers, K P C; Toennes, S W; Ramaekers, J G

2016-09-01

Alcohol and cannabis use have been implicated in aggression. Alcohol consumption is known to facilitate aggression, whereas a causal link between cannabis and aggression has not been clearly demonstrated. This study investigated the acute effects of alcohol and cannabis on subjective aggression in alcohol and cannabis users, respectively, following aggression exposure. Drug-free controls served as a reference. It was hypothesized that aggression exposure would increase subjective aggression in alcohol users during alcohol intoxication, whereas it was expected to decrease subjective aggression in cannabis users during cannabis intoxication. Heavy alcohol (n = 20) and regular cannabis users (n = 21), and controls (n = 20) were included in a mixed factorial study. Alcohol and cannabis users received single doses of alcohol and placebo or cannabis and placebo, respectively. Subjective aggression was assessed before and after aggression exposure consisting of administrations of the point-subtraction aggression paradigm (PSAP) and the single category implicit association test (SC-IAT). Testosterone and cortisol levels in response to alcohol/cannabis treatment and aggression exposure were recorded as secondary outcome measures. Subjective aggression significantly increased following aggression exposure in all groups while being sober. Alcohol intoxication increased subjective aggression whereas cannabis decreased the subjective aggression following aggression exposure. Aggressive responses during the PSAP increased following alcohol and decreased following cannabis relative to placebo. Changes in aggressive feeling or response were not correlated to the neuroendocrine response to treatments. It is concluded that alcohol facilitates feelings of aggression whereas cannabis diminishes aggressive feelings in heavy alcohol and regular cannabis users, respectively.

Distinct circuits underlie the effects of 5-HT1B receptors on aggression and impulsivity

PubMed Central

Nautiyal, Katherine M.; Tanaka, Kenji F.; Barr, Mary M.; Tritschler, Laurent; Le Dantec, Yannick; David, Denis J.; Gardier, Alain M.; Blanco, Carlos; Hen, René; Ahmari, Susanne E.

2015-01-01

Summary Impulsive and aggressive behaviors are both modulated by serotonergic signaling, specifically through the serotonin 1B receptor (5-HT1BR). 5-HT1BR knockout mice show increased aggression and impulsivity, and 5-HT1BR polymorphisms are associated with aggression and drug addiction in humans. To dissect the mechanisms by which the 5-HT1BR affects these phenotypes, we developed a mouse model to spatially and temporally regulate 5-HT1BR expression. Our results demonstrate that forebrain 5-HT1B heteroreceptors expressed during an early postnatal period contribute to the development of the neural systems underlying adult aggression. However, distinct heteroreceptors acting during adulthood are involved in mediating impulsivity. Correlating with the impulsivity, dopamine in the nucleus accumbens is elevated in the absence of 5-HT1BRs, and normalized following adult rescue of the receptor. Overall, these data show that while adolescent expression of 5-HT1BRs influences aggressive behavior, a distinct set of 5-HT1B receptors modulate impulsive behavior during adulthood. PMID:25892302

Enabling phenotypic big data with PheNorm.

PubMed

Yu, Sheng; Ma, Yumeng; Gronsbell, Jessica; Cai, Tianrun; Ananthakrishnan, Ashwin N; Gainer, Vivian S; Churchill, Susanne E; Szolovits, Peter; Murphy, Shawn N; Kohane, Isaac S; Liao, Katherine P; Cai, Tianxi

2018-01-01

Electronic health record (EHR)-based phenotyping infers whether a patient has a disease based on the information in his or her EHR. A human-annotated training set with gold-standard disease status labels is usually required to build an algorithm for phenotyping based on a set of predictive features. The time intensiveness of annotation and feature curation severely limits the ability to achieve high-throughput phenotyping. While previous studies have successfully automated feature curation, annotation remains a major bottleneck. In this paper, we present PheNorm, a phenotyping algorithm that does not require expert-labeled samples for training. The most predictive features, such as the number of International Classification of Diseases, Ninth Revision, Clinical Modification (ICD-9-CM) codes or mentions of the target phenotype, are normalized to resemble a normal mixture distribution with high area under the receiver operating curve (AUC) for prediction. The transformed features are then denoised and combined into a score for accurate disease classification. We validated the accuracy of PheNorm with 4 phenotypes: coronary artery disease, rheumatoid arthritis, Crohn's disease, and ulcerative colitis. The AUCs of the PheNorm score reached 0.90, 0.94, 0.95, and 0.94 for the 4 phenotypes, respectively, which were comparable to the accuracy of supervised algorithms trained with sample sizes of 100-300, with no statistically significant difference. The accuracy of the PheNorm algorithms is on par with algorithms trained with annotated samples. PheNorm fully automates the generation of accurate phenotyping algorithms and demonstrates the capacity for EHR-driven annotations to scale to the next level - phenotypic big data. © The Author 2017. Published by Oxford University Press on behalf of the American Medical Informatics Association. All rights reserved. For Permissions, please email: journals.permissions@oup.com

Epigenetic up-regulation of ribosome biogenesis and more aggressive phenotype triggered by the lack of the histone demethylase JHDM1B in mammary epithelial cells.

PubMed

Galbiati, Alice; Penzo, Marianna; Bacalini, Maria Giulia; Onofrillo, Carmine; Guerrieri, Ania Naila; Garagnani, Paolo; Franceschi, Claudio; Treré, Davide; Montanaro, Lorenzo

2017-06-06

The alterations of ribosome biogenesis and protein synthesis play a direct role in the development of tumors. The accessibility and transcription of ribosomal genes is controlled at several levels, with their epigenetic regulation being one of the most important. Here we explored the JmjC domain-containing histone demethylase 1B (JHDM1B) function in the epigenetic control of rDNA transcription. Since JHDM1B is a negative regulator of gene transcription, we focused on the effects induced by JHDM1B knock-down (KD). We studied the consequences of stable inducible JHDM1B silencing in cell lines derived from transformed and untransformed mammary epithelial cells. In these cellular models, prolonged JHDM1B downregulation triggered a surge of 45S pre-rRNA transcription and processing, associated with a re-modulation of the H3K36me2 levels at rDNA loci and with changes in DNA methylation of specific CpG sites in rDNA genes. We also found that after JHDM1B KD, cells showed a higher ribosome content: which were engaged in mRNA translation. JHDM1B KD and the consequent stimulation of ribosomes biogenesis conferred more aggressive features to the tested cellular models, which acquired a greater clonogenic, staminal and invasive potential. Taken together, these data indicate that the reduction of JHDM1B leads to a more aggressive cellular phenotype in mammary gland cells, by virtue of its negative regulatory activity on ribosome biogenesis.

Phenotypic heterogeneity associated with a novel mutation (Gly112Glu) in the Norrie disease protein.

PubMed

Allen, R C; Russell, S R; Streb, L M; Alsheikheh, A; Stone, E M

2006-02-01

To determine the molecular pathology and clinical severity of two pedigrees with a history of early retinal detachment and peripheral retinal vascular abnormalities. Longitudinal cohort study. A longitudinal clinical study and DNA analysis was performed on 49 family members of two pedigrees. Nine individuals were found to be hemizygous for a mutation at codon 112 (Gly112Glu) of the Norrie disease protein (NDP) in one pedigree. Significant phenotypic heterogeneity was found. The proband presented with a unilateral subtotal retinal detachment at the age of 3 years, and subsequently developed a slowly progressive tractional retinal detachment involving the macula in the contralateral eye at the age of 4 years. One individual had only mild peripheral retinal pigmentary changes with normal vision at the age of 79 years. The remaining seven individuals had varying degrees of peripheral retinal vascular abnormalities and anterior segment findings. Seven affected members of a second pedigree affected by a previously reported mutation, Arg74Cys, also demonstrated wide ocular phenotypic variation. A novel mutation (Gly112Glu), which represents the most carboxy located, NDP mutation reported, results in significant phenotypic heterogeneity. These data support the contention that the spectrum of ocular disease severity associated with these NDP mutations is broad. Use of terms that characterize this entity by phenotypic appearance, such as familial exudative vitreoretinopathy, do not adequately communicate the potential spectrum of severity of this disorder to affected or carrier family members.

Computational Approaches to Phenotyping

PubMed Central

Lussier, Yves A.; Liu, Yang

2007-01-01

The recent completion of the Human Genome Project has made possible a high-throughput “systems approach” for accelerating the elucidation of molecular underpinnings of human diseases, and subsequent derivation of molecular-based strategies to more effectively prevent, diagnose, and treat these diseases. Although altered phenotypes are among the most reliable manifestations of altered gene functions, research using systematic analysis of phenotype relationships to study human biology is still in its infancy. This article focuses on the emerging field of high-throughput phenotyping (HTP) phenomics research, which aims to capitalize on novel high-throughput computation and informatics technology developments to derive genomewide molecular networks of genotype–phenotype associations, or “phenomic associations.” The HTP phenomics research field faces the challenge of technological research and development to generate novel tools in computation and informatics that will allow researchers to amass, access, integrate, organize, and manage phenotypic databases across species and enable genomewide analysis to associate phenotypic information with genomic data at different scales of biology. Key state-of-the-art technological advancements critical for HTP phenomics research are covered in this review. In particular, we highlight the power of computational approaches to conduct large-scale phenomics studies. PMID:17202287

Emerging molecular phenotypes of asthma

PubMed Central

Ray, Anuradha; Oriss, Timothy B.

2014-01-01

Although asthma has long been considered a heterogeneous disease, attempts to define subgroups of asthma have been limited. In recent years, both clinical and statistical approaches have been utilized to better merge clinical characteristics, biology, and genetics. These combined characteristics have been used to define phenotypes of asthma, the observable characteristics of a patient determined by the interaction of genes and environment. Identification of consistent clinical phenotypes has now been reported across studies. Now the addition of various 'omics and identification of specific molecular pathways have moved the concept of clinical phenotypes toward the concept of molecular phenotypes. The importance of these molecular phenotypes is being confirmed through the integration of molecularly targeted biological therapies. Thus the global term asthma is poised to become obsolete, being replaced by terms that more specifically identify the pathology associated with the disease. PMID:25326577

Opportunities for collaborative phenotyping for disease resistance traits in a large beef cattle resource population.

PubMed

Thallman, R M; Kuehn, L A; Allan, M F; Bennett, G L; Koohmaraie, M

2008-01-01

The Germplasm Evaluation (GPE) Project at the US Meat Animal Research Center (USMARC) is planned to produce about 3,000 calves per year in support of the following objectives: identification and validation of genetic polymorphisms related to economically relevant traits (ERT), estimation of breed and heterosis effects among 16 breeds for ERT, and estimation of genetic correlations among ERT and physiological indicator traits (PIT). Opportunities exist for collaboration in the development and collection of PIT phenotypes for disease resistance. Other areas of potential collaboration include detailed diagnosis (identification of disease causing organisms, etc.) of treated animals, collaborative development of epidemiological statistical models that would extract more information from the records of diagnoses and treatments, or pharmacogenetics. Concentrating a variety of different phenotypes and research approaches on the same population makes each component much more valuable than it would be individually.

Signaling aggression.

PubMed

van Staaden, Moira J; Searcy, William A; Hanlon, Roger T

2011-01-01

From psychological and sociological standpoints, aggression is regarded as intentional behavior aimed at inflicting pain and manifested by hostility and attacking behaviors. In contrast, biologists define aggression as behavior associated with attack or escalation toward attack, omitting any stipulation about intentions and goals. Certain animal signals are strongly associated with escalation toward attack and have the same function as physical attack in intimidating opponents and winning contests, and ethologists therefore consider them an integral part of aggressive behavior. Aggressive signals have been molded by evolution to make them ever more effective in mediating interactions between the contestants. Early theoretical analyses of aggressive signaling suggested that signals could never be honest about fighting ability or aggressive intentions because weak individuals would exaggerate such signals whenever they were effective in influencing the behavior of opponents. More recent game theory models, however, demonstrate that given the right costs and constraints, aggressive signals are both reliable about strength and intentions and effective in influencing contest outcomes. Here, we review the role of signaling in lieu of physical violence, considering threat displays from an ethological perspective as an adaptive outcome of evolutionary selection pressures. Fighting prowess is conveyed by performance signals whose production is constrained by physical ability and thus limited to just some individuals, whereas aggressive intent is encoded in strategic signals that all signalers are able to produce. We illustrate recent advances in the study of aggressive signaling with case studies of charismatic taxa that employ a range of sensory modalities, viz. visual and chemical signaling in cephalopod behavior, and indicators of aggressive intent in the territorial calls of songbirds. Copyright © 2011 Elsevier Inc. All rights reserved.

Macrophage phenotypic subtypes diametrically regulate epithelial-mesenchymal plasticity in breast cancer cells.

PubMed

Yang, Min; Ma, Bo; Shao, Hanshuang; Clark, Amanda M; Wells, Alan

2016-07-07

Metastatic progression of breast cancer involves phenotypic plasticity of the carcinoma cells moving between epithelial and mesenchymal behaviors. During metastatic seeding and dormancy, even highly aggressive carcinoma cells take on an E-cadherin-positive epithelial phenotype that is absent from the emergent, lethal metastatic outgrowths. These phenotypes are linked to the metastatic microenvironment, though the specific cells and induction signals are still to be deciphered. Recent evidence suggests that macrophages impact tumor progression, and may alter the balance between cancer cell EMT and MErT in the metastatic microenvironment. Here we explore the role of M1/M2 macrophages in epithelial-mesenchymal plasticity of breast cancer cells by coculturing epithelial and mesenchymal cells lines with macrophages. We found that after polarizing the THP-1 human monocyte cell line, the M1 and M2-types were stable and maintained when co-cultured with breast cancer cells. Surprisingly, M2 macrophages may conferred a growth advantage to the epithelial MCF-7 cells, with these cells being driven to a partial mesenchymal phenotypic as indicated by spindle morphology. Notably, E-cadherin protein expression is significantly decreased in MCF-7 cells co-cultured with M2 macrophages. M0 and M1 macrophages had no effect on the MCF-7 epithelial phenotype. However, the M1 macrophages impacted the highly aggressive mesenchymal-like MDA-MB-231 breast cancer cells to take on a quiescent, epithelial phenotype with re-expression of E-cadherin. The M2 macrophages if anything exacerbated the mesenchymal phenotype of the MDA-MB-231 cells. Our findings demonstrate M2 macrophages might impart outgrowth and M1 macrophages may contribute to dormancy behaviors in metastatic breast cancer cells. Thus EMT and MErT are regulated by selected macrophage phenotype in the liver metastatic microenvironment. These results indicate macrophage could be a potential therapeutic target for limiting death due

GeneYenta: a phenotype-based rare disease case matching tool based on online dating algorithms for the acceleration of exome interpretation.

PubMed

Gottlieb, Michael M; Arenillas, David J; Maithripala, Savanie; Maurer, Zachary D; Tarailo Graovac, Maja; Armstrong, Linlea; Patel, Millan; van Karnebeek, Clara; Wasserman, Wyeth W

2015-04-01

Advances in next-generation sequencing (NGS) technologies have helped reveal causal variants for genetic diseases. In order to establish causality, it is often necessary to compare genomes of unrelated individuals with similar disease phenotypes to identify common disrupted genes. When working with cases of rare genetic disorders, finding similar individuals can be extremely difficult. We introduce a web tool, GeneYenta, which facilitates the matchmaking process, allowing clinicians to coordinate detailed comparisons for phenotypically similar cases. Importantly, the system is focused on phenotype annotation, with explicit limitations on highly confidential data that create barriers to participation. The procedure for matching of patient phenotypes, inspired by online dating services, uses an ontology-based semantic case matching algorithm with attribute weighting. We evaluate the capacity of the system using a curated reference data set and 19 clinician entered cases comparing four matching algorithms. We find that the inclusion of clinician weights can augment phenotype matching. © 2015 WILEY PERIODICALS, INC.

Aggression By Whom–Aggression Toward Whom: Behavioral Predictors of Same- and Other-Gender Aggression in Early Childhood

PubMed Central

Hanish, Laura D.; Sallquist, Julie; DiDonato, Matthew; Fabes, Richard A.; Martin, Carol Lynn

2012-01-01

This study assessed girls’ and boys’ dominance-related behaviors (aggressive, commanding, submissive, and neutral behaviors) as they naturally occurred during interactions with male and female peers and evaluated the possibility that such behaviors elicit aggression from peers. Using a focal observational procedure, young girls’ and boys’ (N = 170; 54% boys) naturally occurring dominance-related behaviors and male and female peers’ aggressive responses to those behaviors were recorded multiple times each week across the academic year. Findings suggested that same-gender aggression occurred at similar rates as other-gender aggression once tendencies toward gender segregated play were controlled. Additionally, there were both gender-based similarities and differences in children’s use of dominance-related behaviors in peer interactions and as antecedents for peers’ aggression. The findings have implications for the literatures on aggression and gendered peer interactions. PMID:22369337

Genetic dissection of intermale aggressive behavior in BALB/cJ and A/J mice.

PubMed

Dow, H C; Kreibich, A S; Kaercher, K A; Sankoorikal, G M V; Pauley, E D; Lohoff, F W; Ferraro, T N; Li, H; Brodkin, E S

2011-02-01

Aggressive behaviors are disabling, treatment refractory, and sometimes lethal symptoms of several neuropsychiatric disorders. However, currently available treatments for patients are inadequate, and the underlying genetics and neurobiology of aggression is only beginning to be elucidated. Inbred mouse strains are useful for identifying genomic regions, and ultimately the relevant gene variants (alleles) in these regions, that affect mammalian aggressive behaviors, which, in turn, may help to identify neurobiological pathways that mediate aggression. The BALB/cJ inbred mouse strain exhibits relatively high levels of intermale aggressive behaviors and shows multiple brain and behavioral phenotypes relevant to neuropsychiatric syndromes associated with aggression. The A/J strain shows very low levels of aggression. We hypothesized that a cross between BALB/cJ and A/J inbred strains would reveal genomic loci that influence the tendency to initiate intermale aggressive behavior. To identify such loci, we conducted a genomewide scan in an F2 population of 660 male mice bred from BALB/cJ and A/J inbred mouse strains. Three significant loci on chromosomes 5, 10 and 15 that influence aggression were identified. The chromosome 5 and 15 loci are completely novel, and the chromosome 10 locus overlaps an aggression locus mapped in our previous study that used NZB/B1NJ and A/J as progenitor strains. Haplotype analysis of BALB/cJ, NZB/B1NJ and A/J strains showed three positional candidate genes in the chromosome 10 locus. Future studies involving fine genetic mapping of these loci as well as additional candidate gene analysis may lead to an improved biological understanding of mammalian aggressive behaviors. © 2010 The Authors. Genes, Brain and Behavior © 2010 Blackwell Publishing Ltd and International Behavioural and Neural Genetics Society.

Renal Cell Carcinoma, Unclassified with Medullary Phenotype and Synchronous Renal Clear Cell Carcinoma Present in a Patient with No Sickle Cell Trait/Disease: Diagnostic and Therapeutic Challenges.

PubMed

Lai, Jenny Z; Lai, H Henry; Cao, Dengfeng

2018-06-01

Renal medullary carcinoma (RMC) is an aggressive high-grade renal cell carcinoma (RCC) associated almost exclusively with sickle cell trait or sickle cell disease. However, RCC with RMC features has rarely been reported in patients with no sickle cell trait or disease. Renal cell carcinoma unclassified with medullary phenotype (RCCU-MP) is a newly-coined term used by an international panel of experts to describe renal cell carcinoma showing morphologic and immunohistochemical features of renal medullary carcinoma in patients without sickle cell trait/disease. So far, only one study in the English literature has described five such cases. Here, we report a case with unique clinical and pathological features in a 76-year-old male patient without sickle cell trait. The patient had a history of colon cancer with liver and lung metastases and was found to have a new renal mass in his right kidney during the follow up. A right nephrectomy was performed and showed two separate masses (tumor 1 and tumor 2). Tumor 1 had histologic features of RMC and the tumor cells were positive for CK7, Pax8, and OCT4 and showed loss of nuclear INI1 expression. Tumor 1 was diagnosed as RCCU-MP (6.3 cm, pT3aNx, WHO/ISUP nuclear grade 3). Tumor 2 showed features of clear cell type of RCC (0.6 cm, pT1aNx, WHO/ISUP grade 2) with intact nuclear INI1 expression. Three-months post-nephrectomy, the patient developed lung metastasis of RCCU-MP. To the best of our knowledge, this was the first documented case with synchronous RCCU-MP and clear cell RCC presenting in a patient without sickle cell trait. Careful histologic assessment with a panel of immunohistochemical biomarkers was helpful to render a correct diagnosis for early aggressive treatment. Copyright© 2018, International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.

[NOD2 gene mutation in Moroccan patients with Crohn's disease: prevalence, genotypic study and correlation of NOD2 gene mutation with the phenotype of Crohn's disease].

PubMed

Tamzaourte, Mouna; Errabih, Ikram; Krami, Hayat; Maha, Fadlouallah; Maria, Lahmiri; Benzzoubeir, Nadia; Ouazzani, Laaziza; Sefiani, Ahmed; Ouazzani, Houria

2017-01-01

The aim of this study was to determine the prevalence of NOD2/CARD15 gene mutations in a group of Moroccan patients with Crohn's disease and to study its correlation with genotype-phenotypic expression. We conducted a cross-sectional case-control study over a period of 16 months. 101 patients with Crohn's disease were enrolled between January 2012 and April 2013 as well as a control group of 107 patients. We performed a genetic analysis to identify 3 NOD2 gene variants: p.Arg702Trp, p.Gly908Arg and p.Leu1007fsins. Then we conducted a study of the correlation between genotype and phenotypic expression. The genetic analysis of patients with Crohn's disease highlighted the presence of NOD2 mutation in 14 patients (13.77%) versus 7 patients (6.53%) in the control group. The study of the frequency of different alleles showed p.Gly908Arg mutation in 6.43%, p.Leu1007fsins in 0.99% and p.Arg702Trp in 0.49% versus 2.80%, 0% and 0.46% in the control group respectively. The study of the correlation between genotype and phenotypic expression showed that CARD15 mutation is associated with ileocecal Crohn's disease, with fistulizing and stenosing behavior in Crohn's disease as well as with severe evolution and frequent recourse to surgery and immunosuppressants. The prevalence of NOD2/ CARD15 mutation in our case series is low. This mutation is correlated with severe Crohn's disease.

Agreeableness and alcohol-related aggression: the mediating effect of trait aggressivity.

PubMed

Miller, Cameron A; Parrott, Dominic J; Giancola, Peter R

2009-12-01

This study investigated the mediating effect of trait aggressivity on the relation between agreeableness and alcohol-related aggression in a laboratory setting. Participants were 116 healthy male social drinkers between 21 and 30 years of age. Agreeableness and trait aggressivity were measured using the Big Five Inventory and the Buss-Perry Aggression Questionnaire, respectively. Following the consumption of an alcohol or no-alcohol control beverage, participants completed a modified version of the Taylor Aggression Paradigm, in which electric shocks were received from and administered to a fictitious opponent during a competitive task. Aggression was operationalized as the proportion of the most extreme shocks delivered to the fictitious opponent under conditions of low and high provocation. Results indicated that lower levels of agreeableness were associated with higher levels of trait aggressivity. In turn, higher levels of trait aggressivity predicted extreme aggression in intoxicated, but not sober, participants under low, but not high, provocation. Findings highlight the importance of examining determinants of intoxicated aggression within a broader theoretical framework of personality.

Normative beliefs about aggression and cyber aggression among young adults: a longitudinal investigation.

PubMed

Wright, Michelle F; Li, Yan

2013-01-01

This longitudinal study examined normative beliefs about aggression (e.g., face-to-face, cyber) in relation to the engagement in cyber aggression 6 months later among 126 (69 women) young adults. Participants completed electronically administered measures assessing their normative beliefs, face-to-face and cyber aggression at Time 1, and cyber aggression 6 months later (Time 2). We found that men reported more cyber relational and verbal aggression when compared to women. After controlling for each other, Time 1 face-to-face relational aggression was positively related to Time 2 cyber relational aggression, whereas Time 1 face-to-face verbal aggression was positively related to Time 2 cyber verbal aggression. Normative beliefs regarding cyber aggression was positively related to both forms of cyber aggression 6 months later, after controlling for normative beliefs about face-to-face aggression. Furthermore, a significant two-way interaction between Time 1 cyber relational aggression and normative beliefs about cyber relational aggression was found. Follow-up analysis showed that Time 1 cyber relational aggression was more strongly related to Time 2 cyber relational aggression when young adults held higher normative beliefs about cyber relational aggression. A similar two-way interaction was found for cyber verbal aggression such that the association between Time 1 and Time 2 cyber verbal aggression was stronger at higher levels of normative beliefs about cyber verbal aggression. Results are discussed in terms of the social cognitive and behavioral mechanisms associated with the engagement of cyber aggression. © 2013 Wiley Periodicals, Inc.

Identifying aggressive prostate cancer foci using a DNA methylation classifier.

PubMed

Mundbjerg, Kamilla; Chopra, Sameer; Alemozaffar, Mehrdad; Duymich, Christopher; Lakshminarasimhan, Ranjani; Nichols, Peter W; Aron, Manju; Siegmund, Kimberly D; Ukimura, Osamu; Aron, Monish; Stern, Mariana; Gill, Parkash; Carpten, John D; Ørntoft, Torben F; Sørensen, Karina D; Weisenberger, Daniel J; Jones, Peter A; Duddalwar, Vinay; Gill, Inderbir; Liang, Gangning

2017-01-12

Slow-growing prostate cancer (PC) can be aggressive in a subset of cases. Therefore, prognostic tools to guide clinical decision-making and avoid overtreatment of indolent PC and undertreatment of aggressive disease are urgently needed. PC has a propensity to be multifocal with several different cancerous foci per gland. Here, we have taken advantage of the multifocal propensity of PC and categorized aggressiveness of individual PC foci based on DNA methylation patterns in primary PC foci and matched lymph node metastases. In a set of 14 patients, we demonstrate that over half of the cases have multiple epigenetically distinct subclones and determine the primary subclone from which the metastatic lesion(s) originated. Furthermore, we develop an aggressiveness classifier consisting of 25 DNA methylation probes to determine aggressive and non-aggressive subclones. Upon validation of the classifier in an independent cohort, the predicted aggressive tumors are significantly associated with the presence of lymph node metastases and invasive tumor stages. Overall, this study provides molecular-based support for determining PC aggressiveness with the potential to impact clinical decision-making, such as targeted biopsy approaches for early diagnosis and active surveillance, in addition to focal therapy.

Muscarine- and carbachol-induced aggressions: fear and irritable kinds of aggressions.

PubMed

Beleslin, D B; Samardzić, R

1977-12-28

In unaneasthetized and unrestrained cats, muscarine and carbachol were injected into the cerebral ventricles. The kind of aggressive behaviour depended on the cholinomimetic drug and was classified as fear and an irritable kind of aggression. Muscarine induced the fear kind of aggression. The aggressive behaviour was usually preceded by attempts to escape and the attack was relevant to the situation. For the attack the presence of some threatening agent was needed. The aggression was accompanied by intense motor but less autonomic activation. On the other hand, carbachol induced an irritable kind of aggression and had the following characteristics: for the attack the presence of some threatening agent was not needed; the attack was not relevant to the situation; the aggression was not preceded by attempts to escape; and the aggressive behaviour was accompanied by intense motor and autonomic activation. It is concluded that cholinoceptive mechanisms are involved in the control of aggressive behaviour.

VB-CHEP chemotherapy regimen for aggressive non-Hodgkin's lymphomas.

PubMed

Yalçin, S; Kars, A; Ozişik, Y; Tekuzman, G; Ozyilkan, O; Celik, I; Barişta, I; Güllü, I; Güler, N; Baltali, E; Firat, D

1998-10-01

Despite intensive search for the optimal combination chemotherapy for aggressive non-Hodgkin's lymphoma (NHL), the CHOP (cyclophosphamide, adriamycin, vincristine and prednisolone) regimen is still the standard therapy. We investigated the clinical efficacy of a new combination regimen consisting of vincristine, bleomycin-cyclophosphamide, adriamycin, etoposide and prednisolone (VB-CHEP) in patients with aggressive NHL. A total of 29 patients with aggressive NHL was enrolled into the protocol. Eight patients were consolidated with cisplatin and cytarabine and 5 patients received radiotherapy for bulky disease. Objective response was achieved in 82.8% of the patients. Complete remission (CR) and partial remission rates were 72.4%, and 10.3%, respectively. CR rate was significantly lower in patients with advanced stage, extranodal disease and bone marrow involvement. Median follow-up time is 34+ months; 17 patients are disease-free while 12 died and only 2 patients with CR have relapsed so far. Median response duration is 29+ months and the median survival is 48+ months. The survival rate is 69% in the first year and 66% in the second year. A total of 152 cycles were evaluated for toxicity. Major hematological toxicity was myelosuppression and neutropenia, detected in 50.65%, was mostly grades 1-2. Neutropenic fever occurred in only 11 cycles. The side effects of the consolidation therapy were also acceptable. We conclude that the VB-CHEP regimen with consolidation therapy for high-risk patients may be an effective treatment for advanced stage aggressive NHL.

Implicit cognitive aggression among young male prisoners: Association with dispositional and current aggression.

PubMed

Ireland, Jane L; Adams, Christine

2015-01-01

The current study explores associations between implicit and explicit aggression in young adult male prisoners, seeking to apply the Reflection-Impulsive Model and indicate parity with elements of the General Aggression Model and social cognition. Implicit cognitive aggressive processing is not an area that has been examined among prisoners. Two hundred and sixty two prisoners completed an implicit cognitive aggression measure (Puzzle Test) and explicit aggression measures, covering current behaviour (DIPC-R) and aggression disposition (AQ). It was predicted that dispositional aggression would be predicted by implicit cognitive aggression, and that implicit cognitive aggression would predict current engagement in aggressive behaviour. It was also predicted that more impulsive implicit cognitive processing would associate with aggressive behaviour whereas cognitively effortful implicit cognitive processing would not. Implicit aggressive cognitive processing was associated with increased dispositional aggression but not current reports of aggressive behaviour. Impulsive implicit cognitive processing of an aggressive nature predicted increased dispositional aggression whereas more cognitively effortful implicit cognitive aggression did not. The article concludes by outlining the importance of accounting for implicit cognitive processing among prisoners and the need to separate such processing into facets (i.e. impulsive vs. cognitively effortful). Implications for future research and practice in this novel area of study are indicated. Copyright © 2015 Elsevier Ltd. All rights reserved.

Modulating membrane fluidity corrects Batten disease phenotypes in vitro and in vivo.

PubMed

Schultz, Mark L; Tecedor, Luis; Lysenko, Elena; Ramachandran, Shyam; Stein, Colleen S; Davidson, Beverly L

2018-07-01

The neuronal ceroid lipofuscinoses are a class of inherited neurodegenerative diseases characterized by the accumulation of autofluorescent storage material. The most common neuronal ceroid lipofuscinosis has juvenile onset with rapid onset blindness and progressive degeneration of cognitive processes. The juvenile form is caused by mutations in the CLN3 gene, which encodes the protein CLN3. While mouse models of Cln3 deficiency show mild disease phenotypes, it is apparent from patient tissue- and cell-based studies that its loss impacts many cellular processes. Using Cln3 deficient mice, we previously described defects in mouse brain endothelial cells and blood-brain barrier (BBB) permeability. Here we expand on this to other components of the BBB and show that Cln3 deficient mice have increased astrocyte endfeet area. Interestingly, this phenotype is corrected by treatment with a commonly used GAP junction inhibitor, carbenoxolone (CBX). In addition to its action on GAP junctions, CBX has also been proposed to alter lipid microdomains. In this work, we show that CBX modifies lipid microdomains and corrects membrane fluidity alterations in Cln3 deficient endothelial cells, which in turn improves defects in endocytosis, caveolin-1 distribution at the plasma membrane, and Cdc42 activity. In further work using the NIH Library of Integrated Network-based Cellular Signatures (LINCS), we discovered other small molecules whose impact was similar to CBX in that they improved Cln3-deficient cell phenotypes. Moreover, Cln3 deficient mice treated orally with CBX exhibited recovery of impaired BBB responses and reduced autofluorescence. CBX and the compounds identified by LINCS, many of which have been used in humans or approved for other indications, may find therapeutic benefit in children suffering from CLN3 deficiency through mechanisms independent of their original intended use. Copyright © 2018 The Authors. Published by Elsevier Inc. All rights reserved.

Genetic or pharmacological activation of the Drosophila PGC-1α ortholog spargel rescues the disease phenotypes of genetic models of Parkinson's disease.

PubMed

Ng, Chee-Hoe; Basil, Adeline H; Hang, Liting; Tan, Royston; Goh, Kian-Leong; O'Neill, Sharon; Zhang, Xiaodong; Yu, Fengwei; Lim, Kah-Leong

2017-07-01

Despite intensive research, the etiology of Parkinson's disease (PD) remains poorly understood and the disease remains incurable. However, compelling evidence gathered over decades of research strongly support a role for mitochondrial dysfunction in PD pathogenesis. Related to this, PGC-1α, a key regulator of mitochondrial biogenesis, has recently been proposed to be an attractive target for intervention in PD. Here, we showed that silencing of expression of the Drosophila PGC-1α ortholog spargel results in PD-related phenotypes in flies and also seem to negate the effects of AMPK activation, which we have previously demonstrated to be neuroprotective, that is, AMPK-mediated neuroprotection appears to require PGC-1α. Importantly, we further showed that genetic or pharmacological activation of the Drosophila PGC-1α ortholog spargel is sufficient to rescue the disease phenotypes of Parkin and LRRK2 genetic fly models of PD, thus supporting the proposed use of PGC-1α-related strategies for neuroprotection in PD. Copyright © 2017 National Neuroscience Institute. Published by Elsevier Inc. All rights reserved.

Inherited determinants of Crohn's disease and ulcerative colitis phenotypes: a genetic association study

PubMed Central

Cleynen, Isabelle; Boucher, Gabrielle; Jostins, Luke; Schumm, L Philip; Zeissig, Sebastian; Ahmad, Tariq; Andersen, Vibeke; Andrews, Jane M; Annese, Vito; Brand, Stephan; Brant, Steven R; Cho, Judy H; Daly, Mark J; Dubinsky, Marla; Duerr, Richard H; Ferguson, Lynnette R; Franke, Andre; Gearry, Richard B; Goyette, Philippe; Hakonarson, Hakon; Halfvarson, Jonas; Hov, Johannes R; Huang, Hailang; Kennedy, Nicholas A; Kupcinskas, Limas; Lawrance, Ian C; Lee, James C; Satsangi, Jack; Schreiber, Stephan; Théâtre, Emilie; van der Meulen-de Jong, Andrea E; Weersma, Rinse K; Wilson, David C; Parkes, Miles; Vermeire, Severine; Rioux, John D; Mansfield, John; Silverberg, Mark S; Radford-Smith, Graham; McGovern, Dermot P B; Barrett, Jeffrey C; Lees, Charlie W

2016-01-01

Summary Background Crohn's disease and ulcerative colitis are the two major forms of inflammatory bowel disease; treatment strategies have historically been determined by this binary categorisation. Genetic studies have identified 163 susceptibility loci for inflammatory bowel disease, mostly shared between Crohn's disease and ulcerative colitis. We undertook the largest genotype association study, to date, in widely used clinical subphenotypes of inflammatory bowel disease with the goal of further understanding the biological relations between diseases. Methods This study included patients from 49 centres in 16 countries in Europe, North America, and Australasia. We applied the Montreal classification system of inflammatory bowel disease subphenotypes to 34 819 patients (19 713 with Crohn's disease, 14 683 with ulcerative colitis) genotyped on the Immunochip array. We tested for genotype–phenotype associations across 156 154 genetic variants. We generated genetic risk scores by combining information from all known inflammatory bowel disease associations to summarise the total load of genetic risk for a particular phenotype. We used these risk scores to test the hypothesis that colonic Crohn's disease, ileal Crohn's disease, and ulcerative colitis are all genetically distinct from each other, and to attempt to identify patients with a mismatch between clinical diagnosis and genetic risk profile. Findings After quality control, the primary analysis included 29 838 patients (16 902 with Crohn's disease, 12 597 with ulcerative colitis). Three loci (NOD2, MHC, and MST1 3p21) were associated with subphenotypes of inflammatory bowel disease, mainly disease location (essentially fixed over time; median follow-up of 10·5 years). Little or no genetic association with disease behaviour (which changed dramatically over time) remained after conditioning on disease location and age at onset. The genetic risk score representing all known risk alleles for

Complexity and diversity of gastroesophageal reflux disease phenotypes.

PubMed

Zentilin, Patrizia; Marabotto, Elisa; Pellegatta, Gaia; Coppo, Claudia; Furnari, Manuele; Savarino, Edoardo; Savarino, Vincenzo

2017-09-01

Gastroesophageal reflux disease (GERD) is defined as a condition which develops when the reflux of gastric contents causes troublesome symptoms, impairs quality of life, or leads to mucosal damage or complications. There are two main phenotypic presentations of GERD, the erosive (ERD) and non-erosive reflux disease (NERD), with the latter one representing up to 70% of GERD spectrum. Moreover, patients with GERD can be clinically subdivided into two distinct syndromes: patients with esophageal and extraesophageal symptoms. The diagnosis of NERD should be supported by the evidence that symptoms are due to reflux episodes on the basis of an excess of acid into the esophagus or a positive correlation between symptoms and acid and/or weakly acidic reflux episodes as evidenced by 24-hour impedance-pH monitoring. Patients with normal esophageal acid exposure and no correlation between heartburn and any kind of chemical reflux are considered affected by functional heartburn and do not pertain to the realm of NERD. They do not usually respond to PPI therapy as further empirical criterion and are included in the large group of functional digestive disorders with the expression of altered generation or perception of symptoms at the esophageal level and can often overlap with functional dyspepsia and irritable bowel syndrome.

Text-based phenotypic profiles incorporating biochemical phenotypes of inborn errors of metabolism improve phenomics-based diagnosis.

PubMed

Lee, Jessica J Y; Gottlieb, Michael M; Lever, Jake; Jones, Steven J M; Blau, Nenad; van Karnebeek, Clara D M; Wasserman, Wyeth W

2018-05-01

Phenomics is the comprehensive study of phenotypes at every level of biology: from metabolites to organisms. With high throughput technologies increasing the scope of biological discoveries, the field of phenomics has been developing rapid and precise methods to collect, catalog, and analyze phenotypes. Such methods have allowed phenotypic data to be widely used in medical applications, from assisting clinical diagnoses to prioritizing genomic diagnoses. To channel the benefits of phenomics into the field of inborn errors of metabolism (IEM), we have recently launched IEMbase, an expert-curated knowledgebase of IEM and their disease-characterizing phenotypes. While our efforts with IEMbase have realized benefits, taking full advantage of phenomics requires a comprehensive curation of IEM phenotypes in core phenomics projects, which is dependent upon contributions from the IEM clinical and research community. Here, we assess the inclusion of IEM biochemical phenotypes in a core phenomics project, the Human Phenotype Ontology. We then demonstrate the utility of biochemical phenotypes using a text-based phenomics method to predict gene-disease relationships, showing that the prediction of IEM genes is significantly better using biochemical rather than clinical profiles. The findings herein provide a motivating goal for the IEM community to expand the computationally accessible descriptions of biochemical phenotypes associated with IEM in phenomics resources.

Heightened aggressive behavior in mice deficient in aldo-keto reductase 1a (Akr1a).

PubMed

Homma, Takujiro; Akihara, Ryusuke; Okano, Satoshi; Shichiri, Mototada; Yoshida, Yasukazu; Yamada, Ken-Ichi; Miyata, Satoshi; Nakajima, Osamu; Fujii, Junichi

2017-02-15

Aldehyde reductase (Akr1a) is involved in the synthesis of ascorbic acid (AsA) which may play a role in social behavior. In the current study, we performed analyses on Akr1a-deficient (Akr1a -/- ) mice that synthesize about 10% as much AsA as wild-type mice from the viewpoint of intermale aggression. The use of the resident-intruder test revealed that the Akr1a -/- mice exhibited more aggressive phenotypes than wild-type control mice. Unexpectedly, however, the oral administration of additional AsA failed to reduce the aggressive behavior of Akr1a -/- mice, suggesting that the heightened aggression was independent of AsA biosynthesis. The findings also show that the plasma levels of corticosterone, but not serotonin and testosterone, were increased in the absence of Akr1a in mice, suggesting that the mice were highly stressed. These results suggest that Akr1a might be involved in the metabolism of steroids and other carbonyl-containing compounds and, hence, the absence of Akr1a results in heightened aggression via a malfunction in a metabolic pathway. Copyright © 2016 Elsevier B.V. All rights reserved.

A CTD-Pfizer collaboration: manual curation of 88,000 scientific articles text mined for drug-disease and drug-phenotype interactions.

PubMed

Davis, Allan Peter; Wiegers, Thomas C; Roberts, Phoebe M; King, Benjamin L; Lay, Jean M; Lennon-Hopkins, Kelley; Sciaky, Daniela; Johnson, Robin; Keating, Heather; Greene, Nigel; Hernandez, Robert; McConnell, Kevin J; Enayetallah, Ahmed E; Mattingly, Carolyn J

2013-01-01

Improving the prediction of chemical toxicity is a goal common to both environmental health research and pharmaceutical drug development. To improve safety detection assays, it is critical to have a reference set of molecules with well-defined toxicity annotations for training and validation purposes. Here, we describe a collaboration between safety researchers at Pfizer and the research team at the Comparative Toxicogenomics Database (CTD) to text mine and manually review a collection of 88,629 articles relating over 1,200 pharmaceutical drugs to their potential involvement in cardiovascular, neurological, renal and hepatic toxicity. In 1 year, CTD biocurators curated 254,173 toxicogenomic interactions (152,173 chemical-disease, 58,572 chemical-gene, 5,345 gene-disease and 38,083 phenotype interactions). All chemical-gene-disease interactions are fully integrated with public CTD, and phenotype interactions can be downloaded. We describe Pfizer's text-mining process to collate the articles, and CTD's curation strategy, performance metrics, enhanced data content and new module to curate phenotype information. As well, we show how data integration can connect phenotypes to diseases. This curation can be leveraged for information about toxic endpoints important to drug safety and help develop testable hypotheses for drug-disease events. The availability of these detailed, contextualized, high-quality annotations curated from seven decades' worth of the scientific literature should help facilitate new mechanistic screening assays for pharmaceutical compound survival. This unique partnership demonstrates the importance of resource sharing and collaboration between public and private entities and underscores the complementary needs of the environmental health science and pharmaceutical communities. Database URL: http://ctdbase.org/

Epigenetic up-regulation of ribosome biogenesis and more aggressive phenotype triggered by the lack of the histone demethylase JHDM1B in mammary epithelial cells

PubMed Central

Galbiati, Alice; Penzo, Marianna; Bacalini, Maria Giulia; Onofrillo, Carmine; Guerrieri, Ania Naila; Garagnani, Paolo; Franceschi, Claudio; Treré, Davide; Montanaro, Lorenzo

2017-01-01

The alterations of ribosome biogenesis and protein synthesis play a direct role in the development of tumors. The accessibility and transcription of ribosomal genes is controlled at several levels, with their epigenetic regulation being one of the most important. Here we explored the JmjC domain-containing histone demethylase 1B (JHDM1B) function in the epigenetic control of rDNA transcription. Since JHDM1B is a negative regulator of gene transcription, we focused on the effects induced by JHDM1B knock-down (KD). We studied the consequences of stable inducible JHDM1B silencing in cell lines derived from transformed and untransformed mammary epithelial cells. In these cellular models, prolonged JHDM1B downregulation triggered a surge of 45S pre-rRNA transcription and processing, associated with a re-modulation of the H3K36me2 levels at rDNA loci and with changes in DNA methylation of specific CpG sites in rDNA genes. We also found that after JHDM1B KD, cells showed a higher ribosome content: which were engaged in mRNA translation. JHDM1B KD and the consequent stimulation of ribosomes biogenesis conferred more aggressive features to the tested cellular models, which acquired a greater clonogenic, staminal and invasive potential. Taken together, these data indicate that the reduction of JHDM1B leads to a more aggressive cellular phenotype in mammary gland cells, by virtue of its negative regulatory activity on ribosome biogenesis. PMID:28415746

Phenotypes of organ involvement in sarcoidosis.

PubMed

Schupp, Jonas Christian; Freitag-Wolf, Sandra; Bargagli, Elena; Mihailović-Vučinić, Violeta; Rottoli, Paola; Grubanovic, Aleksandar; Müller, Annegret; Jochens, Arne; Tittmann, Lukas; Schnerch, Jasmin; Olivieri, Carmela; Fischer, Annegret; Jovanovic, Dragana; Filipovic, Snežana; Videnovic-Ivanovic, Jelica; Bresser, Paul; Jonkers, René; O'Reilly, Kate; Ho, Ling-Pei; Gaede, Karoline I; Zabel, Peter; Dubaniewicz, Anna; Marshall, Ben; Kieszko, Robert; Milanowski, Janusz; Günther, Andreas; Weihrich, Anette; Petrek, Martin; Kolek, Vitezslav; Keane, Michael P; O'Beirne, Sarah; Donnelly, Seamas; Haraldsdottir, Sigridur Olina; Jorundsdottir, Kristin B; Costabel, Ulrich; Bonella, Francesco; Wallaert, Benoît; Grah, Christian; Peroš-Golubičić, Tatjana; Luisetti, Mauritio; Kadija, Zamir; Pabst, Stefan; Grohé, Christian; Strausz, János; Vašáková, Martina; Sterclova, Martina; Millar, Ann; Homolka, Jiří; Slováková, Alena; Kendrick, Yvonne; Crawshaw, Anjali; Wuyts, Wim; Spencer, Lisa; Pfeifer, Michael; Valeyre, Dominique; Poletti, Venerino; Wirtz, Hubertus; Prasse, Antje; Schreiber, Stefan; Krawczak, Michael; Müller-Quernheim, Joachim

2018-01-01

Sarcoidosis is a highly variable, systemic granulomatous disease of hitherto unknown aetiology. The GenPhenReSa (Genotype-Phenotype Relationship in Sarcoidosis) project represents a European multicentre study to investigate the influence of genotype on disease phenotypes in sarcoidosis.The baseline phenotype module of GenPhenReSa comprised 2163 Caucasian patients with sarcoidosis who were phenotyped at 31 study centres according to a standardised protocol.From this module, we found that patients with acute onset were mainly female, young and of Scadding type I or II. Female patients showed a significantly higher frequency of eye and skin involvement, and complained more of fatigue. Based on multidimensional correspondence analysis and subsequent cluster analysis, patients could be clearly stratified into five distinct, yet undescribed, subgroups according to predominant organ involvement: 1) abdominal organ involvement, 2) ocular-cardiac-cutaneous-central nervous system disease involvement, 3) musculoskeletal-cutaneous involvement, 4) pulmonary and intrathoracic lymph node involvement, and 5) extrapulmonary involvement.These five new clinical phenotypes will be useful to recruit homogenous cohorts in future biomedical studies. Copyright ©ERS 2018.

Genotype-phenotype relations for the Parkinson's Disease genes Parkin, PINK1, DJ1: MDSGene Systematic Review.

PubMed

Kasten, Meike; Hartmann, Corinna; Hampf, Jennie; Schaake, Susen; Westenberger, Ana; Vollstedt, Eva-Juliane; Balck, Alexander; Domingo, Aloysius; Vulinovic, Franca; Dulovic, Marija; Zorn, Ingo; Madoev, Harutyun; Zehnle, Hanna; Lembeck, Christina M; Schawe, Leopold; Reginold, Jennifer; Huang, Jana; König, Inke R; Bertram, Lars; Marras, Connie; Lohmann, Katja; Lill, Christina M; Klein, Christine

2018-04-11

This first comprehensive MDSGene review is devoted to the 3 autosomal recessive Parkinson's disease forms: PARK-Parkin, PARK-PINK1, and PARK-DJ1. It followed MDSGene's standardized data extraction protocol and screened a total of 3652 citations and is based on fully curated phenotypic and genotypic data on >1100 patients with recessively inherited PD because of 221 different disease-causing mutations in Parkin, PINK1, or DJ1. All these data are also available in an easily searchable online database (www.mdsgene.org), which also provides descriptive summary statistics on phenotypic and genetic data. Despite the high degree of missingness of phenotypic features and unsystematic reporting of genotype data in the original literature, the present review recapitulates many of the previously described findings including early onset (median age at onset of ∼30 years for carriers of at least 2 mutations in any of the 3 genes) of an overall clinically typical form of PD with excellent treatment response, dystonia and dyskinesia being relatively common and cognitive decline relatively uncommon. However, when comparing actual data with common expert knowledge in previously published reviews, we detected several discrepancies. We conclude that systematic reporting of phenotypes is a pressing need in light of increasingly available molecular genetic testing and the emergence of first gene-specific therapies entering clinical trials. © 2018 International Parkinson and Movement Disorder Society. © 2018 International Parkinson and Movement Disorder Society.

[Functional neuroimaging in the study of aggressive behaviour in patients with schizophrenia].

PubMed

Garciá-Martí, Gracián; Martí-Bonmatí, Luis; Aguilar, Eduardo J; Sanz-Requena, Roberto; Alberich-Bayarri, Ángel; Bonmatí, Ana; Sanjuán, Julio

2013-02-16

Although aggressive behaviours are not always very highly prevalent in schizophrenia, their occurrence does represent a significant problem for patients and those around them. Although neuroimaging studies have made it possible to further our knowledge of the biology of these behaviours, there is still a notable degree of clinical heterogeneity in the study samples that makes it difficult to obtain conclusive results that can be compared with each other. To determine whether there are variations in the brain activity, as measured with functional magnetic resonance imaging, of a homogenous group of patients with schizophrenia and aggressive behaviour. The sample consisted of 32 patients with refractory schizophrenia and auditory hallucinations selected for the study. The subjects were submitted to a functional magnetic resonance imaging examination using an auditory paradigm with emotional stimulation, while the degree of aggressiveness was measured by means of the Brief Psychiatric Rating Scale. Significant correlations were found between functional activation and the degree of aggressiveness, which show focal hyperactivations in patients with a greater association to violent behaviours. The areas identified were located in the left hippocampus (p < 0.003, corrected) and in the right medial frontal gyrus (p < 0.004, corrected). This study determines the association between the degree of aggressiveness and certain regions in the brain that are responsible for cognitive and emotional processing in a phenotypically very homogenous group of patients with chronic auditory hallucinations and schizophrenia. This alteration of the neuronal circuits can favour loss in the processes involved in empathy and sensitivity, thus favouring the appearance of aggressive behaviours.

Genetic Mapping of Fixed Phenotypes: Disease Frequency as a Breed Characteristic

PubMed Central

Jones, Paul; Martin, Alan; Ostrander, Elaine A.; Lark, Karl G.

2009-01-01

Traits that have been stringently selected to conform to specific criteria in a closed population are phenotypic stereotypes. In dogs, Canis familiaris, such stereotypes have been produced by breeding for conformation, performance (behaviors), etc. We measured phenotypes on a representative sample to establish breed stereotypes. DNA samples from 147 dog breeds were used to characterize single nucleotide polymorphism allele frequencies for association mapping of breed stereotypes. We identified significant size loci (quantitative trait loci [QTLs]), implicating candidate genes appropriate to regulation of size (e.g., IGF1, IGF2BP2 SMAD2, etc.). Analysis of other morphological stereotypes, also under extreme selection, identified many additional significant loci. Behavioral loci for herding, pointing, and boldness implicated candidate genes appropriate to behavior (e.g., MC2R, DRD1, and PCDH9). Significant loci for longevity, a breed characteristic inversely correlated with breed size, were identified. The power of this approach to identify loci regulating the incidence of specific polygenic diseases is demonstrated by the association of a specific IGF1 haplotype with hip dysplasia, patella luxation, and pacreatitis. PMID:19321632

Genetic mapping of fixed phenotypes: disease frequency as a breed characteristic.

PubMed

Chase, Kevin; Jones, Paul; Martin, Alan; Ostrander, Elaine A; Lark, Karl G

2009-01-01

Traits that have been stringently selected to conform to specific criteria in a closed population are phenotypic stereotypes. In dogs, Canis familiaris, such stereotypes have been produced by breeding for conformation, performance (behaviors), etc. We measured phenotypes on a representative sample to establish breed stereotypes. DNA samples from 147 dog breeds were used to characterize single nucleotide polymorphism allele frequencies for association mapping of breed stereotypes. We identified significant size loci (quantitative trait loci [QTLs]), implicating candidate genes appropriate to regulation of size (e.g., IGF1, IGF2BP2 SMAD2, etc.). Analysis of other morphological stereotypes, also under extreme selection, identified many additional significant loci. Behavioral loci for herding, pointing, and boldness implicated candidate genes appropriate to behavior (e.g., MC2R, DRD1, and PCDH9). Significant loci for longevity, a breed characteristic inversely correlated with breed size, were identified. The power of this approach to identify loci regulating the incidence of specific polygenic diseases is demonstrated by the association of a specific IGF1 haplotype with hip dysplasia, patella luxation, and pancreatitis.

Persistent conditioned place preference to aggression experience in adult male sexually-experienced CD-1 mice

PubMed Central

Golden, Sam A.; Aleyasin, Hossein; Heins, Robert; Flanigan, Meghan; Heshmati, Mitra; Takahashi, Aki; Russo, Scott J.; Shaham, Yavin

2016-01-01

We recently developed a conditioned place preference (CPP) procedure, commonly used to study rewarding drug effects, to demonstrate that dominant sexually-experienced CD-1 male mice form CPP to contexts previously associated with defeating subordinate male C57BL/6J mice. Here we further characterized conditioned and unconditioned aggression behavior in CD-1 mice. In Exp. 1 we used CD-1 mice that displayed a variable spectrum of unconditioned aggressive behavior toward younger subordinate C57BL/6J intruder mice. We then trained the CD-1 mice in the CPP procedure where one context was intruder-paired, while a different context was not. We then tested for aggression CPP 1 day after training. In Exp. 2, we tested CD-1 mice for aggression CPP 1 day and 18 days after training. In Exp. 3–4, we trained the CD-1 mice to lever-press for palatable food and tested them for footshock punishment-induced suppression of food-reinforced responding. In Exp. 5, we characterized unconditioned aggression in hybrid CD-1xC57BL/6J D1-Cre or D2-Cre F1 generation crosses. Persistent aggression CPP was observed in CD-1 mice that either immediately attacked C57BL/6J mice during all screening sessions or mice that gradually developed aggressive behavior during the screening phase. In contrast, CD-1 mice that did not attack the C57BL/6J mice during screening didn’t develop CPP to contexts previously paired with C57BL/6J mice. The aggressive phenotype did not predict resistance to punishment-induced suppression of food-reinforced responding. CD-1xD1-Cre or D2-Cre F1 transgenic mice showed strong unconditioned aggression. Our study demonstrates that aggression experience causes persistent CPP and introduces transgenic mice for circuit studies of aggression. PMID:27457669

The Behavioural Phenotype of Smith-Magenis Syndrome: Evidence for a Gene-Environment Interaction

ERIC Educational Resources Information Center

Taylor, L.; Oliver, C.

2008-01-01

Background: Behaviour problems and a preference for adult contact are reported to be prominent in the phenotype of Smith-Magenis syndrome. In this study we examined the relationship between social interactions and self-injurious and aggressive/disruptive behaviour in Smith-Magenis syndrome to explore potential operant reinforcement of problem…

Age-dependent phenotypic characteristics of a triple transgenic mouse model of Alzheimer disease.

PubMed

Pietropaolo, Susanna; Feldon, Joram; Yee, Benjamin K

2008-08-01

The triple-transgenic mouse line (3 x Tg-AD) harboring PS1M146V, APPSwe, and taup301L transgenes represents the only transgenic model for Alzheimer's disease (AD) to date capturing both beta-amyloid and tau neuropathology. The present study provides an extensive behavioral characterization of the 3 x Tg-AD mouse line, evaluating the emergence of noncognitive and cognitive AD-like symptoms at two ages corresponding to the early (6-7 months) and advanced (12-13 months) stages of AD-pathology. Enhanced responsiveness to aversive stimulation was detected in mutant mice at both ages: the 3 x Tg-AD genotype enhanced acoustic startle response and facilitated performance in the cued-version of the water maze. These noncognitive phenotypes were accompanied by hyperactivity and reduced locomotor habituation in the open field at the older age. Signs of cognitive aberrations were also detected at both ages, but they were limited to associative learning. The present study suggests that this popular transgenic mouse model of AD has clear phenotypes beyond the cognitive domain, and their potential relationship to the cognitive phenotypes should be further explored.

Chronic low dose ethanol induces an aggressive metastatic phenotype in TRAMP mice, which is counteracted by parthenolide.

PubMed

Morel, Katherine L; Ormsby, Rebecca J; Solly, Emma L; Tran, Linh N K; Sweeney, Christopher J; Klebe, Sonja; Cordes, Nils; Sykes, Pamela J

2018-06-23

Despite advances in prostate cancer therapy, dissemination and growth of metastases results in shortened survival. Here we examined the potential anti-cancer effect of the NF-κB inhibitor parthenolide (PTL) and its water soluble analogue dimethylaminoparthenolide (DMAPT) on tumour progression and metastasis in the TRansgenic Adenocarcinoma of the Mouse Prostate (TRAMP) model of prostate cancer. Six-week-old male TRAMP mice received PTL (40 mg/kg in 10% ethanol/saline), DMAPT (100 mg/kg in sterile water), or vehicle controls by oral gavage thrice weekly until palpable tumour formation. DMAPT treatment slowed normal tumour development in TRAMP mice, extending the time-to-palpable prostate tumour by 20%. PTL did not slow overall tumour development, while the ethanol/saline vehicle used to administer PTL unexpectedly induced an aggressive metastatic tumour phenotype. Chronic ethanol/saline vehicle upregulated expression of NF-κB, MMP2, integrin β1, collagen IV, and laminin, and induced vascular basement membrane degradation in primary prostate tumours, as well as increased metastatic spread to the lung and liver. All of these changes were largely prevented by co-administration with PTL. DMAPT (in water) reduced metastasis to below that of water-control. These data suggest that DMAPT has the potential to be used as a cancer preventive and anti-metastatic therapy for prostate cancer. Although low levels of ethanol consumption have not been shown to strongly correlate with prostate cancer epidemiology, these results would support a potential effect of chronic low dose ethanol on metastasis and the TRAMP model provides a useful system in which to further explore the mechanisms involved.

New mutation of the MPZ gene in a family with the Dejerine-Sottas disease phenotype.

PubMed

Floroskufi, Paraskewi; Panas, Marios; Karadima, Georgia; Vassilopoulos, Demetris

2007-05-01

Charcot-Marie-Tooth disease type 1B is associated with mutations in the myelin protein zero gene. In the present study a new myelin protein zero gene mutation (c.89T>C,Ile30Thr) was detected in a family with the Dejerine-Sottas disease phenotype. The results support the hypothesis that severe, early-onset neuropathy may be related to either an alteration of a conserved amino acid or a disruption of the tertiary structure of myelin protein zero.

Phenotypic variability in familial prion diseases due to the D178N mutation

PubMed Central

Zarranz, J; Digon, A; Atares, B; Rodriguez-Martine..., A; Arce, A; Carrera, N; Fernandez-Manchol..., I; Fernandez-Martine..., M; Fernandez-Maizteg..., C; Forcadas, I; Galdos, L; Gomez-Esteban, J; Ibanez, A; Lezcano, E; d Lopez; Marti-Masso, J; Mendibe, M; Urtasun, M; Uterga, J; Saracibar, N; Velasco, F; de Pancorbo, M M

2005-01-01

Background: Between January 1993 and December 2003, 19 patients with familial prion diseases due to the D178N mutation were referred to the regional epidemiological registry for spongiform encephalopathies in the Basque Country in Spain, a small community of some 2 100 000 inhabitants. Methods: Ten further patients belonging to the same pedigrees were retrospectively ascertained through neurological or neuropathological records. In four of the patients, the diagnosis was confirmed by analysing DNA obtained from paraffin blocks. In this article, we report on the clinical, genetic, and pathological features of the 23 patients carrying the D178N mutation confirmed by genetic molecular analysis. Haplotyping studies suggest a founder effect among Basque born families, explaining in part this unusually high incidence of the D178N mutation in a small community. Only two patients (8%) lack familial antecedents. Results: We have observed a phenotypic variability even among homozygous 129MM patients. Our findings challenge the currently accepted belief that MM homozygosity in codon 129 is always related to a fatal familial insomnia (FFI) phenotype. Indeed, seven out of 17 patients with a 129MM genotype in this series presented with a Creutzfeldt-Jakob disease (CJD) clinicopathological picture. Conclusions: The considerable clinical and pathological overlapping observed among homozygous 129MM patients favours the view that FFI and CJD178 are the extremes of a spectrum rather than two discrete and separate entities. Other genetic or environmental factors apart from the polymorphism in codon 129 may play a role in determining the phenotypic expression of the D178N mutation in the PRNP gene. PMID:16227536

A Phenotypic Change But Not Proliferation Underlies Glial Responses in Alzheimer Disease

PubMed Central

Serrano-Pozo, Alberto; Gómez-Isla, Teresa; Growdon, John H.; Frosch, Matthew P.; Hyman, Bradley T.

2014-01-01

Classical immunohistochemical studies in the Alzheimer disease (AD) brain reveal prominent glial reactions, but whether this pathological feature is due primarily to cell proliferation or to a phenotypic change of existing resting cells remains controversial. We performed double-fluorescence immunohistochemical studies of astrocytes and microglia, followed by unbiased stereology-based quantitation in temporal cortex of 40 AD patients and 32 age-matched nondemented subjects. Glial fibrillary acidic protein (GFAP) and major histocompatibility complex II (MHC2) were used as markers of astrocytic and microglial activation, respectively. Aldehyde dehydrogenase 1 L1 and glutamine synthetase were used as constitutive astrocytic markers, and ionized calcium-binding adaptor molecule 1 (IBA1) as a constitutive microglial marker. As expected, AD patients had higher numbers of GFAP+ astrocytes and MHC2+ microglia than the nondemented subjects. However, both groups had similar numbers of total astrocytes and microglia and, in the AD group, these total numbers remained essentially constant over the clinical course of the disease. The GFAP immunoreactivity of astrocytes, but not the MHC2 immunoreactivity of microglia, increased in parallel with the duration of the clinical illness in the AD group. Cortical atrophy contributed to the perception of increased glia density. We conclude that a phenotypic change of existing glial cells, rather than a marked proliferation of glial precursors, accounts for the majority of the glial responses observed in the AD brain. PMID:23602650

Proximal correlates of metabolic phenotypes during ‘at-risk' and ‘case' stages of the metabolic disease continuum

PubMed Central

Haren, M T; Misan, G; Grant, J F; Buckley, J D; Howe, P R C; Taylor, A W; Newbury, J; McDermott, R A

2012-01-01

Objective: To examine the social and behavioural correlates of metabolic phenotypes during ‘at-risk' and ‘case' stages of the metabolic disease continuum. Design: Cross-sectional study of a random population sample. Participants: A total of 718 community-dwelling adults (57% female), aged 18–92 years from a regional South Australian city. Measurements: Total body fat and lean mass and abdominal fat mass were assessed by dual energy x-ray absorptiometry. Fasting venous blood was collected in the morning for assessment of glycated haemoglobin, plasma glucose, serum triglycerides, cholesterol lipoproteins and insulin. Seated blood pressure (BP) was measured. Physical activity and smoking, alcohol and diet (96-item food frequency), sleep duration and frequency of sleep disordered breathing (SDB) symptoms, and family history of cardiometabolic disease, education, lifetime occupation and household income were assessed by questionnaire. Current medications were determined by clinical inventory. Results: 36.5% were pharmacologically managed for a metabolic risk factor or had known diabetes (‘cases'), otherwise were classified as the ‘at-risk' population. In both ‘at-risk' and ‘cases', four major metabolic phenotypes were identified using principal components analysis that explained over 77% of the metabolic variance between people: fat mass/insulinemia (FMI); BP; lipidaemia/lean mass (LLM) and glycaemia (GLY). The BP phenotype was uncorrelated with other phenotypes in ‘cases', whereas all phenotypes were inter-correlated in the ‘at-risk'. Over and above other socioeconomic and behavioural factors, medications were the dominant correlates of all phenotypes in ‘cases' and SDB symptom frequency was most strongly associated with FMI, LLM and GLY phenotypes in the ‘at-risk'. Conclusion: Previous research has shown FMI, LLM and GLY phenotypes to be most strongly predictive of diabetes development. Reducing SDB symptom frequency and optimising the duration

Crohn's Disease Candidate Gene Alleles Predict Time to Progression from Inflammatory B1 to Stricturing B2, or Penetrating B3 Phenotype.

PubMed

Pernat Drobež, Cvetka; Ferkolj, Ivan; Potočnik, Uroš; Repnik, Katja

2018-03-01

Crohn's disease (CD) patients are mostly diagnosed with the uncomplicated inflammatory form of disease; however, the majority will progress to complicated stricturing or penetrating disease over time. It is important to identify patients at risk for disease progression at an early stage. The aim of our study was to examine the role of 33 candidate CD genes as possible predictors of disease progression and their influence on time to progression from an inflammatory to a stricturing or penetrating phenotype. Patients with an inflammatory phenotype at diagnosis were followed for 10 years and 33 CD-associated polymorphisms were genotyped. To test for association with CD, 449 healthy individuals were analyzed as the control group. Ten years after diagnosis, 39.1% of patients had not progressed beyond an inflammatory phenotype, but 60.9% had progressed to complicated disease, with average time to progression being 5.91 years. Association analyses of selected single nucleotide polymorphisms (SNPs) confirmed associations with CD for 12 SNPs. Furthermore, seven loci were associated with disease progression, out of which SNP rs4263839 in the gene TNFSF15 showed the strongest association with disease progression and the frameshift mutation rs2066847 in the gene NOD2 showed the strongest association with time to progression. The results of our study identified specific genetic biomarkers as useful predictors of both disease progression and speed of disease progression in patients with CD.

Different prion disease phenotypes result from inoculation of cattle with two temporally separated sources of sheep scrapie from Great Britain

PubMed Central

Konold, Timm; Lee, Yoon Hee; Stack, Michael J; Horrocks, Claire; Green, Robert B; Chaplin, Melanie; Simmons, Marion M; Hawkins, Steve AC; Lockey, Richard; Spiropoulos, John; Wilesmith, John W; Wells, Gerald AH

2006-01-01

Background Given the theoretical proposal that bovine spongiform encephalopathy (BSE) could have originated from sheep scrapie, this study investigated the pathogenicity for cattle, by intracerebral (i.c.) inoculation, of two pools of scrapie agents sourced in Great Britain before and during the BSE epidemic. Two groups of ten cattle were each inoculated with pools of brain material from sheep scrapie cases collected prior to 1975 and after 1990. Control groups comprised five cattle inoculated with sheep brain free from scrapie, five cattle inoculated with saline, and for comparison with BSE, naturally infected cattle and cattle i.c. inoculated with BSE brainstem homogenate from a parallel study. Phenotypic characterisation of the disease forms transmitted to cattle was conducted by morphological, immunohistochemical, biochemical and biological methods. Results Disease occurred in 16 cattle, nine inoculated with the pre-1975 inoculum and seven inoculated with the post-1990 inoculum, with four cattle still alive at 83 months post challenge (as at June 2006). The different inocula produced predominantly two different disease phenotypes as determined by histopathological, immunohistochemical and Western immunoblotting methods and biological characterisation on transmission to mice, neither of which was identical to BSE. Whilst the disease presentation was uniform in all scrapie-affected cattle of the pre-1975 group, the post-1990 inoculum produced a more variable disease, with two animals sharing immunohistochemical and molecular profile characteristics with animals in the pre-1975 group. Conclusion The study has demonstrated that cattle inoculated with different pooled scrapie sources can develop different prion disease phenotypes, which were not consistent with the phenotype of BSE of cattle and whose isolates did not have the strain typing characteristics of the BSE agent on transmission to mice. PMID:17044917

Melanoma cells revive an embryonic transcriptional network to dictate phenotypic heterogeneity.

PubMed

Vandamme, Niels; Berx, Geert

2014-01-01

Compared to the overwhelming amount of literature describing how epithelial-to-mesenchymal transition (EMT)-inducing transcription factors orchestrate cellular plasticity in embryogenesis and epithelial cells, the functions of these factors in non-epithelial contexts, such as melanoma, are less clear. Melanoma is an aggressive tumor arising from melanocytes, endowed with unique features of cellular plasticity. The reversible phenotype-switching between differentiated and invasive phenotypes is increasingly appreciated as a mechanism accounting for heterogeneity in melanoma and is driven by oncogenic signaling and environmental cues. This phenotypic switch is coupled with an intriguing and somewhat counterintuitive signaling switch of EMT-inducing transcription factors. In contrast to carcinomas, different EMT-inducing transcription factors have antagonizing effects in melanoma. Balancing between these different EMT transcription factors is likely the key to successful metastatic spread of melanoma.

Early Detection of Apathetic Phenotypes in Huntington's Disease Knock-in Mice Using Open Source Tools.

PubMed

Minnig, Shawn; Bragg, Robert M; Tiwana, Hardeep S; Solem, Wes T; Hovander, William S; Vik, Eva-Mari S; Hamilton, Madeline; Legg, Samuel R W; Shuttleworth, Dominic D; Coffey, Sydney R; Cantle, Jeffrey P; Carroll, Jeffrey B

2018-02-02

Apathy is one of the most prevalent and progressive psychiatric symptoms in Huntington's disease (HD) patients. However, preclinical work in HD mouse models tends to focus on molecular and motor, rather than affective, phenotypes. Measuring behavior in mice often produces noisy data and requires large cohorts to detect phenotypic rescue with appropriate power. The operant equipment necessary for measuring affective phenotypes is typically expensive, proprietary to commercial entities, and bulky which can render adequately sized mouse cohorts as cost-prohibitive. Thus, we describe here a home-built, open-source alternative to commercial hardware that is reliable, scalable, and reproducible. Using off-the-shelf hardware, we adapted and built several of the rodent operant buckets (ROBucket) to test Htt Q111/+ mice for attention deficits in fixed ratio (FR) and progressive ratio (PR) tasks. We find that, despite normal performance in reward attainment in the FR task, Htt Q111/+ mice exhibit reduced PR performance at 9-11 months of age, suggesting motivational deficits. We replicated this in two independent cohorts, demonstrating the reliability and utility of both the apathetic phenotype, and these ROBuckets, for preclinical HD studies.

Validation and discovery of genotype-phenotype associations in chronic diseases using linked data.

PubMed

Pathak, Jyotishman; Kiefer, Richard; Freimuth, Robert; Chute, Christopher

2012-01-01

This study investigates federated SPARQL queries over Linked Open Data (LOD) in the Semantic Web to validate existing, and potentially discover new genotype-phenotype associations from public datasets. In particular, we report our preliminary findings for identifying such associations for commonly occurring chronic diseases using the Online Mendelian Inheritance in Man (OMIM) and Database for SNPs (dbSNP) within the LOD knowledgebase and compare them with Gene Wiki for coverage and completeness. Our results indicate that Semantic Web technologies can play an important role for in-silico identification of novel disease-gene-SNP associations, although additional verification is required before such information can be applied and used effectively.

Disentangling functions of online aggression: The Cyber-Aggression Typology Questionnaire (CATQ).

PubMed

Runions, Kevin C; Bak, Michal; Shaw, Thérèse

2017-01-01

Aggression in online contexts has received much attention over the last decade, yet there is a need for measures identifying the proximal psychological drivers of cyber-aggressive behavior. The purpose of this study was to present data on the newly developed Cyber-Aggression Typology Questionnaire (CATQ) designed to distinguish between four distinct types of cyber-aggression on dimensions of motivational valence and self-control. A sample 314 undergraduate students participated in the study. The results confirmed the predicted four-factor structure providing evidence for distinct and independent impulsive-aversive, controlled-aversive, impulsive-appetitive, and controlled-appetitive cyber-aggression types. Further analyses with the Berlin Cyberbullying Questionnaire, Reactive Proactive Aggression Questionnaire, and the Behavior Inhibition and Activation Systems Scale provide support for convergent and divergent validity. Understanding the motivations facilitating cyber-aggressive behavior could aid researchers in the development of new prevention and intervention strategies that focus on individual differences in maladaptive proximal drivers of aggression. Aggr. Behav. 43:74-84, 2017. © 2016 Wiley Periodicals, Inc. © 2016 Wiley Periodicals, Inc.

E-cadherin: A determinant molecule associated with ovarian cancer progression, dissemination and aggressiveness

PubMed Central

Devis, Laura; Lapyckyj, Lara; Besso, María José; Llauradó, Marta; Abascal, María Florencia; Matos, María Laura; Lanau, Lucia; Castellví, Josep; Sánchez, José Luis; Pérez Benavente, Asunción; Gil-Moreno, Antonio; Reventós, Jaume; Santamaria Margalef, Anna; Rigau, Marina; Vazquez-Levin, Mónica Hebe

2017-01-01

Ovarian cancer (OC) is the fifth cancer death cause in women worldwide. The malignant nature of this disease stems from its unique dissemination pattern. Epithelial-to-mesenchymal transition (EMT) has been reported in OC and downregulation of Epithelial cadherin (E-cadherin) is a hallmark of this process. However, findings on the relationship between E-cadherin levels and OC progression, dissemination and aggressiveness are controversial. In this study, the evaluation of E-cadherin expression in an OC tissue microarray revealed its prognostic value to discriminate between advanced- and early-stage tumors, as well as serous tumors from other histologies. Moreover, E-cadherin, Neural cadherin (N-cadherin), cytokeratins and vimentin expression was assessed in TOV-112, SKOV-3, OAW-42 and OV-90 OC cell lines grown in monolayers and under anchorage-independent conditions to mimic ovarian tumor cell dissemination, and results were associated with cell aggressiveness. According to these EMT-related markers, cell lines were classified as mesenchymal (M; TOV-112), intermediate mesenchymal (IM; SKOV-3), intermediate epithelial (IE; OAW-42) and epithelial (E; OV-90). M- and IM-cells depicted the highest migration capacity when grown in monolayers, and aggregates derived from M- and IM-cell lines showed lower cell death, higher adhesion to extracellular matrices and higher invasion capacity than E- and IE-aggregates. The analysis of E-cadherin, N-cadherin, cytokeratin 19 and vimentin mRNA levels in 20 advanced-stage high-grade serous human OC ascites showed an IM phenotype in all cases, characterized by higher proportions of N- to E-cadherin and vimentin to cytokeratin 19. In particular, higher E-cadherin mRNA levels were associated with cancer antigen 125 levels more than 500 U/mL and platinum-free intervals less than 6 months. Altogether, E-cadherin expression levels were found relevant for the assessment of OC progression and aggressiveness. PMID:28934230

A CTD–Pfizer collaboration: manual curation of 88 000 scientific articles text mined for drug–disease and drug–phenotype interactions

PubMed Central

Davis, Allan Peter; Wiegers, Thomas C.; Roberts, Phoebe M.; King, Benjamin L.; Lay, Jean M.; Lennon-Hopkins, Kelley; Sciaky, Daniela; Johnson, Robin; Keating, Heather; Greene, Nigel; Hernandez, Robert; McConnell, Kevin J.; Enayetallah, Ahmed E.; Mattingly, Carolyn J.

2013-01-01

Improving the prediction of chemical toxicity is a goal common to both environmental health research and pharmaceutical drug development. To improve safety detection assays, it is critical to have a reference set of molecules with well-defined toxicity annotations for training and validation purposes. Here, we describe a collaboration between safety researchers at Pfizer and the research team at the Comparative Toxicogenomics Database (CTD) to text mine and manually review a collection of 88 629 articles relating over 1 200 pharmaceutical drugs to their potential involvement in cardiovascular, neurological, renal and hepatic toxicity. In 1 year, CTD biocurators curated 2 54 173 toxicogenomic interactions (1 52 173 chemical–disease, 58 572 chemical–gene, 5 345 gene–disease and 38 083 phenotype interactions). All chemical–gene–disease interactions are fully integrated with public CTD, and phenotype interactions can be downloaded. We describe Pfizer’s text-mining process to collate the articles, and CTD’s curation strategy, performance metrics, enhanced data content and new module to curate phenotype information. As well, we show how data integration can connect phenotypes to diseases. This curation can be leveraged for information about toxic endpoints important to drug safety and help develop testable hypotheses for drug–disease events. The availability of these detailed, contextualized, high-quality annotations curated from seven decades’ worth of the scientific literature should help facilitate new mechanistic screening assays for pharmaceutical compound survival. This unique partnership demonstrates the importance of resource sharing and collaboration between public and private entities and underscores the complementary needs of the environmental health science and pharmaceutical communities. Database URL: http://ctdbase.org/ PMID:24288140

Inherited determinants of Crohn's disease and ulcerative colitis phenotypes: a genetic association study.

PubMed

Cleynen, Isabelle; Boucher, Gabrielle; Jostins, Luke; Schumm, L Philip; Zeissig, Sebastian; Ahmad, Tariq; Andersen, Vibeke; Andrews, Jane M; Annese, Vito; Brand, Stephan; Brant, Steven R; Cho, Judy H; Daly, Mark J; Dubinsky, Marla; Duerr, Richard H; Ferguson, Lynnette R; Franke, Andre; Gearry, Richard B; Goyette, Philippe; Hakonarson, Hakon; Halfvarson, Jonas; Hov, Johannes R; Huang, Hailang; Kennedy, Nicholas A; Kupcinskas, Limas; Lawrance, Ian C; Lee, James C; Satsangi, Jack; Schreiber, Stephan; Théâtre, Emilie; van der Meulen-de Jong, Andrea E; Weersma, Rinse K; Wilson, David C; Parkes, Miles; Vermeire, Severine; Rioux, John D; Mansfield, John; Silverberg, Mark S; Radford-Smith, Graham; McGovern, Dermot P B; Barrett, Jeffrey C; Lees, Charlie W

2016-01-09

Crohn's disease and ulcerative colitis are the two major forms of inflammatory bowel disease; treatment strategies have historically been determined by this binary categorisation. Genetic studies have identified 163 susceptibility loci for inflammatory bowel disease, mostly shared between Crohn's disease and ulcerative colitis. We undertook the largest genotype association study, to date, in widely used clinical subphenotypes of inflammatory bowel disease with the goal of further understanding the biological relations between diseases. This study included patients from 49 centres in 16 countries in Europe, North America, and Australasia. We applied the Montreal classification system of inflammatory bowel disease subphenotypes to 34,819 patients (19,713 with Crohn's disease, 14,683 with ulcerative colitis) genotyped on the Immunochip array. We tested for genotype-phenotype associations across 156,154 genetic variants. We generated genetic risk scores by combining information from all known inflammatory bowel disease associations to summarise the total load of genetic risk for a particular phenotype. We used these risk scores to test the hypothesis that colonic Crohn's disease, ileal Crohn's disease, and ulcerative colitis are all genetically distinct from each other, and to attempt to identify patients with a mismatch between clinical diagnosis and genetic risk profile. After quality control, the primary analysis included 29,838 patients (16,902 with Crohn's disease, 12,597 with ulcerative colitis). Three loci (NOD2, MHC, and MST1 3p21) were associated with subphenotypes of inflammatory bowel disease, mainly disease location (essentially fixed over time; median follow-up of 10·5 years). Little or no genetic association with disease behaviour (which changed dramatically over time) remained after conditioning on disease location and age at onset. The genetic risk score representing all known risk alleles for inflammatory bowel disease showed strong association with

Cleft Palate, Retrognathia and Congenital Heart Disease in Velo-Cardio-Facial Syndrome: A Phenotype Correlation Study

PubMed Central

Friedman, Marcia A.; Miletta, Nathanial; Roe, Cheryl; Wang, Dongliang; Morrow, Bernice E.; Kates, Wendy R.; Higgins, Anne Marie; Shprintzen, Robert J.

2011-01-01

Objective Velo-cardio-facial syndrome (VCFS) is caused by a microdeletion of approximately 40 genes from one copy of chromosome 22. Expression of the syndrome is a variable combination of over 190 phenotypic characteristics. As of yet, little is known about how these phenotypes correlate with one another or whether there are predictable patterns of expression. Two of the most common phenotypic categories, congenital heart disease and cleft palate, have been proposed to have a common genetic relationship to the deleted T-box 1 gene (TBX1). The purpose of this study is to determine if congenital heart disease and cleft palate are correlated in a large cohort of human subjects with VCFS. Methods This study is a retrospective chart review including 316 Caucasian non-Hispanic subjects with FISH or CGH microarray confirmed chromosome 22q11.2 deletions. All subjects were evaluated by the interdisciplinary team at the Velo-Cardio-Facial Syndrome International Center at Upstate Medical University, Syracuse, NY. Each combination of congenital heart disease, cleft palates, and retrognathia was analyzed by chi square or Fisher exact test. Results For all categories of congenital heart disease and cleft palate or retrognathia no significant associations were found, with the exception of submucous cleft palate and retrognathia (nominal p=0.0325) and occult submucous cleft palate and retrognathia (nominal p=0.000013). Conclusions Congenital heart disease and cleft palate do not appear to be correlated in human subjects with VCFS despite earlier suggestions from animal models. Possible explanations include modification of the effect of TBX1 by genes outside of the 22q11.2 region that may further influence the formation of the palate or heart, or the presence of epigenetic factors that may effect genes within the deleted region, modifying genes elsewhere, or polymorphisms on the normal copy of chromosome 22. Lastly, it is possible that TBX1 plays a role in palate formation in some

Cleft palate, retrognathia and congenital heart disease in velo-cardio-facial syndrome: a phenotype correlation study.

PubMed

Friedman, Marcia A; Miletta, Nathanial; Roe, Cheryl; Wang, Dongliang; Morrow, Bernice E; Kates, Wendy R; Higgins, Anne Marie; Shprintzen, Robert J

2011-09-01

Velo-cardio-facial syndrome (VCFS) is caused by a microdeletion of approximately 40 genes from one copy of chromosome 22. Expression of the syndrome is a variable combination of over 190 phenotypic characteristics. As of yet, little is known about how these phenotypes correlate with one another or whether there are predictable patterns of expression. Two of the most common phenotypic categories, congenital heart disease and cleft palate, have been proposed to have a common genetic relationship to the deleted T-box 1 gene (TBX1). The purpose of this study is to determine if congenital heart disease and cleft palate are correlated in a large cohort of human subjects with VCFS. This study is a retrospective chart review including 316 Caucasian non-Hispanic subjects with FISH or CGH microarray confirmed chromosome 22q11.2 deletions. All subjects were evaluated by the interdisciplinary team at the Velo-Cardio-Facial Syndrome International Center at Upstate Medical University, Syracuse, NY. Each combination of congenital heart disease, cleft palates, and retrognathia was analyzed by Chi square or Fisher exact test. For all categories of congenital heart disease and cleft palate or retrognathia no significant associations were found, with the exception of submucous cleft palate and retrognathia (nominal p=0.0325) and occult submucous cleft palate and retrognathia (nominal p=0.000013). Congenital heart disease and cleft palate do not appear to be correlated in human subjects with VCFS despite earlier suggestions from animal models. Possible explanations include modification of the effect of TBX1 by genes outside of the 22q11.2 region that may further influence the formation of the palate or heart, or the presence of epigenetic factors that may effect genes within the deleted region, modifying genes elsewhere, or polymorphisms on the normal copy of chromosome 22. Lastly, it is possible that TBX1 plays a role in palate formation in some species, but not in humans. In VCFS

The Value of Phenotypes in Knee Osteoarthritis Research.

PubMed

Nelson, Fred R T

2018-01-01

Over the past decade, phenotypes have been used to help categorize knee osteoarthritis patients relative to being subject to disease, disease progression, and treatment response. A review of potential phenotype selection is now appropriate. The appeal of using phenotypes is that they most rely on simple physical examination, clinically routine imaging, and demographics. The purpose of this review is to describe the panoply of phenotypes that can be potentially used in osteoarthritis research. A search of PubMed was used singularly to review the literature on knee osteoarthritis phenotypes. Four phenotype assembly groups were based on physical features and noninvasive imaging. Demographics included metabolic syndrome (dyslipidemia, hypertension, obesity, and diabetes). Mechanical characteristics included joint morphology, alignment, the effect of injury, and past and present history. Associated musculoskeletal disorder characteristics included multiple joint involvement, spine disorders, neuromuscular diseases, and osteoporosis. With the knee as an organ, tissue characteristics were used to focus on synovium, meniscus, articular cartilage, patella fat pad, bone sclerosis, bone cysts, and location of pain. Many of these phenotype clusters require further validation studies. There is special emphasis on knee osteoarthritis phenotypes due to its predominance in osteoarthritic disorders and the variety of tissues in that joint. More research will be required to determine the most productive phenotypes for future studies. The selection and assignment of phenotypes will take on an increasing role in osteoarthritis research in the future.

Plasma BDNF levels are correlated with aggressiveness in patients with amnestic mild cognitive impairment or Alzheimer disease.

PubMed

Nagata, Tomoyuki; Kobayashi, Nobuyuki; Shinagawa, Shunichiro; Yamada, Hisashi; Kondo, Kazuhiro; Nakayama, Kazuhiko

2014-04-01

In the present study, we examined whether neuropsychiatric symptoms were correlated with plasma brain-derived neurotrophic factor (BDNF) levels as a state marker or were associated with the BDNF polymorphism Val66Met in patients with amnestic mild cognitive impairment (A-MCI) or Alzheimer disease (AD). One hundred and seventy-six outpatients with AD (n = 129) or A-MCI (n = 47) were selected and their plasma BDNF concentrations measured. Next, we investigated the correlation between the plasma BDNF level and the Behavioral Pathology in Alzheimer Disease (Behave-AD) subscale scores, which reflect neuropsychiatric symptoms. We also compared the plasma BDNF level and the Behave-AD subscale scores among the BDNF Val66Met genotypic groups. Among the seven Behave-AD subscale scores, aggressiveness was positively correlated with the plasma BDNF level (ρ = 0.237, P < 0.005), but did not differ significantly among the three BDNF Val66Met genotypic groups. The Behave-AD total and other subscale scores did not differ significantly among the BDNF Val66Met genotypic groups and were not associated with the plasma BDNF level. Moreover, the plasma BDNF level did not differ significantly among the three BDNF Val66Met genotypic groups or between patients with A-MCI and those with AD. The plasma BDNF level was robustly correlated with aggressiveness, implying that the plasma BDNF level might be useful as a behavioral state marker in patients with AD or A-MCI.

Structural and physiological neurovascular changes in idiopathic Parkinson's disease and its clinical phenotypes.

PubMed

Al-Bachari, Sarah; Vidyasagar, Rishma; Emsley, Hedley Ca; Parkes, Laura M

2017-10-01

Neurovascular changes are likely to interact importantly with the neurodegenerative process in idiopathic Parkinson's disease (IPD). Markers of neurovascular status (NVS) include white matter lesion (WML) burden and arterial spin labelling (ASL) measurements of cerebral blood flow (CBF) and arterial arrival time (AAT). We investigated NVS in IPD, including an analysis of IPD clinical phenotypes, by comparison with two control groups, one with a history of clinical cerebrovascular disease (CVD) (control positive, CP) and one without CVD (control negative, CN). Fifty-one patients with IPD (mean age 69.0 ± 7.7 years) (21 tremor dominant (TD), 24 postural instability and gait disorder (PIGD) and six intermediates), 18 CP (mean age 70.1 ± 8.0 years) and 34 CN subjects (mean age 67.4 ± 7.6 years) completed a 3T MRI scan protocol including T 2 -weighted fluid-attenuated inversion recovery (FLAIR) and ASL. IPD patients showed diffuse regions of significantly prolonged AAT, small regions of lower CBF and greater WML burden by comparison with CN subjects. TD patients showed lower WML volume by comparison with PIGD patients. These imaging data thus show altered NVS in IPD, with some evidence for IPD phenotype-specific differences.

Candidate SNP markers of aggressiveness-related complications and comorbidities of genetic diseases are predicted by a significant change in the affinity of TATA-binding protein for human gene promoters.

PubMed

Chadaeva, Irina V; Ponomarenko, Mikhail P; Rasskazov, Dmitry A; Sharypova, Ekaterina B; Kashina, Elena V; Matveeva, Marina Yu; Arshinova, Tatjana V; Ponomarenko, Petr M; Arkova, Olga V; Bondar, Natalia P; Savinkova, Ludmila K; Kolchanov, Nikolay A

2016-12-28

Aggressiveness in humans is a hereditary behavioral trait that mobilizes all systems of the body-first of all, the nervous and endocrine systems, and then the respiratory, vascular, muscular, and others-e.g., for the defense of oneself, children, family, shelter, territory, and other possessions as well as personal interests. The level of aggressiveness of a person determines many other characteristics of quality of life and lifespan, acting as a stress factor. Aggressive behavior depends on many parameters such as age, gender, diseases and treatment, diet, and environmental conditions. Among them, genetic factors are believed to be the main parameters that are well-studied at the factual level, but in actuality, genome-wide studies of aggressive behavior appeared relatively recently. One of the biggest projects of the modern science-1000 Genomes-involves identification of single nucleotide polymorphisms (SNPs), i.e., differences of individual genomes from the reference genome. SNPs can be associated with hereditary diseases, their complications, comorbidities, and responses to stress or a drug. Clinical comparisons between cohorts of patients and healthy volunteers (as a control) allow for identifying SNPs whose allele frequencies significantly separate them from one another as markers of the above conditions. Computer-based preliminary analysis of millions of SNPs detected by the 1000 Genomes project can accelerate clinical search for SNP markers due to preliminary whole-genome search for the most meaningful candidate SNP markers and discarding of neutral and poorly substantiated SNPs. Here, we combine two computer-based search methods for SNPs (that alter gene expression) {i} Web service SNP_TATA_Comparator (DNA sequence analysis) and {ii} PubMed-based manual search for articles on aggressiveness using heuristic keywords. Near the known binding sites for TATA-binding protein (TBP) in human gene promoters, we found aggressiveness-related candidate SNP markers

Children's aggressive responses to neutral peer behavior: a form of unprovoked reactive aggression.

PubMed

Kempes, Maaike; Matthys, Walter; de Vries, Han; van Engeland, Herman

2010-04-30

Previous studies that operationalized reactive aggression using behavioral observations in general populations have not taken into account the type of stimulus that elicits reactive aggression. In the present study we define a specific form of reactive aggression, i.e., reactive aggression in response to neutral behavior of a peer, which we will call unprovoked reactive aggression. We were specifically interested in children with severe aggressive behavior problems, since they may respond with reactive aggression even though the opponent did not clearly provoke them, but instead showed neutral behavior. Children with a disruptive behavior disorder (DBD) and normal control (NC) children participated in separate play sessions in which they played with a normal peer (NP). Children with DBD showed more unprovoked reactive aggression than NC children, during a cooperative game. Moreover, for children with DBD, unprovoked reactive aggressive behavior in this game correlated with parent-rated reactive aggression. Results of this study suggest that an unprovoked reactive form of aggression can be identified in children with DBD. Copyright (c) 2008. Published by Elsevier Ireland Ltd.

JUNCTOPHILIN 3 (JPH3) EXPANSION MUTATIONS CAUSING HUNTINGTON DISEASE LIKE 2 (HDL2) ARE COMMON IN SOUTH AFRICAN PATIENTS WITH AFRICAN ANCESTRY AND A HUNTINGTON DISEASE PHENOTYPE

PubMed Central

Krause, A; Mitchell, CL; Essop, F; Tager, S; Temlett, J; Stevanin, G; Ross, CA; Rudnicki, DD; Margolis, RL

2015-01-01

Huntington disease (HD) is a progressive autosomal dominant neurodegenerative disorder, characterized by abnormal movements, cognitive decline and psychiatric symptoms, caused by a CAG repeat expansion in the huntingtin (HTT) gene on chromosome 4p. A CAG/CTG repeat expansion in the junctophilin-3 (JPH3) gene on chromosome 16q24.2 causes a Huntington disease-like phenotype (HDL2). All patients to date with HDL2 have some African ancestry. The present study aimed to characterize the genetic basis of the Huntington disease phenotype in South Africans and to investigate the possible origin of the JPH3 mutation. In a sample of unrelated South African individuals referred for diagnostic HD testing, 62% (106/171) of white patients compared to only 36% (47/130) of black patients had an expansion in HTT. However, 15% (20/130) of black South African patients and no white patients (0/171) had an expansion in JPH3, confirming the diagnosis of Huntington disease like 2 (HDL2). Individuals with HDL2 share many clinical features with individuals with HD and are clinically indistinguishable in many cases, although the average age of onset and diagnosis in HDL2 is 5 years later than HD and individual clinical features may be more prominent. HDL2 mutations contribute significantly to the HD phenotype in South Africans with African ancestry. JPH3 haplotype studies in 31 families, mainly from South Africa and North America, provide evidence for a founder mutation and support a common African origin for all HDL2 patients. Molecular testing in individuals with an HD phenotype and African ancestry should include testing routinely for JPH3 mutations. PMID:26079385

Relational Aggression and Physical Aggression among Adolescent Cook Islands Students

ERIC Educational Resources Information Center

Page, Angela; Smith, Lisa F.

2016-01-01

Both physical and relational aggression are characterised by the intent to harm another. Physical aggression includes direct behaviours such as hitting or kicking; relational aggression involves behaviours designed to damage relationships, such as excluding others, spreading rumours, and delivering threats and verbal abuse. This study extended…

Incidence, disease phenotype at diagnosis, and early disease course in inflammatory bowel diseases in Western Hungary, 2002-2006.

PubMed

Lakatos, Laszlo; Kiss, Lajos S; David, Gyula; Pandur, Tunde; Erdelyi, Zsuzsanna; Mester, Gabor; Balogh, Mihaly; Szipocs, Istvan; Molnar, Csaba; Komaromi, Erzsebet; Lakatos, Peter Laszlo

2011-12-01

Recent trends indicate a change in the epidemiology of inflammatory bowel diseases (IBD), with previously low incidence areas now reporting a progressive rise in the incidence. Our aim was to analyze the incidence and disease phenotype at diagnosis in IBD in the population-based Veszprem Province database, which included incident patients diagnosed between January 1, 2002 and December 31, 2006. Data of 393 incident patients were analyzed (ulcerative colitis [UC]: 220, age-at-diagnosis: 40.5 years; Crohn's disease [CD]: 163, age-at-diagnosis: 32.5 years; and indeterminate colitis [IC]: 10). Both hospital and outpatient records were collected and comprehensively reviewed. Adjusted mean incidence rates were 8.9/10(5) person-years for CD and 11.9/10(5) person-years in UC. Peak onset age in both CD and UC patients was 21-30 years old. Location at diagnosis in UC was proctitis in 26.8%, left-sided colitis in 50.9%, and pancolitis in 22.3%. The probability of proximal extension and colectomy after 5 years was 12.7% and 2.8%. The disease location in CD was ileal in 20.2%, colonic in 35.6%, ileocolonic in 44.2%, and upper gastrointestinal in four patients. Behavior at diagnosis was stenosing/penetrating in 35.6% and perianal in 11.1%. Patients with colonic disease were older at diagnosis compared to patients with ileal or ileocolonic disease. In a Kaplan-Meier analysis, probability of surgical resection was 9.8%, 18.5%, and 21.3% after 1, 3, and 5 years of disease duration, respectively. The incidence of IBD in Veszprem Province in the last decade was high, equal to that in high-incidence areas in Western European countries. Early disease course is milder compared to data reported in the literature. Copyright © 2011 Crohn's & Colitis Foundation of America, Inc.

Pulmonary phenotypes associated with genetic variation in telomere-related genes.

PubMed

Hoffman, Thijs W; van Moorsel, Coline H M; Borie, Raphael; Crestani, Bruno

2018-05-01

Genomic mutations in telomere-related genes have been recognized as a cause of familial forms of idiopathic pulmonary fibrosis (IPF). However, it has become increasingly clear that telomere syndromes and telomere shortening are associated with various types of pulmonary disease. Additionally, it was found that also single nucleotide polymorphisms (SNPs) in telomere-related genes are risk factors for the development of pulmonary disease. This review focuses on recent updates on pulmonary phenotypes associated with genetic variation in telomere-related genes. Genomic mutations in seven telomere-related genes cause pulmonary disease. Pulmonary phenotypes associated with these mutations range from many forms of pulmonary fibrosis to emphysema and pulmonary vascular disease. Telomere-related mutations account for up to 10% of sporadic IPF, 25% of familial IPF, 10% of connective-tissue disease-associated interstitial lung disease, and 1% of COPD. Mixed disease forms have also been found. Furthermore, SNPs in TERT, TERC, OBFC1, and RTEL1, as well as short telomere length, have been associated with several pulmonary diseases. Treatment of pulmonary disease caused by telomere-related gene variation is currently based on disease diagnosis and not on the underlying cause. Pulmonary phenotypes found in carriers of telomere-related gene mutations and SNPs are primarily pulmonary fibrosis, sometimes emphysema and rarely pulmonary vascular disease. Genotype-phenotype relations are weak, suggesting that environmental factors and genetic background of patients determine disease phenotypes to a large degree. A disease model is presented wherever genomic variation in telomere-related genes cause specific pulmonary disease phenotypes whenever triggered by environmental exposure, comorbidity, or unknown factors.

Longitudinal Relations between Beliefs Supporting Aggression,Anger Regulation, and Dating Aggression among Early Adolescents.

PubMed

Sullivan, Terri N; Garthe, Rachel C; Goncy, Elizabeth A; Carlson, Megan M; Behrhorst, Kathryn L

2017-05-01

Dating aggression occurs frequently in early to mid-adolescence and has negative repercussions for psychosocial adjustment and physical health. The patterns of behavior learned during this developmental timeframe may persist in future dating relationships, underscoring the need to identify risk factors for this outcome. The current study examined longitudinal relations between beliefs supporting aggression, anger regulation, and dating aggression. Participants were 176 middle school students in sixth, seventh, and eighth grade (50 % female; 82 % African American). No direct effects were found between beliefs supporting reactive or proactive aggression and dating aggression. Beliefs supporting reactive aggression predicted increased rates of anger dysregulation, and beliefs supporting proactive aggression led to subsequent increases in anger inhibition. Anger dysregulation and inhibition were associated with higher frequencies of dating aggression. An indirect effect was found for the relation between beliefs supporting reactive aggression and dating aggression via anger dysregulation. Another indirect effect emerged for the relation between beliefs supporting proactive aggression and dating aggression through anger inhibition. The study's findings suggested that beliefs supporting proactive and reactive aggression were differentially related to emotion regulation processes, and identified anger dysregulation and inhibition as risk factors for dating aggression among adolescents.

Parents' Aggressive Influences and Children's Aggressive Problem Solutions with Peers

ERIC Educational Resources Information Center

Duman, Sarah; Margolin, Gayla

2007-01-01

This study examined children's aggressive and assertive solutions to hypothetical peer scenarios in relation to parents' responses to similar hypothetical social scenarios and parents' actual marital aggression. The study included 118 children ages 9 to 10 years old and their mothers and fathers. Children's aggressive solutions correlated with…

Clinical Phenotype Predicts Early Staged Bilateral Deep Brain Stimulation in Parkinson’s Disease

PubMed Central

Sung, Victor W.; Watts, Ray L.; Schrandt, Christian J.; Guthrie, Stephanie; Wang, Deli; Amara, Amy W.; Guthrie, Barton L.; Walker, Harrison C.

2014-01-01

Object While many centers place bilateral DBS systems simultaneously, unilateral STN DBS followed by a staged contralateral procedure has emerged as a treatment option for many patients. However little is known about whether the preoperative phenotype predicts when staged placement of a DBS electrode in the opposite subthalamic nucleus will be required. We aimed to determine whether preoperative clinical phenotype predicts early staged placement of a second subthalamic deep brain stimulation (DBS) electrode in patients who undergo unilateral subthalamic DBS for Parkinson's disease (PD). Methods Eighty-two consecutive patients with advanced PD underwent unilateral subthalamic DBS contralateral to the most affected hemibody and had at least 2 years of follow-up. Multivariate logistic regression determined preoperative characteristics that predicted staged placement of a second electrode in the opposite subthalamic nucleus. Preoperative measurements included aspects of the Unified Parkinson Disease Rating Scale (UPDRS), motor asymmetry index, and body weight. Results At 2 years follow-up, 28 of the 82 patients (34%) had undergone staged placement of a contralateral electrode while the remainder chose to continue with unilateral stimulation. Statistically significant improvements in UPDRS total and part 3 scores were retained at the end of the 2 year follow-up period in both subsets of patients. Multivariate logistic regression showed that the most important predictors for early staged placement of a second subthalamic stimulator were low asymmetry index (odds ratio 13.4; 95% confidence interval 2.8, 64.9), high tremor subscore (OR 7.2; CI 1.5, 35.0), and low body weight (OR 5.5; CI 1.4, 22.3). Conclusions This single center study provides evidence that elements of the preoperative PD phenotype predict whether patients will require early staged bilateral subthalamic DBS. These data may aid in the management of patients with advanced PD who undergo subthalamic DBS. PMID

Violent aggression predicted by multiple pre-adult environmental hits.

PubMed

Mitjans, Marina; Seidel, Jan; Begemann, Martin; Bockhop, Fabian; Moya-Higueras, Jorge; Bansal, Vikas; Wesolowski, Janina; Seelbach, Anna; Ibáñez, Manuel Ignacio; Kovacevic, Fatka; Duvar, Oguzhan; Fañanás, Lourdes; Wolf, Hannah-Ulrike; Ortet, Generós; Zwanzger, Peter; Klein, Verena; Lange, Ina; Tänzer, Andreas; Dudeck, Manuela; Penke, Lars; van Elst, Ludger Tebartz; Bittner, Robert A; Schmidmeier, Richard; Freese, Roland; Müller-Isberner, Rüdiger; Wiltfang, Jens; Bliesener, Thomas; Bonn, Stefan; Poustka, Luise; Müller, Jürgen L; Arias, Bárbara; Ehrenreich, Hannelore

2018-05-24

Early exposure to negative environmental impact shapes individual behavior and potentially contributes to any mental disease. We reported previously that accumulated environmental risk markedly decreases age at schizophrenia onset. Follow-up of matched extreme group individuals (≤1 vs. ≥3 risks) unexpectedly revealed that high-risk subjects had >5 times greater probability of forensic hospitalization. In line with longstanding sociological theories, we hypothesized that risk accumulation before adulthood induces violent aggression and criminal conduct, independent of mental illness. We determined in 6 independent cohorts (4 schizophrenia and 2 general population samples) pre-adult risk exposure, comprising urbanicity, migration, physical and sexual abuse as primary, and cannabis or alcohol as secondary hits. All single hits by themselves were marginally associated with higher violent aggression. Most strikingly, however, their accumulation strongly predicted violent aggression (odds ratio 10.5). An epigenome-wide association scan to detect differential methylation of blood-derived DNA of selected extreme group individuals yielded overall negative results. Conversely, determination in peripheral blood mononuclear cells of histone-deacetylase1 mRNA as 'umbrella mediator' of epigenetic processes revealed an increase in the high-risk group, suggesting lasting epigenetic alterations. Together, we provide sound evidence of a disease-independent unfortunate relationship between well-defined pre-adult environmental hits and violent aggression, calling for more efficient prevention.

Development and validation of an electronic phenotyping algorithm for chronic kidney disease

PubMed Central

Nadkarni, Girish N; Gottesman, Omri; Linneman, James G; Chase, Herbert; Berg, Richard L; Farouk, Samira; Nadukuru, Rajiv; Lotay, Vaneet; Ellis, Steve; Hripcsak, George; Peissig, Peggy; Weng, Chunhua; Bottinger, Erwin P

2014-01-01

Twenty-six million Americans are estimated to have chronic kidney disease (CKD) with increased risk for cardiovascular disease and end stage renal disease. CKD is frequently undiagnosed and patients are unaware, hampering intervention. A tool for accurate and timely identification of CKD from electronic medical records (EMR) could improve healthcare quality and identify patients for research. As members of eMERGE (electronic medical records and genomics) Network, we developed an automated phenotyping algorithm that can be deployed to identify rapidly diabetic and/or hypertensive CKD cases and controls in health systems with EMRs It uses diagnostic codes, laboratory results, medication and blood pressure records, and textual information culled from notes. Validation statistics demonstrated positive predictive values of 96% and negative predictive values of 93.3. Similar results were obtained on implementation by two independent eMERGE member institutions. The algorithm dramatically outperformed identification by ICD-9-CM codes with 63% positive and 54% negative predictive values, respectively. PMID:25954398

Monogenic Autoinflammatory Diseases with Mendelian Inheritance: Genes, Mutations, and Genotype/Phenotype Correlations

PubMed Central

Martorana, Davide; Bonatti, Francesco; Mozzoni, Paola; Vaglio, Augusto; Percesepe, Antonio

2017-01-01

Autoinflammatory diseases (AIDs) are a genetically heterogeneous group of diseases caused by mutations of genes encoding proteins, which play a pivotal role in the regulation of the inflammatory response. In the pathogenesis of AIDs, the role of the genetic background is triggered by environmental factors through the modulation of the innate immune system. Monogenic AIDs are characterized by Mendelian inheritance and are caused by highly penetrant genetic variants in single genes. During the last years, remarkable progress has been made in the identification of disease-associated genes by using new technologies, such as next-generation sequencing, which has allowed the genetic characterization in undiagnosed patients and in sporadic cases by means of targeted resequencing of a gene panel and whole exome sequencing. In this review, we delineate the genetics of the monogenic AIDs, report the role of the most common gene mutations, and describe the evidences of the most sound genotype/phenotype correlations in AID. PMID:28421071

RNAi phenotype profiling of kinases identifies potential therapeutic targets in Ewing's sarcoma.

PubMed

Arora, Shilpi; Gonzales, Irma M; Hagelstrom, R Tanner; Beaudry, Christian; Choudhary, Ashish; Sima, Chao; Tibes, Raoul; Mousses, Spyro; Azorsa, David O

2010-08-18

Ewing's sarcomas are aggressive musculoskeletal tumors occurring most frequently in the long and flat bones as a solitary lesion mostly during the teen-age years of life. With current treatments, significant number of patients relapse and survival is poor for those with metastatic disease. As part of novel target discovery in Ewing's sarcoma, we applied RNAi mediated phenotypic profiling to identify kinase targets involved in growth and survival of Ewing's sarcoma cells. Four Ewing's sarcoma cell lines TC-32, TC-71, SK-ES-1 and RD-ES were tested in high throughput-RNAi screens using a siRNA library targeting 572 kinases. Knockdown of 25 siRNAs reduced the growth of all four Ewing's sarcoma cell lines in replicate screens. Of these, 16 siRNA were specific and reduced proliferation of Ewing's sarcoma cells as compared to normal fibroblasts. Secondary validation and preliminary mechanistic studies highlighted the kinases STK10 and TNK2 as having important roles in growth and survival of Ewing's sarcoma cells. Furthermore, knockdown of STK10 and TNK2 by siRNA showed increased apoptosis. In summary, RNAi-based phenotypic profiling proved to be a powerful gene target discovery strategy, leading to successful identification and validation of STK10 and TNK2 as two novel potential therapeutic targets for Ewing's sarcoma.

The Influence of Classroom Aggression and Classroom Climate on Aggressive-Disruptive Behavior

PubMed Central

Thomas, Duane E.; Bierman, Karen L.; Powers, CJ

2011-01-01

Research suggests that early classroom experiences influence the socialization of aggression. Tracking changes in the aggressive behavior of 4179 children from kindergarten to second-grade (ages 5–8) this study examined the impact of two important features of the classroom context–aggregate peer aggression and climates characterized by supportive teacher-student interactions. The aggregate aggression scores of children assigned to first-grade classrooms predicted the level of classroom aggression (assessed by teacher ratings) and quality of classroom climate (assessed by observers) that emerged by the end of grade 1. HLM analyses revealed that first-grade classroom aggression and quality of classroom climate made independent contributions to changes in student aggression, as students moved from kindergarten to second grade. Implications for policy and practice are discussed. PMID:21434887

Targeted next-generation sequencing reveals novel USH2A mutations associated with diverse disease phenotypes: implications for clinical and molecular diagnosis.

PubMed

Chen, Xue; Sheng, Xunlun; Liu, Xiaoxing; Li, Huiping; Liu, Yani; Rong, Weining; Ha, Shaoping; Liu, Wenzhou; Kang, Xiaoli; Zhao, Kanxing; Zhao, Chen

2014-01-01

USH2A mutations have been implicated in the disease etiology of several inherited diseases, including Usher syndrome type 2 (USH2), nonsyndromic retinitis pigmentosa (RP), and nonsyndromic deafness. The complex genetic and phenotypic spectrums relevant to USH2A defects make it difficult to manage patients with such mutations. In the present study, we aim to determine the genetic etiology and to characterize the correlated clinical phenotypes for three Chinese pedigrees with nonsyndromic RP, one with RP sine pigmento (RPSP), and one with USH2. Family histories and clinical details for all included patients were reviewed. Ophthalmic examinations included best corrected visual acuities, visual field measurements, funduscopy, and electroretinography. Targeted next-generation sequencing (NGS) was applied using two sequence capture arrays to reveal the disease causative mutations for each family. Genotype-phenotype correlations were also annotated. Seven USH2A mutations, including four missense substitutions (p.P2762A, p.G3320C, p.R3719H, and p.G4763R), two splice site variants (c.8223+1G>A and c.8559-2T>C), and a nonsense mutation (p.Y3745*), were identified as disease causative in the five investigated families, of which three reported to have consanguineous marriage. Among all seven mutations, six were novel, and one was recurrent. Two homozygous missense mutations (p.P2762A and p.G3320C) were found in one individual family suggesting a potential double hit effect. Significant phenotypic divergences were revealed among the five families. Three families of the five families were affected with early, moderated, or late onset RP, one with RPSP, and the other one with USH2. Our study expands the genotypic and phenotypic variability relevant to USH2A mutations, which would help with a clear insight into the complex genetic and phenotypic spectrums relevant to USH2A defects, and is complementary for a better management of patients with such mutations. We have also

Targeted Next-Generation Sequencing Reveals Novel USH2A Mutations Associated with Diverse Disease Phenotypes: Implications for Clinical and Molecular Diagnosis

PubMed Central

Li, Huiping; Liu, Yani; Rong, Weining; Ha, Shaoping; Liu, Wenzhou; Kang, Xiaoli; Zhao, Kanxing; Zhao, Chen

2014-01-01

USH2A mutations have been implicated in the disease etiology of several inherited diseases, including Usher syndrome type 2 (USH2), nonsyndromic retinitis pigmentosa (RP), and nonsyndromic deafness. The complex genetic and phenotypic spectrums relevant to USH2A defects make it difficult to manage patients with such mutations. In the present study, we aim to determine the genetic etiology and to characterize the correlated clinical phenotypes for three Chinese pedigrees with nonsyndromic RP, one with RP sine pigmento (RPSP), and one with USH2. Family histories and clinical details for all included patients were reviewed. Ophthalmic examinations included best corrected visual acuities, visual field measurements, funduscopy, and electroretinography. Targeted next-generation sequencing (NGS) was applied using two sequence capture arrays to reveal the disease causative mutations for each family. Genotype-phenotype correlations were also annotated. Seven USH2A mutations, including four missense substitutions (p.P2762A, p.G3320C, p.R3719H, and p.G4763R), two splice site variants (c.8223+1G>A and c.8559-2T>C), and a nonsense mutation (p.Y3745*), were identified as disease causative in the five investigated families, of which three reported to have consanguineous marriage. Among all seven mutations, six were novel, and one was recurrent. Two homozygous missense mutations (p.P2762A and p.G3320C) were found in one individual family suggesting a potential double hit effect. Significant phenotypic divergences were revealed among the five families. Three families of the five families were affected with early, moderated, or late onset RP, one with RPSP, and the other one with USH2. Our study expands the genotypic and phenotypic variability relevant to USH2A mutations, which would help with a clear insight into the complex genetic and phenotypic spectrums relevant to USH2A defects, and is complementary for a better management of patients with such mutations. We have also

Clinical correlates of verbal aggression, physical aggression and inappropriate sexual behaviour after brain injury.

PubMed

James, Andrew I W; Young, Andrew W

2013-01-01

To explore the relationships between verbal aggression, physical aggression and inappropriate sexual behaviour following acquired brain injury. Multivariate statistical modelling of observed verbal aggression, physical aggression and inappropriate sexual behaviour utilizing demographic, pre-morbid, injury-related and neurocognitive predictors. Clinical records of 152 participants with acquired brain injury were reviewed, providing an important data set as disordered behaviours had been recorded at the time of occurrence with the Brain Injury Rehabilitation Trust (BIRT) Aggression Rating Scale and complementary measures of inappropriate sexual behaviour. Three behavioural components (verbal aggression, physical aggression and inappropriate sexual behaviour) were identified and subjected to separate logistical regression modelling in a sub-set of 77 participants. Successful modelling was achieved for both verbal and physical aggression (correctly classifying 74% and 65% of participants, respectively), with use of psychotropic medication and poorer verbal function increasing the odds of aggression occurring. Pre-morbid history of aggression predicted verbal but not physical aggression. No variables predicted inappropriate sexual behaviour. Verbal aggression, physical aggression and inappropriate sexual behaviour following acquired brain injury appear to reflect separate clinical phenomena rather than general behavioural dysregulation. Clinical markers that indicate an increased risk of post-injury aggression were not related to inappropriate sexual behaviour.

Kindergarten Children's Genetic Vulnerabilities Interact with Friends' Aggression to Promote Children's Own Aggression

ERIC Educational Resources Information Center

van Lier, Pol; Boivin, Michel; Dionne, Ginette; Vitaro, Frank; Brendgen, Mara; Koot, Hans; Tremblay, Richard E.; Perusse, Daniel

2007-01-01

Objective: To examine whether kindergarten children's genetic liability to physically aggress moderates the contribution of friends' aggression to their aggressive behaviors. Method: Teacher and peer reports of aggression were available for 359 6-year-old twin pairs (145 MZ, 212 DZ) as well as teacher and peer reports of aggression of the two best…

Immune phenotype in children with therapy-naïve remitted and relapsed Crohn’s disease

PubMed Central

Cseh, Aron; Vasarhelyi, Barna; Molnar, Kriszta; Szalay, Balazs; Svec, Peter; Treszl, Andras; Dezsofi, Antal; Lakatos, Peter Laszlo; Arato, Andras; Tulassay, Tivadar; Veres, Gabor

2010-01-01

AIM: To characterize the prevalence of subpopulations of CD4+ cells along with that of major inhibitor or stimulator cell types in therapy-naïve childhood Crohn’s disease (CD) and to test whether abnormalities of immune phenotype are normalized with the improvement of clinical signs and symptoms of disease. METHODS: We enrolled 26 pediatric patients with CD. 14 therapy-naïve CD children; of those, 10 children remitted on conventional therapy and formed the remission group. We also tested another group of 12 children who relapsed with conventional therapy and were given infliximab; and 15 healthy children who served as controls. The prevalence of Th1 and Th2, naïve and memory, activated and regulatory T cells, along with the members of innate immunity such as natural killer (NK), NK-T, myeloid and plasmocytoid dendritic cells (DCs), monocytes and Toll-like receptor (TLR)-2 and TLR-4 expression were determined in peripheral blood samples. RESULTS: Children with therapy-naïve CD and those in relapse showed a decrease in Th1 cell prevalence. Simultaneously, an increased prevalence of memory and activated lymphocytes along with that of DCs and monocytes was observed. In addition, the ratio of myeloid /plasmocytoid DCs and the prevalence of TLR-2 or TLR-4 positive DCs and monocytes were also higher in therapy-naïve CD than in controls. The majority of alterations diminished in remitted CD irrespective of whether remission was obtained by conventional or biological therapy. CONCLUSION: The finding that immune phenotype is normalized in remission suggests a link between immune phenotype and disease activity in childhood CD. Our observations support the involvement of members of the adaptive and innate immune systems in childhood CD. PMID:21157977

Characterizing Aggressive Behavior with the Impulsive/Premeditated Aggression Scale among Adolescents with Conduct Disorder

PubMed Central

Mathias, Charles W.; Stanford, Matthew S.; Marsh, Dawn M.; Frick, Paul J.; Moeller, F. Gerard; Swann, Alan C.; Dougherty, Donald M.

2007-01-01

This study extends the use of the Impulsive/Premeditated Aggression Scale for subtyping aggressive behavior among adolescents with Conduct Disorder. Of the Conduct Disorder symptoms, aggression has the strongest prognostic and treatment implications. While aggression is a complex construct, convergent evidence supports a dichotomy of impulsive and premeditated aggressive subtypes that are qualitatively different from one another in terms of phenomenology and neurobiology. Previous attempts at measuring subtypes of aggression in children and adults are not clearly generalizable to adolescents. Sixty-six adolescents completed a questionnaire for characterizing aggression (Impulsive/Premeditated Aggression Scale), along with standard measures of personality and general functioning. Principal components analysis demonstrated two stable factors of aggression with good internal consistency and construct validity. Compared to the premeditated aggression factor, the impulsive aggression factor was associated with a broader range of personality, thought, emotional, and social problems. As in the adult and child literature, characterization of aggressive behavior into two subtypes appears to be relevant to understanding individual differences among adolescents with Conduct Disorder. PMID:17383014

Alcohol Expectancies and Evaluations of Aggression in Alcohol-Related Intimate-Partner Verbal and Physical Aggression

PubMed Central

Kachadourian, Lorig K; Quigley, Brian M; Leonard, Kenneth E

2014-01-01

Objective: Alcohol aggression expectancies have been found to be associated with increases in aggressive behavior. However, research has not consistently examined evaluations of such behavior. This is unfortunate as both expectancies and evaluations may play a role in whether such behavior will occur. Given this, the current study cross-sectionally examined the associations between alcohol aggression expectancies, evaluations of alcohol-related aggression, indicators of excessive drinking, and alcohol-related verbal and physical aggression. Method: The sample consisted of 280 married and cohabiting couples. These couples reported on excessive drinking indicators, alcohol expectancies and evaluations, and alcohol-related verbal and physical aggression during the past year. Results: Findings showed that verbal aggression was positively associated with indicators of excessive drinking among females and with alcohol aggression expectancies for females who evaluated such aggression positively. For males, aggression expectancies and indicators of excessive drinking were positively associated with verbal aggression. For physical aggression, results showed that indicators of excessive drinking and aggression expectancies were associated with physical aggression for females. For males, aggression expectancies were positively associated and evaluations were negatively associated with physical aggression. Conclusions: These findings add to previous research on alcohol aggression expectancies in close relationships and emphasize the importance of considering evaluations of alcohol-related behavior and how they may play a role in intimate-partner violence and aggression. PMID:25208191

Renal cell carcinoma, unclassified with medullary phenotype: poorly differentiated adenocarcinomas overlapping with renal medullary carcinoma.

PubMed

Sirohi, Deepika; Smith, Steven C; Ohe, Chisato; Colombo, Piergiuseppe; Divatia, Mukul; Dragoescu, Ema; Rao, Priya; Hirsch, Michelle S; Chen, Ying-Bei; Mehra, Rohit; Amin, Mahul B

2017-09-01

Renal medullary carcinoma (RMC) is a highly aggressive renal cell carcinoma arising in the collecting system and requiring careful correlation with status of sickle cell trait. A panel of international experts has recently proposed provisional diagnostic terminology, renal cell carcinoma, unclassified, with medullary phenotype, based on encountering an extraordinarily rare tumor with RMC morphology and immunophenotype in an individual proven not to have a hemoglobinopathy. Herein, we extend this observation to a cohort of 5 such tumors, morphologically similar to RMC, lacking SMARCB1 expression by immunohistochemistry, but each without evidence of a hemoglobinopathy. The tumors arose in 4 men and 1 woman with a mean age of 44 years, occurring in 3 left and 2 right kidneys. Clinically, aggression was apparent with involvement of perinephric adipose tissue in all 5 cases, nodal metastasis in 4 of 5 cases, and death of disease in 4 of 5 cases within 3-27 months. Histologic sections showed poorly differentiated adenocarcinoma, often with solid and nested growth patterns, as well as infiltrative glandular, tubulopapillary, cribriform, or reticular growth. Rhabdoid and sarcomatoid cytomorphology was seen in a subset. All tumors showed PAX8 nuclear positivity and SMARCB1 loss, with OCT3/4 expression in 4 of 5 cases. In summary, this first series of renal cell carcinoma, unclassified, with medullary phenotype documents tumors with morphologic, immunophenotypic, and prognostic features of RMC occurring in individuals without sickle cell trait. Although greater biologic and molecular understanding is needed, the available evidence points to these cases representing a sporadic counterpart to sickle cell trait-associated RMC. Copyright © 2017 Elsevier Inc. All rights reserved.

Genome-wide association analysis of secondary imaging phenotypes from the Alzheimer's disease neuroimaging initiative study.

PubMed

Zhu, Wensheng; Yuan, Ying; Zhang, Jingwen; Zhou, Fan; Knickmeyer, Rebecca C; Zhu, Hongtu

2017-02-01

The aim of this paper is to systematically evaluate a biased sampling issue associated with genome-wide association analysis (GWAS) of imaging phenotypes for most imaging genetic studies, including the Alzheimer's Disease Neuroimaging Initiative (ADNI). Specifically, the original sampling scheme of these imaging genetic studies is primarily the retrospective case-control design, whereas most existing statistical analyses of these studies ignore such sampling scheme by directly correlating imaging phenotypes (called the secondary traits) with genotype. Although it has been well documented in genetic epidemiology that ignoring the case-control sampling scheme can produce highly biased estimates, and subsequently lead to misleading results and suspicious associations, such findings are not well documented in imaging genetics. We use extensive simulations and a large-scale imaging genetic data analysis of the Alzheimer's Disease Neuroimaging Initiative (ADNI) data to evaluate the effects of the case-control sampling scheme on GWAS results based on some standard statistical methods, such as linear regression methods, while comparing it with several advanced statistical methods that appropriately adjust for the case-control sampling scheme. Copyright © 2016 Elsevier Inc. All rights reserved.

Chronic Obstructive Pulmonary Disease Exacerbations in the COPDGene Study: Associated Radiologic Phenotypes

PubMed Central

Kazerooni, Ella A.; Lynch, David A.; Liu, Lyrica X.; Murray, Susan; Curtis, Jeffrey L.; Criner, Gerard J.; Kim, Victor; Bowler, Russell P.; Hanania, Nicola A.; Anzueto, Antonio R.; Make, Barry J.; Hokanson, John E.; Crapo, James D.; Silverman, Edwin K.; Martinez, Fernando J.; Washko, George R.

2011-01-01

Purpose: To test the hypothesis—given the increasing emphasis on quantitative computed tomographic (CT) phenotypes of chronic obstructive pulmonary disease (COPD)—that a relationship exists between COPD exacerbation frequency and quantitative CT measures of emphysema and airway disease. Materials and Methods: This research protocol was approved by the institutional review board of each participating institution, and all participants provided written informed consent. One thousand two subjects who were enrolled in the COPDGene Study and met the GOLD (Global Initiative for Chronic Obstructive Lung Disease) criteria for COPD with quantitative CT analysis were included. Total lung emphysema percentage was measured by using the attenuation mask technique with a −950-HU threshold. An automated program measured the mean wall thickness and mean wall area percentage in six segmental bronchi. The frequency of COPD exacerbation in the prior year was determined by using a questionnaire. Statistical analysis was performed to examine the relationship of exacerbation frequency with lung function and quantitative CT measurements. Results: In a multivariate analysis adjusted for lung function, bronchial wall thickness and total lung emphysema percentage were associated with COPD exacerbation frequency. Each 1-mm increase in bronchial wall thickness was associated with a 1.84-fold increase in annual exacerbation rate (P = .004). For patients with 35% or greater total emphysema, each 5% increase in emphysema was associated with a 1.18-fold increase in this rate (P = .047). Conclusion: Greater lung emphysema and airway wall thickness were associated with COPD exacerbations, independent of the severity of airflow obstruction. Quantitative CT can help identify subgroups of patients with COPD who experience exacerbations for targeted research and therapy development for individual phenotypes. © RSNA, 2011 Supplemental material: http://radiology.rsna.org/lookup/suppl/doi:10

Serotonin Dysfunction, Aggressive Behavior, and Mental Illness: Exploring the Link Using a Dimensional Approach.

PubMed

Manchia, Mirko; Carpiniello, Bernardo; Valtorta, Flavia; Comai, Stefano

2017-05-17

Aggressive individuals have higher rates of mental illness compared to non-aggressive individuals. Multiple factors, including psychosocial, genetic, and neurobiological determinants modulate the liability to both aggressive behavior and mental illness. Concerning the latter factors, multiple lines of evidence have shown a dysfunction in the serotonin (5-HT) system occurring in aggressive and in mentally ill individuals. In particular, reduced 5-HT activity has been associated with depression as well as with aggressive behavior, especially with impulsive aggression. Consistently, psychopharmacological interventions aimed at boosting the 5-HT system (e.g., with selective serotonin reuptake inhibitors) have demonstrated therapeutic efficacy in a high percentage of patients with either or both pathological conditions. Current knowledge does not yet allow to clearly disentangle whether 5-HT dysfunction, most often a 5-HT deficiency, is the cause or the consequence of the aggressive/violent behavior, of the underlying mental disease/s, or the expression of the comorbidity. Future studies are thus needed to clarify the association between changes in 5-HT levels, altered activity of 5-HT receptors and their intracellular signaling cascades, and modifications of 5-HT genes, and in particular the neurobiological link between the altered 5-HT machinery and aggressive behavior in the context or in the absence of mental illness. In this Review, we employ a dimensional approach to discuss the trivariate relationship among the 5-HT system, aggressive behavior, and mental illness, focusing our attention on 5-HT levels, 5-HT receptors, metabolic enzymes, and their genes. Emphasis is given to controversial findings, still unanswered questions, and future perspectives.

Differential role of Wnt signaling and base excision repair pathways in gastric adenocarcinoma aggressiveness.

PubMed

Korourian, Alireza; Roudi, Raheleh; Shariftabrizi, Ahmad; Kalantari, Elham; Sotoodeh, Kambiz; Madjd, Zahra

2017-11-01

Aberrant activation of Wnt and base excision repair (BER) signaling pathways are implicated in tumor progression and chemotherapy resistance in gastric adenocarcinoma. This study was conducted to clarify the role of E2F6 and RhoA, components of the Wnt signaling pathway, and SMUG1, a component of the BER pathway in gastric adenocarcinoma. Expression levels and clinicopathological significance of three biomarkers, namely E2F6, RhoA, and SMUG1, as potential signaling molecules involved in tumorigenesis and aggressive behavior, were examined using tissue microarray. Our analysis showed a relative increase in the expression of E2F6 in gastric adenocarcinoma with no lymph node metastasis (χ 2 , P = 0.04 and OR, P = 0.08), while overexpression of RhoA and SMUG1 was found more often in the diffuse subtype of gastric adenocarcinoma as compared to the intestinal subtype (χ 2 , P = 0.05, OR, P = 0.08 and χ 2 , P = 0.001, OR, P = 0.009, respectively). Higher expression of RhoA was frequently seen in tumors with vascular invasion (χ 2 , P = 0.01 and OR, P = 0.01). In addition, increased expression of SMUG1 was found more often in poorly differentiated tumors (χ 2 , P = 0.01 and OR, P = 0.01). The distinct phenotype of E2F6 Low /SMUG1 High was more common in poorly differentiated tumors (P = 0.04) and with omental involvement (P = 0.01). The RhoA High /SMUG1 High expression pattern was significantly more often found in diffuse subtype compared to the intestinal subtype (P = 0.001) as well as in poorly differentiated tumors (P = 0.004). The E2F6 Low /SMUG1 High and RhoA High /SMUG1 High phenotypes can be considered as aggressive phenotypes of gastric adenocarcinoma. Our findings also demonstrated the synergistic effect of RhoA and SMUG1 in conferring tumor aggressiveness in diffuse subtype of gastric adenocarcinoma.

The influence of classroom aggression and classroom climate on aggressive-disruptive behavior.

PubMed

Thomas, Duane E; Bierman, Karen L; Powers, C J

2011-01-01

Research suggests that early classroom experiences influence the socialization of aggression. Tracking changes in the aggressive behavior of 4,179 children from kindergarten to second-grade (ages 5-8), this study examined the impact of 2 important features of the classroom context--aggregate peer aggression and climates characterized by supportive teacher-student interactions. The aggregate aggression scores of children assigned to first-grade classrooms predicted the level of classroom aggression (assessed by teacher ratings) and quality of classroom climate (assessed by observers) that emerged by the end of Grade 1. Hierarchical linear model analyses revealed that first-grade classroom aggression and quality of classroom climate made independent contributions to changes in student aggression, as students moved from kindergarten to second grade. Implications for policy and practice are discussed. © 2011 The Authors. Child Development © 2011 Society for Research in Child Development, Inc.

Intra- Versus Intersex Aggression: Testing Theories of Sex Differences Using Aggression Networks.

PubMed

Wölfer, Ralf; Hewstone, Miles

2015-08-01

Two theories offer competing explanations of sex differences in aggressive behavior: sexual-selection theory and social-role theory. While each theory has specific strengths and limitations depending on the victim's sex, research hardly differentiates between intrasex and intersex aggression. In the present study, 11,307 students (mean age = 14.96 years; 50% girls, 50% boys) from 597 school classes provided social-network data (aggression and friendship networks) as well as physical (body mass index) and psychosocial (gender and masculinity norms) information. Aggression networks were used to disentangle intra- and intersex aggression, whereas their class-aggregated sex differences were analyzed using contextual predictors derived from sexual-selection and social-role theories. As expected, results revealed that sexual-selection theory predicted male-biased sex differences in intrasex aggression, whereas social-role theory predicted male-biased sex differences in intersex aggression. Findings suggest the value of explaining sex differences separately for intra- and intersex aggression with a dual-theory framework covering both evolutionary and normative components. © The Author(s) 2015.

Atrazine induced epigenetic transgenerational inheritance of disease, lean phenotype and sperm epimutation pathology biomarkers

PubMed Central

McBirney, Margaux; King, Stephanie E.; Pappalardo, Michelle; Houser, Elizabeth; Unkefer, Margaret; Nilsson, Eric; Sadler-Riggleman, Ingrid; Beck, Daniel; Winchester, Paul

2017-01-01

Ancestral environmental exposures to a variety of environmental toxicants and other factors have been shown to promote the epigenetic transgenerational inheritance of adult onset disease. The current study examined the potential transgenerational actions of the herbicide atrazine. Atrazine is one of the most commonly used herbicides in the agricultural industry, in particular with corn and soy crops. Outbred gestating female rats were transiently exposed to a vehicle control or atrazine. The F1 generation offspring were bred to generate the F2 generation and then the F2 generation bred to generate the F3 generation. The F1, F2 and F3 generation control and atrazine lineage rats were aged and various pathologies investigated. The male sperm were collected to investigate DNA methylation differences between the control and atrazine lineage sperm. The F1 generation offspring (directly exposed as a fetus) did not develop disease, but weighed less compared to controls. The F2 generation (grand-offspring) was found to have increased frequency of testis disease and mammary tumors in males and females, early onset puberty in males, and decreased body weight in females compared to controls. The transgenerational F3 generation rats were found to have increased frequency of testis disease, early onset puberty in females, behavioral alterations (motor hyperactivity) and a lean phenotype in males and females. The frequency of multiple diseases was significantly higher in the transgenerational F3 generation atrazine lineage males and females. The transgenerational transmission of disease requires germline (egg or sperm) epigenetic alterations. The sperm differential DNA methylation regions (DMRs), termed epimutations, induced by atrazine were identified in the F1, F2 and F3 generations. Gene associations with the DMRs were identified. For the transgenerational F3 generation sperm, unique sets of DMRs (epimutations) were found to be associated with the lean phenotype or testis

Relationship between boys' normative beliefs about aggression and their physical, verbal, and indirect aggressive behaviors.

PubMed

Lim, Si Huan; Ang, Rebecca P

2009-01-01

This study examined the contribution of general normative beliefs about aggression and specific normative beliefs about retaliatory aggression in predicting physical, verbal, and indirect aggressive behaviors. Two hundred and forty-nine Grade 4 and Grade 5 boys completed the Normative Beliefs about Aggression Scale (NOBAGS) and provided self-reports on the frequency of their physical, verbal, and indirect aggressive behaviors. A series of hierarchical multiple regression analyses revealed that general normative beliefs about aggression contributed significantly in predicting all three types of aggressive behaviors. When general normative beliefs about aggression were controlled for, specific normative beliefs about retaliatory aggression against males but not specific normative beliefs about retaliatory aggression against females, contributed significantly to predict physical, verbal, and indirect aggressive behaviors. Implications for intervention programs are discussed.

Translational studies support a role for serotonin 2B receptor (HTR2B) gene in aggression-related cannabis response.

PubMed

Montalvo-Ortiz, Janitza L; Zhou, Hang; D'Andrea, Ivana; Maroteaux, Luc; Lori, Adriana; Smith, Alicia; Ressler, Kerry J; Nuñez, Yaira Z; Farrer, Lindsay A; Zhao, Hongyu; Kranzler, Henry R; Gelernter, Joel

2018-06-06

Cannabis use is increasing in the United States, as are its adverse effects. We investigated the genetics of an adverse consequence of cannabis use: cannabis-related aggression (CRA) using a genome-wide association study (GWAS) design. Our GWAS sample included 3269 African Americans (AAs) and 2546 European Americans (EAs). An additional 89 AA subjects from the Grady Trauma Project (GTP) were also examined using a proxy-phenotype replication approach. We identified genome-wide significant risk loci contributing to CRA in AAs at the serotonin receptor 2B receptor gene (HTR2B), and the lead SNP, HTR2B*rs17440378, showed nominal association to aggression in the GTP cohort of cannabis-exposed subjects. A priori evidence linked HTR2B to impulsivity/aggression but not to cannabis response. Human functional data regarding the HTR2B variant further supported our finding. Treating an Htr2b -/- knockout mouse with THC resulted in increased aggressive behavior, whereas wild-type mice following THC administration showed decreased aggression in the resident-intruder paradigm, demonstrating that HTR2B variation moderates the effects of cannabis on aggression. These concordant findings in mice and humans implicate HTR2B as a major locus associated with cannabis-induced aggression.

Definitions of the Phenotypic Manifestations of Sickle Cell Disease

PubMed Central

Ballas, Samir K.; Lieff, Susan; Benjamin, Lennette J.; Dampier, Carlton D.; Heeney, Matthew M.; Hoppe, Carolyn; Johnson, Cage S.; Rogers, Zora R.; Smith-Whitley, Kim; Wang, Winfred C.; Telen, Marilyn J.

2016-01-01

Sickle cell disease (SCD) is a pleiotropic genetic disorder of hemoglobin that has profound multi-organ effects. The low prevalence of SCD (~100,000/US) has limited progress in clinical, basic, and translational research. Lack of a large, readily accessible population for clinical studies has contributed to the absence of standard definitions and diagnostic criteria for the numerous complications of SCD and inadequate understanding of SCD pathophysiology. In 2005, the Comprehensive Sickle Cell Centers initiated a project to establish consensus definitions of the most frequently occurring complications. A group of clinicians and scientists with extensive expertise in research and treatment of SCD gathered to identify and categorize the most common complications. From this group, a formal writing team was formed that further reviewed the literature, sought specialist input, and produced definitions in a standard format. This manuscript provides an overview of the process and describes twelve body system categories and the most prevalent or severe complications within these categories. A detailed Appendix provides standardized definitions for all complications identified within each system. This report proposes use of these definitions for studies of SCD complications, so future studies can be comparably robust and treatment efficacy measured. Use of these definitions will support greater accuracy in genotype-phenotype studies, thereby achieving a better understanding of SCD pathophysiology. This should nevertheless be viewed as a dynamic rather than final document; phenotype descriptions should be reevaluated and revised periodically to provide the most current standard definitions as etiologic factors are better understood and new diagnostic options are developed. PMID:19902523

The displaced aggression questionnaire.

PubMed

Denson, Thomas F; Pedersen, William C; Miller, Norman

2006-06-01

Previous measures of aggressive personality have focused on direct aggression (i.e., retaliation toward the provoking agent). An original self-report measure of trait displaced aggression is presented. Exploratory and confirmatory factor analyses provided support for a 3-factor conceptualization of the construct. These analyses identified an affective dimension (angry rumination), a cognitive dimension (revenge planning), and a behavioral dimension (general tendency to engage in displaced aggression). The trait measure demonstrated good internal consistency and test-retest reliability as well as convergent and discriminant construct validity. Unlike other related personality measures, trait displaced aggression significantly predicted indirect indicators of real-world displaced aggression (i.e., self-reported domestic abuse and road rage) as well as laboratory displaced aggression in 2 experiments. Copyright 2006 APA, all rights reserved.

Hearing regulates Drosophila aggression.

PubMed

Versteven, Marijke; Vanden Broeck, Lies; Geurten, Bart; Zwarts, Liesbeth; Decraecker, Lisse; Beelen, Melissa; Göpfert, Martin C; Heinrich, Ralf; Callaerts, Patrick

2017-02-21

Aggression is a universal social behavior important for the acquisition of food, mates, territory, and social status. Aggression in Drosophila is context-dependent and can thus be expected to involve inputs from multiple sensory modalities. Here, we use mechanical disruption and genetic approaches in Drosophila melanogaster to identify hearing as an important sensory modality in the context of intermale aggressive behavior. We demonstrate that neuronal silencing and targeted knockdown of hearing genes in the fly's auditory organ elicit abnormal aggression. Further, we show that exposure to courtship or aggression song has opposite effects on aggression. Our data define the importance of hearing in the control of Drosophila intermale aggression and open perspectives to decipher how hearing and other sensory modalities are integrated at the neural circuit level.

Persistent conditioned place preference to aggression experience in adult male sexually-experienced CD-1 mice.

PubMed

Golden, S A; Aleyasin, H; Heins, R; Flanigan, M; Heshmati, M; Takahashi, A; Russo, S J; Shaham, Y

2017-01-01

We recently developed a conditioned place preference (CPP) procedure, commonly used to study rewarding drug effects, to demonstrate that dominant sexually-experienced CD-1 male mice form CPP to contexts previously associated with defeating subordinate male C57BL/6J mice. Here we further characterized conditioned and unconditioned aggression behavior in CD-1 mice. In Exp. 1 we used CD-1 mice that displayed a variable spectrum of unconditioned aggressive behavior toward younger subordinate C57BL/6J intruder mice. We then trained the CD-1 mice in the CPP procedure where one context was intruder-paired, while a different context was not. We then tested for aggression CPP 1 day after training. In Exp. 2, we tested CD-1 mice for aggression CPP 1 day and 18 days after training. In Exp. 3-4, we trained the CD-1 mice to lever-press for palatable food and tested them for footshock punishment-induced suppression of food-reinforced responding. In Exp. 5, we characterized unconditioned aggression in hybrid CD-1 × C57BL/6J D1-Cre or D2-Cre F1 generation crosses. Persistent aggression CPP was observed in CD-1 mice that either immediately attacked C57BL/6J mice during all screening sessions or mice that gradually developed aggressive behavior during the screening phase. In contrast, CD-1 mice that did not attack the C57BL/6J mice during screening did not develop CPP to contexts previously paired with C57BL/6J mice. The aggressive phenotype did not predict resistance to punishment-induced suppression of food-reinforced responding. CD-1 × D1-Cre or D2-Cre F1 transgenic mice showed strong unconditioned aggression. Our study demonstrates that aggression experience causes persistent CPP and introduces transgenic mice for circuit studies of aggression. © 2016 John Wiley & Sons Ltd and International Behavioural and Neural Genetics Society.

Eosinophilic and Neutrophilic Airway Inflammation in the Phenotyping of Mild-to-Moderate Asthma and Chronic Obstructive Pulmonary Disease.

PubMed

Górska, Katarzyna; Paplińska-Goryca, Magdalena; Nejman-Gryz, Patrycja; Goryca, Krzysztof; Krenke, Rafał

2017-04-01

Asthma and chronic obstructive pulmonary disease (COPD) are heterogeneous diseases with different inflammatory phenotypes. Various inflammatory mediators play a role in these diseases. The aim of this study was to analyze the neutrophilic and eosinophilic airway and systemic inflammation as the phenotypic characterization of patients with asthma and COPD. Twenty-four patients with asthma and 33 patients with COPD were enrolled in the study. All the patients were in mild-to-moderate stage of disease, and none of them were treated with inhaled corticosteroids. Concentrations of IL-6, neutrophil elastase (NE), matrix metalloproteinase 9 (MMP-9), eosinophil cationic protein (ECP), and IL-33 and IL-17 in serum and induced sputum (IS) were measured by enzyme-linked immunosorbent assay (ELISA). The cellular composition of blood and IS was evaluated. Hierarchical clustering of patients was performed for the combination of selected clinical features and mediators. Asthma and COPD can be differentiated based on eosinophilic/neutrophilic systemic or airway inflammation with unsatisfactory efficiency. Hierarchical clustering of patients based on blood eosinophil percentage and clinical data revealed two asthma clusters differing in the number of positive skin prick tests and one COPD cluster with two subclusters characterized by low and high blood eosinophil concentrations. Clustering of patients according to IS measurements and clinical data showed two main clusters: pure asthma characterized by high eosinophil/atopy status and mixed asthma and COPD cluster with low eosinophil/atopy status. The neutrophilic phenotype of COPD was associated with more severe airway obstruction and hyperinflation.

Differential serotonergic mediation of aggression in roosters selected for resistance and susceptibility to Marek's disease

USDA-ARS?s Scientific Manuscript database

Serotonin (5-HT) is a primary regulating neurotransmitter involved in aggressive and impulsive behaviors in mammals. Previous studies have also demonstrated the function of serotonergic system in regulating aggression is affected by both genetic and environmental factors. The serotonergic system m...

Disease severity and treatment requirements in familial inflammatory bowel disease.

PubMed

Ballester, María Pilar; Martí, David; Tosca, Joan; Bosca-Watts, Marta Maia; Sanahuja, Ana; Navarro, Pablo; Pascual, Isabel; Antón, Rosario; Mora, Francisco; Mínguez, Miguel

2017-08-01

Several studies demonstrate an increased prevalence and concordance of inflammatory bowel disease among the relatives of patients. Other studies suggest that genetic influence is over-estimated. The aims of this study are to evaluate the phenotypic expression and the treatment requirements in familial inflammatory bowel disease, to study the relationship between number of relatives and degree of kinship with disease severity and to quantify the impact of family aggregation compared to other environmental factors. Observational analytical study of 1211 patients followed in our unit. We analyzed, according to the existence of familial association, number and degree of consanguinity, the phenotypic expression, complications, extraintestinal manifestations, treatment requirements, and mortality. A multivariable analysis considering smoking habits and non-steroidal-anti-inflammatory drugs was performed. 14.2% of patients had relatives affected. Median age at diagnosis tended to be lower in the familial group, 32 vs 29, p = 0.07. In familial ulcerative colitis, there was a higher proportion of extraintestinal manifestations: peripheral arthropathy (OR = 2.3, p = 0.015) and erythema nodosum (OR = 7.6, p = 0.001). In familial Crohn's disease, there were higher treatment requirements: immunomodulators (OR = 1.8, p = 0.029); biologics (OR = 1.9, p = 0.011); and surgery (OR = 1.7, p = 0.044). The abdominal abscess increased with the number of relatives affected: 5.1% (sporadic), 7.0% (one), and 14.3% (two or more), p=0.039. These associations were maintained in the multivariate analysis. Familial aggregation is considered a risk factor for more aggressive disease and higher treatment requirements, a tendency for earlier onset, more abdominal abscess, and extraintestinal manifestations, remaining a risk factor analyzing the influence of some environmental factors.

Distinctive Menkes disease variant with occipital horns: Delineation of natural history and clinical phenotype

DOE Office of Scientific and Technical Information (OSTI.GOV)

Proud, V.K.; Mussell, H.G.; Percy, A.K.

1996-10-02

To delineate further the clinical spectrum of Menkes disease, an X-linked recessive disorder of copper transport, we studied 4 related males, ranging in age from 4-38 years, with a unique phenotype that combines manifestations of classical and mild Menkes disease and occipital horn syndrome (OHS). The propositus, an 18-year-old man, was evaluated following an intracerebral hemorrhage at age 15 years and was noted to have marked hypotonia, motor delay with mental retardation, bladder diverticula, failure to thrive, and diarrhea from infancy; seizures from age 3 years; and abnormal hair (pili torti) and face, cutis laxa, and multiple joint dislocations. Radiographicmore » abnormalities included occipital exostoses, tortuous cerebral blood vessels with multiple branch occlusions, and hammer-shaped clavicles. Biochemical studies demonstrated reduced copper and ceruloplasmin levels in serum, and abnormal plasma catecholamine ratios. We reported previously the molecular defect in this family, a splice-site mutation that predicts formation of approximately 20% of the normal Menkes gene product. Here, we detail the clinical course and physical features and radiographic findings in these 4 individuals, and compare their phenotype with classical and mild Menkes and OHS. Unusual Menkes disease variants such as this may escape recognition due to anomalies that appear inconsistent with the diagnosis, particularly prolonged survival and later onset of seizures. Males with mental retardation and connective tissue abnormalities should be evaluated for biochemical evidence of defective copper transport. 28 refs., 8 figs.« less

The International Mouse Phenotyping Consortium Web Portal, a unified point of access for knockout mice and related phenotyping data

PubMed Central

Koscielny, Gautier; Yaikhom, Gagarine; Iyer, Vivek; Meehan, Terrence F.; Morgan, Hugh; Atienza-Herrero, Julian; Blake, Andrew; Chen, Chao-Kung; Easty, Richard; Di Fenza, Armida; Fiegel, Tanja; Grifiths, Mark; Horne, Alan; Karp, Natasha A.; Kurbatova, Natalja; Mason, Jeremy C.; Matthews, Peter; Oakley, Darren J.; Qazi, Asfand; Regnart, Jack; Retha, Ahmad; Santos, Luis A.; Sneddon, Duncan J.; Warren, Jonathan; Westerberg, Henrik; Wilson, Robert J.; Melvin, David G.; Smedley, Damian; Brown, Steve D. M.; Flicek, Paul; Skarnes, William C.; Mallon, Ann-Marie; Parkinson, Helen

2014-01-01

The International Mouse Phenotyping Consortium (IMPC) web portal (http://www.mousephenotype.org) provides the biomedical community with a unified point of access to mutant mice and rich collection of related emerging and existing mouse phenotype data. IMPC mouse clinics worldwide follow rigorous highly structured and standardized protocols for the experimentation, collection and dissemination of data. Dedicated ‘data wranglers’ work with each phenotyping center to collate data and perform quality control of data. An automated statistical analysis pipeline has been developed to identify knockout strains with a significant change in the phenotype parameters. Annotation with biomedical ontologies allows biologists and clinicians to easily find mouse strains with phenotypic traits relevant to their research. Data integration with other resources will provide insights into mammalian gene function and human disease. As phenotype data become available for every gene in the mouse, the IMPC web portal will become an invaluable tool for researchers studying the genetic contributions of genes to human diseases. PMID:24194600

Physiological Aβ Concentrations Produce a More Biomimetic Representation of the Alzheimer's Disease Phenotype in iPSC Derived Human Neurons.

PubMed

Berry, Bonnie J; Smith, Alec S T; Long, Christopher J; Martin, Candace C; Hickman, James J

2018-05-22

Alzheimer's disease (AD) is characterized by slow, progressive neurodegeneration leading to severe neurological impairment, but current drug development efforts are limited by the lack of robust, human-based disease models. Amyloid-β (Aβ) is known to play an integral role in AD progression as it has been shown to interfere with neurological function. However, studies into AD pathology commonly apply Aβ to neurons for short durations at nonphysiological concentrations to induce an exaggerated dysfunctional phenotype. Such methods are unlikely to elucidate early stage disease dysfunction, when treatment is still possible, since damage to neurons by these high concentrations is extensive. In this study, we investigated chronic, pathologically relevant Aβ oligomer concentrations to induce an electrophysiological phenotype that is more representative of early AD progression compared to an acute high-dose application in human cortical neurons. The high, acute oligomer dose resulted in severe neuronal toxicity as well as upregulation of tau and phosphorylated tau. Chronic, low-dose treatment produced significant functional impairment without increased cell death or accumulation of tau protein. This in vitro phenotype more closely mirrors the status of early stage neural decline in AD pathology and could provide a valuable tool to further understanding of early stage AD pathophysiology and for screening potential therapeutic compounds.

Dopamine and serotonin signaling during two sensitive developmental periods differentially impact adult aggressive and affective behaviors in mice.

PubMed

Yu, Q; Teixeira, C M; Mahadevia, D; Huang, Y; Balsam, D; Mann, J J; Gingrich, J A; Ansorge, M S

2014-06-01

Pharmacologic blockade of monoamine oxidase A (MAOA) or serotonin transporter (5-HTT) has antidepressant and anxiolytic efficacy in adulthood. Yet, genetically conferred MAOA or 5-HTT hypoactivity is associated with altered aggression and increased anxiety/depression. Here we test the hypothesis that increased monoamine signaling during development causes these paradoxical aggressive and affective phenotypes. We find that pharmacologic MAOA blockade during early postnatal development (P2-P21) but not during peri-adolescence (P22-41) increases anxiety- and depression-like behavior in adult (>P90) mice, mimicking the effect of P2-21 5-HTT inhibition. Moreover, MAOA blockade during peri-adolescence, but not P2-21 or P182-201, increases adult aggressive behavior, and 5-HTT blockade from P22-P41 reduced adult aggression. Blockade of the dopamine transporter, but not the norepinephrine transporter, during P22-41 also increases adult aggressive behavior. Thus, P2-21 is a sensitive period during which 5-HT modulates adult anxiety/depression-like behavior, and P22-41 is a sensitive period during which DA and 5-HT bi-directionally modulate adult aggression. Permanently altered DAergic function as a consequence of increased P22-P41 monoamine signaling might underlie altered aggression. In support of this hypothesis, we find altered aggression correlating positively with locomotor response to amphetamine challenge in adulthood. Proving that altered DA function and aggression are causally linked, we demonstrate that optogenetic activation of VTA DAergic neurons increases aggression. It therefore appears that genetic and pharmacologic factors impacting dopamine and serotonin signaling during sensitive developmental periods can modulate adult monoaminergic function and thereby alter risk for aggressive and emotional dysfunction.

From genotype to phenotype; clinical variability in Lesch-Nyhan disease. The role of epigenetics.

PubMed

Trigueros Genao, M; Torres, R J

2014-11-01

Lesch-Nyhan disease is a rare genetic disease characterized by a deficiency in the function of the enzyme hypoxanthine-guanine phosphoribosyltransferase (HGPRT). Patients affected by this disease experience hyperuricemia, motor disorders, mental retardation and, in the most severe cases, self-mutilation. Its clinical manifestations depend on the enzymatic activity of HGPRT, which is classically linked to the type of alteration in the HGPRT gene. More than 400 mutations of this gene have been found. At present, one of the controversial aspects of the disease is the relationship between the genotype and phenotype; cases have been described lacking a mutation, such as the patient presented in this article, as well as families who despite sharing the same genetic defect show disorders with differing severity. Epigenetic processes, which modify the genetic expression without changing the sequence of the deoxyribonucleic acid (DNA), could explain the clinical variability observed in this disease. Copyright © 2014 Elsevier España, S.L.U. All rights reserved.

Position of human blood group O(H) and phenotype-determining enzymes in growth and infectious disease.

PubMed

Arend, Peter

2018-05-12

The human ABO(H) blood group phenotypes arise from the evolutionarily oldest genetic system found in primate populations. While the blood group antigen A is considered the ancestral primordial structure, under the selective pressure of life-threatening diseases blood group O(H) came to dominate as the most frequently occurring blood group worldwide. Non-O(H) phenotypes demonstrate impaired formation of adaptive and innate immunoglobulin specificities due to clonal selection and phenotype formation in plasma proteins. Compared with individuals with blood group O(H), blood group A individuals not only have a significantly higher risk of developing certain types of cancer but also exhibit high susceptibility to malaria tropica or infection by Plasmodium falciparum. The phenotype-determining blood group A glycotransferase(s), which affect the levels of anti-A/Tn cross-reactive immunoglobulins in phenotypic glycosidic accommodation, might also mediate adhesion and entry of the parasite to host cells via trans-species O-GalNAc glycosylation of abundantly expressed serine residues that arise throughout the parasite's life cycle, while excluding the possibility of antibody formation against the resulting hybrid Tn antigen. In contrast, human blood group O(H), lacking this enzyme, is indicated to confer a survival advantage regarding the overall risk of developing cancer, and individuals with this blood group rarely develop life-threatening infections involving evolutionarily selective malaria strains. © 2018 New York Academy of Sciences.

Hearing regulates Drosophila aggression

PubMed Central

Versteven, Marijke; Vanden Broeck, Lies; Geurten, Bart; Zwarts, Liesbeth; Decraecker, Lisse; Beelen, Melissa; Göpfert, Martin C.; Heinrich, Ralf; Callaerts, Patrick

2017-01-01

Aggression is a universal social behavior important for the acquisition of food, mates, territory, and social status. Aggression in Drosophila is context-dependent and can thus be expected to involve inputs from multiple sensory modalities. Here, we use mechanical disruption and genetic approaches in Drosophila melanogaster to identify hearing as an important sensory modality in the context of intermale aggressive behavior. We demonstrate that neuronal silencing and targeted knockdown of hearing genes in the fly’s auditory organ elicit abnormal aggression. Further, we show that exposure to courtship or aggression song has opposite effects on aggression. Our data define the importance of hearing in the control of Drosophila intermale aggression and open perspectives to decipher how hearing and other sensory modalities are integrated at the neural circuit level. PMID:28115690

Phenotypic integration and the evolution of signal repertoires: A case study of treefrog acoustic communication.

PubMed

Reichert, Michael S; Höbel, Gerlinde

2018-03-01

Animal signals are inherently complex phenotypes with many interacting parts combining to elicit responses from receivers. The pattern of interrelationships between signal components reflects the extent to which each component is expressed, and responds to selection, either in concert with or independently of others. Furthermore, many species have complex repertoires consisting of multiple signal types used in different contexts, and common morphological and physiological constraints may result in interrelationships extending across the multiple signals in species' repertoires. The evolutionary significance of interrelationships between signal traits can be explored within the framework of phenotypic integration, which offers a suite of quantitative techniques to characterize complex phenotypes. In particular, these techniques allow for the assessment of modularity and integration, which describe, respectively, the extent to which sets of traits covary either independently or jointly. Although signal and repertoire complexity are thought to be major drivers of diversification and social evolution, few studies have explicitly measured the phenotypic integration of signals to investigate the evolution of diverse communication systems. We applied methods from phenotypic integration studies to quantify integration in the two primary vocalization types (advertisement and aggressive calls) in the treefrogs Hyla versicolor , Hyla cinerea, and Dendropsophus ebraccatus . We recorded male calls and calculated standardized phenotypic variance-covariance ( P ) matrices for characteristics within and across call types. We found significant integration across call types, but the strength of integration varied by species and corresponded with the acoustic similarity of the call types within each species. H. versicolor had the most modular advertisement and aggressive calls and the least acoustically similar call types. Additionally, P was robust to changing social competition

House finch responses to Mycoplasma gallisepticum infection do not vary with experimentally increased aggression.

PubMed

Adelman, James Stephen; Moore, Ignacio Tomás; Hawley, Dana Michelle

2015-01-01

Aggression can alter infectious disease dynamics through two, non-exclusive mechanisms: 1) increasing direct contact among hosts and 2) altering hosts' physiological response to pathogens. Here we examined the latter mechanism in a social songbird by manipulating intraspecific aggression in the absence of direct physical contact. We asked whether the extent of aggression an individual experiences alters glucocorticoid levels, androgen levels, and individual responses to infection in an ecologically relevant disease model: house finches (Haemorhous mexicanus) infected with Mycoplasma gallisepticum (MG). Wild-caught male finches were housed in one of three settings, designed to produce increasing levels of aggression: 1) alone, with no neighbor ("no neighbor"), 2) next to a sham-implanted stimulus male ("sham neighbor"), or 3) next to a testosterone-implanted stimulus male ("testosterone neighbor"). Following one week of social treatment, focal males were experimentally infected with MG, which causes severe conjunctivitis and induces sickness behaviors such as lethargy and anorexia. While social treatment increased aggression as predicted, there were no differences among groups in baseline corticosterone levels, total circulating androgens, or responses to infection. Across all focal individuals regardless of social treatment, pre-infection baseline corticosterone levels were negatively associated with the severity of conjunctivitis and sickness behaviors, suggesting that corticosterone may dampen inflammatory responses in this host-pathogen system. However, because corticosterone levels differed based upon population of origin, caution must be taken in interpreting this result. Taken together, these results suggest that in captivity, although aggression does not alter individual responses to MG, corticosterone may play a role in this disease. © 2014 Wiley Periodicals, Inc.

IGF2BP1 enhances an aggressive tumor cell phenotype by impairing miRNA-directed downregulation of oncogenic factors.

PubMed

Müller, Simon; Bley, Nadine; Glaß, Markus; Busch, Bianca; Rousseau, Vanessa; Misiak, Danny; Fuchs, Tommy; Lederer, Marcell; Hüttelmaier, Stefan

2018-04-12

The oncofetal IGF2 mRNA binding proteins (IGF2BPs) are upregulated in most cancers but their paralogue-specific roles in tumor cells remain poorly understood. In a panel of five cancer-derived cell lines, IGF2BP1 shows highly conserved oncogenic potential. Consistently, the deletion of IGF2BP1 impairs the growth and metastasis of ovarian cancer-derived cells in nude mice. Gene expression analyses in ovarian cancer-derived cells reveal that the knockdown of IGF2BPs is associated with the downregulation of mRNAs that are prone to miRNA regulation. All three IGF2BPs preferentially associate upstream of miRNA binding sites (MBSs) in the 3'UTR of mRNAs. The downregulation of mRNAs co-regulated by miRNAs and IGF2BP1 is abrogated at low miRNA abundance or when miRNAs are depleted. IGF2BP1 associates with these target mRNAs in RISC-free complexes and its deletion enhances their association with AGO2. The knockdown of most miRNA-regulated target mRNAs of IGF2BP1 impairs tumor cell properties. In four primary cancers, elevated synthesis of these target mRNAs is largely associated with upregulated IGF2BP1 mRNA levels. In ovarian cancer, the enhanced expression of IGF2BP1 and most of its miRNA-controlled target mRNAs is associated with poor prognosis. In conclusion, these findings indicate that IGF2BP1 enhances an aggressive tumor cell phenotype by antagonizing miRNA-impaired gene expression.

Rhabdoid glioblastoma: an aggressive variaty of astrocytic tumor.

PubMed

Hiroyuki, Momota; Ogino, Jiro; Takahashi, Akira; Hasegawa, Tadashi; Wakabayashi, Toshihiko

2015-02-01

Rhabdoid glioblastoma (RGBM) is rare, but the most malignant among astrocytic tumors. Accumulating evidence indicates its highly aggressive nature and distinct histopathological features. Here, we report a new case of RGBM and review previously reported cases of astrocytic tumors with rhabdoid components. We describe a 58-year-old man who presented with aphasia and right-sided weakness. Magnetic resonance imaging revealed a well-delineated intramedullary tumor in the left cerebral hemisphere. Partial resection of the tumor was performed. The tumor was histologically found to contain two distinct areas: a typical glioblastoma, and a rhabdoid component. Immunohistochemical analyses revealed expression of glial fibrillary acidic protein (GFAP) and focal loss of the INI1 protein in rhabdoid cells, although fluorescence in situ hybridization analysis showed no loss of the INI1 gene. Despite subsequent radiochemotherapy for the glioblastoma, the patient died 4.3 months after surgery. Our literature review illustrates the aggressive clinical course and histopathological features of these tumors with GFAP and INI1 expression. INI1 protein dysfunction may be a possible cause of the rhabdoid phenotype. Gross total resection of the tumor and intensive radiochemotherapy may lead to better survival outcomes.

Lymphocyte Antigen 75 Polymorphisms Are Associated with Disease Susceptibility and Phenotype in Japanese Patients with Inflammatory Bowel Disease.

PubMed

Hirayama, Atsuhiro; Joshita, Satoru; Kitahara, Kei; Mukawa, Kenji; Suga, Tomoaki; Umemura, Takeji; Tanaka, Eiji; Ota, Masao

2016-01-01

Recent genome-wide association studies have rapidly improved our understanding of the molecular pathways leading to inflammatory bowel disease (IBD), which includes Crohn's disease (CD) and ulcerative colitis (UC). Although several reports have demonstrated that gene single nucleotide polymorphisms (SNPs) are associated with susceptibility to IBD, its precise genetic factors have not been fully clarified. Here, we performed an association analysis between lymphocyte antigen 75 ( LY75 ) genetic variations and IBD susceptibility or phenotype. SNPs were genotyped in 51 CD patients, 94 UC patients, and 269 healthy controls of Japanese ethnicity. We detected a significant relationship with CD susceptibility for the rs16822581 LY75 SNP ( P = 0.045). One haplotype (GT, P = 0.042) was also associated with CD susceptibility, while another carrying the opposite SNP (CA) was linked to an absence of surgical history for CD. Our findings confirm that LY75 is involved in CD susceptibility and may play a role in disease activity in the Japanese population.

Tumor morphology and phenotypic evolution driven by selective pressure from the microenvironment.

PubMed

Anderson, Alexander R A; Weaver, Alissa M; Cummings, Peter T; Quaranta, Vito

2006-12-01

Emergence of invasive behavior in cancer is life-threatening, yet ill-defined due to its multifactorial nature. We present a multiscale mathematical model of cancer invasion, which considers cellular and microenvironmental factors simultaneously and interactively. Unexpectedly, the model simulations predict that harsh tumor microenvironment conditions (e.g., hypoxia, heterogenous extracellular matrix) exert a dramatic selective force on the tumor, which grows as an invasive mass with fingering margins, dominated by a few clones with aggressive traits. In contrast, mild microenvironment conditions (e.g., normoxia, homogeneous matrix) allow clones with similar aggressive traits to coexist with less aggressive phenotypes in a heterogeneous tumor mass with smooth, noninvasive margins. Thus, the genetic make-up of a cancer cell may realize its invasive potential through a clonal evolution process driven by definable microenvironmental selective forces. Our mathematical model provides a theoretical/experimental framework to quantitatively characterize this selective pressure for invasion and test ways to eliminate it.

Identification of chronic kidney disease risk in relatively lean Southern Chinese: the hypertriglyceridemic waist phenotype vs. anthropometric indexes.

PubMed

Zhou, Chaomin; Li, Yongqiang; Shao, Xiaofei; Zou, Hequn

2018-01-25

Assessing and comparing the ability of the hypertriglyceridemic waist (HW) phenotype and anthropometric obesity indexes to identify subjects at high risk of chronic kidney disease (CKD) in a relatively lean population in South China. Using data from a community-based, cross-sectional study conducted in Zhuhai City, Southern China, we examined associations between the HW phenotype, anthropometric obesity indexes, and incident CKD risk in a relatively lean population. Multiple logistic regression analyses were used to evaluate the associations. The HW phenotype associated with CKD significantly in the unadjusted analysis (OR 3.53, 95% CI 1.65-7.52, P = 0.001). Further adjustment for gender, age, and other potential confounding variables had an impact on the odd ratios (OR); the OR decreased but still existed (OR 2.91, 95% 1.23-6.87, P = 0.016). The association of the HW phenotype with CKD remained significant after further adjustment for hypertension and diabetes. No significant association between the anthropometric indexes and incident CKD was found. The HW phenotype, but not the anthropometric indexes, is associated with an elevated risk of CKD in relatively lean subjects. The HW phenotype appears to be a better predictor of CKD than the anthropometric indexes. Level V, descriptive study.

Clinical improvement of the aggressive neurobehavioral phenotype in a patient with a deletion of PITX3 and the absence of L-DOPA in the cerebrospinal fluid.

PubMed

Derwińska, Katarzyna; Mierzewska, Hanna; Goszczańska, Alicja; Szczepanik, Elżbieta; Xia, Zhilian; Kuśmierska, Katarzyna; Tryfon, Jolanta; Kutkowska-Kaźmierczak, Anna; Bocian, Ewa; Mazurczak, Tadeusz; Obersztyn, Ewa; Stankiewicz, Paweł

2012-03-01

The development of midbrain dopamine (DA) neurons is regulated by several transcription factors, including Nurr1, Wnt1, Lmx1a/1b, En1, En2, Foxa1, Foxa2, and Pitx3. PITX3 is an upstream co-activator of the TH (tyrosine hydroxylase) promoter. Pitx3(-/-) mice have a selective loss of dopaminergic neurons in the substantia nigra and ventral tegmental area, leading to the significantly reduced DA levels in the nigrostriatal pathway and in the dorsal striatum and manifest anomalous striatum-dependent cognitive impairment and neurobehavioral activity. Treatment with L-DOPA, dopamine, or dopamine receptor agonists in these mice reversed several of their sensorimotor impairments. Heterozygous missense mutations in PITX3 have been reported in patients with autosomal dominant congenital cataract and anterior segment (ocular) mesenchymal dysgenesis (ASMD) whereas homozygous missense mutations have been found in patients with microphthalmia and neurological impairment. Using a clinical oligonucleotide array comparative genomic hybridization (aCGH), we have identified an ∼317 kb hemizygous deletion in 10q24.32, involving PITX3 in a 17-year-old male with a Smith-Magenis syndrome-like phenotype, including mild intellectual impairment, sleep disturbance, hyperactivity, and aggressive and self-destructive behavior. Interestingly, no eye anomalies were found in our patient. Analysis of neurotransmitters in his cerebrospinal fluid revealed an absence of L-DOPA and significantly decreased levels of catecholamine metabolites. Importantly, L-DOPA treatment of our patient has led to mild mitigation of his aggressive behavior and mild improvement of his attention span, extended time periods of concentration, and better sleep. Copyright © 2012 Wiley Periodicals, Inc.

A Role for Prefrontal Cortical NMDA Receptors in Murine Alcohol-Heightened Aggression.

PubMed

Newman, Emily L; Terunuma, Miho; Wang, Tiffany L; Hewage, Nishani; Bicakci, Matthew B; Moss, Stephen J; DeBold, Joseph F; Miczek, Klaus A

2018-05-01

Alcohol is associated with nearly half of all violent crimes committed in the United States; yet, a potential neural basis for this type of pathological aggression remains elusive. Alcohol may act on N-methyl-d-aspartate receptors (NMDARs) within cortical circuits to impede processing and to promote aggression. Here, male mice were characterized as alcohol-heightened (AHAs) or alcohol non-heightened aggressors (ANAs) during resident-intruder confrontations after self-administering 1.0 g/kg alcohol (6% w/v) or water. Alcohol produced a pathological-like pattern of aggression in AHAs; these mice shifted their bites to more vulnerable locations on the body of a submissive animal, including the anterior back and ventrum after consuming alcohol. In addition, through immunoblotting, we found that AHAs overexpressed the NMDAR GluN2D subunit in the prefrontal cortex (PFC) as compared to ANAs while the two phenotypes expressed similar levels of GluN1, GluN2A and GluN2B. After identifying several behavioral and molecular characteristics that distinguish AHAs from ANAs, we tested additional mice for their aggression following preferential antagonism of GluN2D-containing NMDARs. In these experiments, groups of AHAs and ANAs self-administered 1.0 g/kg alcohol (6% w/v) or water before receiving intraperitoneal (i.p.) doses of ketamine or memantine, or infusions of memantine directly into the prelimbic (PLmPFC) or infralimbic medial PFC (ILmPFC). Moderate doses of IP ketamine, IP memantine, or intra-PLmPFC memantine increased aggression in AHAs, but only in the absence of alcohol. Prior alcohol intake blocked the pro-aggressive effects of ketamine or memantine. In contrast, only memantine, administered systemically or intra-PLmPFC, interacted with prior alcohol intake to escalate aggression in ANAs. Intra-ILmPFC memantine had no effect on aggression in either AHAs or ANAs. In sum, this work illustrates a potential role of GluN2D-containing NMDARs in the PLmPFC in alcohol

Supporting the annotation of chronic obstructive pulmonary disease (COPD) phenotypes with text mining workflows.

PubMed

Fu, Xiao; Batista-Navarro, Riza; Rak, Rafal; Ananiadou, Sophia

2015-01-01

Chronic obstructive pulmonary disease (COPD) is a life-threatening lung disorder whose recent prevalence has led to an increasing burden on public healthcare. Phenotypic information in electronic clinical records is essential in providing suitable personalised treatment to patients with COPD. However, as phenotypes are often "hidden" within free text in clinical records, clinicians could benefit from text mining systems that facilitate their prompt recognition. This paper reports on a semi-automatic methodology for producing a corpus that can ultimately support the development of text mining tools that, in turn, will expedite the process of identifying groups of COPD patients. A corpus of 30 full-text papers was formed based on selection criteria informed by the expertise of COPD specialists. We developed an annotation scheme that is aimed at producing fine-grained, expressive and computable COPD annotations without burdening our curators with a highly complicated task. This was implemented in the Argo platform by means of a semi-automatic annotation workflow that integrates several text mining tools, including a graphical user interface for marking up documents. When evaluated using gold standard (i.e., manually validated) annotations, the semi-automatic workflow was shown to obtain a micro-averaged F-score of 45.70% (with relaxed matching). Utilising the gold standard data to train new concept recognisers, we demonstrated that our corpus, although still a work in progress, can foster the development of significantly better performing COPD phenotype extractors. We describe in this work the means by which we aim to eventually support the process of COPD phenotype curation, i.e., by the application of various text mining tools integrated into an annotation workflow. Although the corpus being described is still under development, our results thus far are encouraging and show great potential in stimulating the development of further automatic COPD phenotype extractors.

Kinesin Mutations Cause Motor Neuron Disease Phenotypes by Disrupting Fast Axonal Transport in Drosophila

PubMed Central

Hurd, D. D.; Saxton, W. M.

1996-01-01

Previous work has shown that mutation of the gene that encodes the microtubule motor subunit kinesin heavy chain (Khc) in Drosophila inhibits neuronal sodium channel activity, action potentials and neurotransmitter secretion. These physiological defects cause progressive distal paralysis in larvae. To identify the cellular defects that cause these phenotypes, larval nerves were studied by light and electron microscopy. The axons of Khc mutants develop dramatic focal swellings along their lengths. The swellings are packed with fast axonal transport cargoes including vesicles, synaptic membrane proteins, mitochondria and prelysosomal organelles, but not with slow axonal transport cargoes such as cytoskeletal elements. Khc mutations also impair the development of larval motor axon terminals, causing dystrophic morphology and marked reductions in synaptic bouton numbers. These observations suggest that as the concentration of maternally provided wild-type KHC decreases, axonal organelles transported by kinesin periodically stall. This causes organelle jams that disrupt retrograde as well as anterograde fast axonal transport, leading to defective action potentials, dystrophic terminals, reduced transmitter secretion and progressive distal paralysis. These phenotypes parallel the pathologies of some vertebrate motor neuron diseases, including some forms of amyotrophic lateral sclerosis (ALS), and suggest that impaired fast axonal transport is a key element in those diseases. PMID:8913751

Clinical outcomes in managed-care patients with coronary heart disease treated aggressively in lipid-lowering disease management clinics: the alliance study.

PubMed

Koren, Michael J; Hunninghake, Donald B

2004-11-02

This study sought to determine if an aggressive, focused low-density lipoprotein cholesterol (LDL-C)-lowering strategy was superior to usual care for coronary heart disease (CHD) patients enrolled in health maintenance organization or Veterans Administration settings. Statin therapy benefits are well established. No prospective, randomized studies have tested strategies to optimize these benefits in a "real-world" setting. A total of 2,442 CHD patients with hyperlipidemia were randomized to either an aggressive treatment arm using atorvastatin or usual care and followed for 51.5 months on average. Atorvastatin-group patients were titrated to LDL-C goals of <80 mg/dl (2.1 mmol/l) or a maximum atorvastatin dose of 80 mg/day. Usual-care patients received any treatment deemed appropriate by their regular physicians. End point assessments were complete in 958 atorvastatin-group and 941 usual-care patients. Partial assessments occurred in 259 patients in the atorvastatin group and 284 patients in the usual care group who did not complete four years of study participation because of adverse events, withdrawn consent, or follow-up loss. The primary efficacy parameter was time to first cardiovascular event. A total of 289 (23.7%) patients in the atorvastatin group compared with 333 (27.7%) patients in the usual care group experienced a primary outcome (hazard ratio, 0.83; 95% confidence interval 0.71 to 0.97, p = 0.02). This reduction in morbidity was largely due to fewer non-fatal myocardial infarctions (4.3% vs. 7.7%, p = 0.0002). Levels of LDL-C were reduced more (34.3% vs. 23.3%, p < 0.0001) and National Cholesterol Education Program goals (LDL-C <100 mg/dl) more likely met at end-of-study visits (72.4% vs. 40.0%) in patients receiving atorvastatin compared with those receiving usual care. An aggressive, focused statin therapy management strategy outperformed usual care in health maintenance organization and Veterans Administration clinic patients with CHD.

The immature dentate gyrus represents a shared phenotype of mouse models of epilepsy and psychiatric disease

PubMed Central

Shin, Rick; Kobayashi, Katsunori; Hagihara, Hideo; Kogan, Jeffrey H; Miyake, Shinichi; Tajinda, Katsunori; Walton, Noah M; Gross, Adam K; Heusner, Carrie L; Chen, Qian; Tamura, Kouichi; Miyakawa, Tsuyoshi; Matsumoto, Mitsuyuki

2013-01-01

Objectives There is accumulating evidence to suggest psychiatric disorders, such as bipolar disorder and schizophrenia, share common etiologies, pathophysiologies, genetics, and drug responses with many of the epilepsies. Here, we explored overlaps in cellular/molecular, electrophysiological, and behavioral phenotypes between putative mouse models of bipolar disorder/schizophrenia and epilepsy. We tested the hypothesis that an immature dentate gyrus (iDG), whose association with psychosis in patients has recently been reported, represents a common phenotype of both diseases. Methods Behaviors of calcium/calmodulin-dependent protein kinase II alpha (α-CaMKII) heterozygous knock-out (KO) mice, which are a representative bipolar disorder/schizophrenia model displaying iDG, and pilocarpine-treated mice, which are a representative epilepsy model, were tested followed by quantitative polymerase chain reaction (qPCR)/immunohistochemistry for mRNA/protein expression associated with an iDG phenotype. In vitro electrophysiology of dentate gyrus granule cells (DG GCs) was examined in pilocarpine-treated epileptic mice. Results The two disease models demonstrated similar behavioral deficits, such as hyperactivity, poor working memory performance, and social withdrawal. Significant reductions in mRNA expression and immunoreactivity of the mature neuronal marker calbindin and concomitant increases in mRNA expression and immunoreactivity of the immature neuronal marker calretinin represent iDG signatures that are present in both mice models. Electrophysiologically, we have confirmed that DG GCs from pilocarpine-treated mice represent an immature state. A significant decrease in hippocampal α-CaMKII protein levels was also found in both models. Conclusions Our data have shown iDG signatures from mouse models of both bipolar disorder/schizophrenia and epilepsy. The evidence suggests that the iDG may, in part, be responsible for the abnormal behavioral phenotype, and that the

The immature dentate gyrus represents a shared phenotype of mouse models of epilepsy and psychiatric disease.

PubMed

Shin, Rick; Kobayashi, Katsunori; Hagihara, Hideo; Kogan, Jeffrey H; Miyake, Shinichi; Tajinda, Katsunori; Walton, Noah M; Gross, Adam K; Heusner, Carrie L; Chen, Qian; Tamura, Kouichi; Miyakawa, Tsuyoshi; Matsumoto, Mitsuyuki

2013-06-01

There is accumulating evidence to suggest psychiatric disorders, such as bipolar disorder and schizophrenia, share common etiologies, pathophysiologies, genetics, and drug responses with many of the epilepsies. Here, we explored overlaps in cellular/molecular, electrophysiological, and behavioral phenotypes between putative mouse models of bipolar disorder/schizophrenia and epilepsy. We tested the hypothesis that an immature dentate gyrus (iDG), whose association with psychosis in patients has recently been reported, represents a common phenotype of both diseases. Behaviors of calcium/calmodulin-dependent protein kinase II alpha (α-CaMKII) heterozygous knock-out (KO) mice, which are a representative bipolar disorder/schizophrenia model displaying iDG, and pilocarpine-treated mice, which are a representative epilepsy model, were tested followed by quantitative polymerase chain reaction (qPCR)/immunohistochemistry for mRNA/protein expression associated with an iDG phenotype. In vitro electrophysiology of dentate gyrus granule cells (DG GCs) was examined in pilocarpine-treated epileptic mice. The two disease models demonstrated similar behavioral deficits, such as hyperactivity, poor working memory performance, and social withdrawal. Significant reductions in mRNA expression and immunoreactivity of the mature neuronal marker calbindin and concomitant increases in mRNA expression and immunoreactivity of the immature neuronal marker calretinin represent iDG signatures that are present in both mice models. Electrophysiologically, we have confirmed that DG GCs from pilocarpine-treated mice represent an immature state. A significant decrease in hippocampal α-CaMKII protein levels was also found in both models. Our data have shown iDG signatures from mouse models of both bipolar disorder/schizophrenia and epilepsy. The evidence suggests that the iDG may, in part, be responsible for the abnormal behavioral phenotype, and that the underlying pathophysiologies in epilepsy

The object of my aggression: Sexual objectification increases physical aggression toward women.

PubMed

Vasquez, Eduardo A; Ball, Louisa; Loughnan, Steve; Pina, Afroditi

2018-01-01

Objectification involves reducing someone to a sexual object, rather than seeing them as a full person. Despite numerous theoretical claims that people are more aggressive toward the objectified, and empirical evidence that objectification is linked to high willingness to aggress, rape proclivity, and aggressive attitudes, no research has examined a causal link between objectification and physical aggression, particularly in the context of provocation. In two experiments, we examined this predicted link. In Experiment 1, using a 2 (objectification: no/yes) × 2 (provocation: no/yes) factorial between-subjects design, we investigated the effects of objectification, induced via body focus during a face-to-face interaction, and provocation on physical aggression toward a female confederate. Our results revealed a significant main effect of provocation, a marginal main effect of objectification, and a significant interaction between these variables. In the absence of a provocation, focusing on a woman's body increased aggression toward her. Experiment 2 replicated Experiment 1 using a video of a target woman instead of a face-to-face interaction. Again, our results showed a significant two-way interaction between objectification and provocation, wherein objectification increased aggression in the absence of provocation. Overall, this research indicates that objectification can lead to heightened physical aggression toward objectified women. © 2017 Wiley Periodicals, Inc.

Husbands' and Wives' Marital Adjustment, Verbal Aggression, and Physical Aggression as Longitudinal Predictors of Physical Aggression in Early Marriage

ERIC Educational Resources Information Center

Schumacher, Julie A.; Leonard, Kenneth E.

2005-01-01

Marital adjustment, verbal aggression, and physical aggression have long been associated in the marital literature, but the nature of their associations remains unclear. In this study, the authors examined these 3 constructs as risk factors for physical aggression during the first 2 years of marriage in 634 couples recruited as they applied for…

Successful Management of Aggressive Fibromatosis of the Neck: A Case Report

PubMed

Avinçsal, Özgür Mehmet; Shinomiya, Hirotaka; Otsuki, Naoki; Sasaki, Ryohei; Nibu, Ken-ichi

2018-05-29

Aggressive fibromatoses are histologically benign fibrous neoplasms originating from musculoaponeurotic structures throughout the body. They are locally invasive and erode adjacent vital structures. The head and neck region constitutes 7-25% of all extra-abdominal cases. Here, we report the case of a patient with aggressive fibromatosis in the left side of the neck. While the tumor deeply invaded the scalene muscles, the lesion was successfully treated by surgery followed by radiotherapy. The patient has been disease free for the last 7 years following treatment. Due to its unusual location in the head and neck region, aggressive fibromatosis should be considered in the differential diagnosis of invading lesions of the neck.

Influence of phenotype at diagnosis and of other potential prognostic factors on the course of inflammatory bowel disease.

PubMed

Romberg-Camps, M J L; Dagnelie, P C; Kester, A D M; Hesselink-van de Kruijs, M A M; Cilissen, M; Engels, L G J B; Van Deursen, C; Hameeteman, W H A; Wolters, F L; Russel, M G V M; Stockbrügger, R W

2009-02-01

Disease course in inflammatory bowel disease (IBD) is variable and difficult to predict. To optimize prognosis, it is of interest to identify phenotypic characteristics at disease onset and other prognostic factors that predict disease course. The aim of this study was to evaluate such factors in a population-based IBD group. IBD patients diagnosed between 1 January 1991 and 1 January 2003 were included. A follow-up questionnaire was developed and medical records were reviewed. Patients were classified according to phenotype at diagnosis and risk factors were registered. Disease severity, cumulative medication use, and "surgical" and "nonsurgical" recurrence rates were calculated as outcome parameters. In total, 476 Crohn's disease (CD), 630 ulcerative colitis (UC), and 81 indeterminate colitis (IC) patients were diagnosed. In CD (mean follow-up 7.6 years), 50% had undergone resective surgery. In UC (mean follow-up 7 years), colectomy rate was 8.3%. First year cumulative recurrence rates per 100 patient-years for CD, UC, and IC were 53, 44, and 42%, respectively. In CD, small bowel localization and stricturing disease were negative prognostic factors for surgery, as was young age. Overall recurrence rate was increased by young age and current smoking. In UC, extensive colitis increased surgical risk. In UC, older age at diagnosis initially increased recurrence risk but was subsequently protective. This population-based IBD study showed high recurrence rates in the first year. In CD, small bowel localization, stricturing disease, and young age were predictive for disease recurrence. In UC, extensive colitis and older age at diagnosis were negative prognostic predictors.

Social Aggression on Television and Its Relationship to Children's Aggression in the Classroom

ERIC Educational Resources Information Center

Martins, Nicole; Wilson, Barbara J.

2012-01-01

A survey was conducted with over 500 children in grades K-5 to examine whether exposure to socially aggressive content was related to children's use of social aggression. The results of the survey revealed a significant relationship between exposure to televised social aggression and increased social aggression at school, but only for girls and…

Cruel intentions on television and in real life: can viewing indirect aggression increase viewers' subsequent indirect aggression?

PubMed

Coyne, Sarah M; Archer, John; Eslea, Mike

2004-07-01

Numerous studies have shown that viewing violence in the media can influence an individual's subsequent aggression, but none have examined the effect of viewing indirect aggression. This study examines the immediate effect of viewing indirect and direct aggression on subsequent indirect aggression among 199 children ages 11 to 14 years. They were shown an indirect, direct, or no-aggression video and their subsequent indirect aggression was measured by negative evaluation of a confederate and responses to a vignette. Participants viewing indirect or direct aggression gave a more negative evaluation of and less money to a confederate than participants viewing no-aggression. Participants viewing indirect aggression gave less money to the confederate than those viewing direct aggression. Participants viewing indirect aggression gave more indirectly aggressive responses to an ambiguous situation and participants viewing direct aggression gave more directly aggressive responses. This study provides the first evidence that viewing indirect aggression in the media can have an immediate impact on subsequent aggression.

Glycolytic activity in breast cancer using 18F-FDG PET/CT as prognostic predictor: A molecular phenotype approach.

PubMed

Garcia Vicente, A M; Soriano Castrejón, A; Amo-Salas, M; Lopez Fidalgo, J F; Muñoz Sanchez, M M; Alvarez Cabellos, R; Espinosa Aunion, R; Muñoz Madero, V

2016-01-01

To explore the relationship between basal (18)F-FDG uptake in breast tumors and survival in patients with breast cancer (BC) using a molecular phenotype approach. This prospective and multicentre study included 193 women diagnosed with BC. All patients underwent an (18)F-FDG PET/CT prior to treatment. Maximum standardized uptake value (SUVmax) in tumor (T), lymph nodes (N), and the N/T index was obtained in all the cases. Metabolic stage was established. As regards biological prognostic parameters, tumors were classified into molecular sub-types and risk categories. Overall survival (OS) and disease free survival (DFS) were obtained. An analysis was performed on the relationship between semi-quantitative metabolic parameters with molecular phenotypes and risk categories. The effect of molecular sub-type and risk categories in prognosis was analyzed using Kaplan-Meier and univariate and multivariate tests. Statistical differences were found in both SUVT and SUVN, according to the molecular sub-types and risk classifications, with higher semi-quantitative values in more biologically aggressive tumors. No statistical differences were observed with respect to the N/T index. Kaplan-Meier analysis revealed that risk categories were significantly related to DFS and OS. In the multivariate analysis, metabolic stage and risk phenotype showed a significant association with DFS. High-risk phenotype category showed a worst prognosis with respect to the other categories with higher SUVmax in primary tumor and lymph nodes. Copyright © 2015 Elsevier España, S.L.U. and SEMNIM. All rights reserved.

Transcriptional Analysis of Aggressiveness and Heterogeneity across Grades of Astrocytomas

PubMed Central

Wang, Chunjing; Funk, Cory C.; Eddy, James A.; Price, Nathan D.

2013-01-01

Astrocytoma is the most common glioma, accounting for half of all primary brain and spinal cord tumors. Late detection and the aggressive nature of high-grade astrocytomas contribute to high mortality rates. Though many studies identify candidate biomarkers using high-throughput transcriptomic profiling to stratify grades and subtypes, few have resulted in clinically actionable results. This shortcoming can be attributed, in part, to pronounced lab effects that reduce signature robustness and varied individual gene expression among patients with the same tumor. We addressed these issues by uniformly preprocessing publicly available transcriptomic data, comprising 306 tumor samples from three astrocytoma grades (Grade 2, 3, and 4) and 30 non-tumor samples (normal brain as control tissues). Utilizing Differential Rank Conservation (DIRAC), a network-based classification approach, we examined the global and individual patterns of network regulation across tumor grades. Additionally, we applied gene-based approaches to identify genes whose expression changed consistently with increasing tumor grade and evaluated their robustness across multiple studies using statistical sampling. Applying DIRAC, we observed a global trend of greater network dysregulation with increasing tumor aggressiveness. Individual networks displaying greater differences in regulation between adjacent grades play well-known roles in calcium/PKC, EGF, and transcription signaling. Interestingly, many of the 90 individual genes found to monotonically increase or decrease with astrocytoma grade are implicated in cancer-affected processes such as calcium signaling, mitochondrial metabolism, and apoptosis. The fact that specific genes monotonically increase or decrease with increasing astrocytoma grade may reflect shared oncogenic mechanisms among phenotypically similar tumors. This work presents statistically significant results that enable better characterization of different human astrocytoma grades

Transcriptional analysis of aggressiveness and heterogeneity across grades of astrocytomas.

PubMed

Wang, Chunjing; Funk, Cory C; Eddy, James A; Price, Nathan D

2013-01-01

Astrocytoma is the most common glioma, accounting for half of all primary brain and spinal cord tumors. Late detection and the aggressive nature of high-grade astrocytomas contribute to high mortality rates. Though many studies identify candidate biomarkers using high-throughput transcriptomic profiling to stratify grades and subtypes, few have resulted in clinically actionable results. This shortcoming can be attributed, in part, to pronounced lab effects that reduce signature robustness and varied individual gene expression among patients with the same tumor. We addressed these issues by uniformly preprocessing publicly available transcriptomic data, comprising 306 tumor samples from three astrocytoma grades (Grade 2, 3, and 4) and 30 non-tumor samples (normal brain as control tissues). Utilizing Differential Rank Conservation (DIRAC), a network-based classification approach, we examined the global and individual patterns of network regulation across tumor grades. Additionally, we applied gene-based approaches to identify genes whose expression changed consistently with increasing tumor grade and evaluated their robustness across multiple studies using statistical sampling. Applying DIRAC, we observed a global trend of greater network dysregulation with increasing tumor aggressiveness. Individual networks displaying greater differences in regulation between adjacent grades play well-known roles in calcium/PKC, EGF, and transcription signaling. Interestingly, many of the 90 individual genes found to monotonically increase or decrease with astrocytoma grade are implicated in cancer-affected processes such as calcium signaling, mitochondrial metabolism, and apoptosis. The fact that specific genes monotonically increase or decrease with increasing astrocytoma grade may reflect shared oncogenic mechanisms among phenotypically similar tumors. This work presents statistically significant results that enable better characterization of different human astrocytoma grades

Genetic and phenotypic variations of inherited retinal diseases in dogs: the power of within- and across-breed studies

PubMed Central

Acland, Gregory M.

2014-01-01

Considerable clinical and molecular variations have been known in retinal blinding diseases in man and also in dogs. Different forms of retinal diseases occur in specific breed(s) caused by mutations segregating within each isolated breeding population. While molecular studies to find genes and mutations underlying retinal diseases in dogs have benefited largely from the phenotypic and genetic uniformity within a breed, within- and across-breed variations have often played a key role in elucidating the molecular basis. The increasing knowledge of phenotypic, allelic, and genetic heterogeneities in canine retinal degeneration has shown that the overall picture is rather more complicated than initially thought. Over the past 20 years, various approaches have been developed and tested to search for genes and mutations underlying genetic traits in dogs, depending on the availability of genetic tools and sample resources. Candidate gene, linkage analysis, and genome-wide association studies have so far identified 24 mutations in 18 genes underlying retinal diseases in at least 58 dog breeds. Many of these genes have been associated with retinal diseases in humans, thus providing opportunities to study the role in pathogenesis and in normal vision. Application in therapeutic interventions such as gene therapy has proven successful initially in a naturally occurring dog model followed by trials in human patients. Other genes whose human homologs have not been associated with retinal diseases are potential candidates to explain equivalent human diseases and contribute to the understanding of their function in vision. PMID:22065099

Genetic and phenotypic variations of inherited retinal diseases in dogs: the power of within- and across-breed studies.

PubMed

Miyadera, Keiko; Acland, Gregory M; Aguirre, Gustavo D

2012-02-01

Considerable clinical and molecular variations have been known in retinal blinding diseases in man and also in dogs. Different forms of retinal diseases occur in specific breed(s) caused by mutations segregating within each isolated breeding population. While molecular studies to find genes and mutations underlying retinal diseases in dogs have benefited largely from the phenotypic and genetic uniformity within a breed, within- and across-breed variations have often played a key role in elucidating the molecular basis. The increasing knowledge of phenotypic, allelic, and genetic heterogeneities in canine retinal degeneration has shown that the overall picture is rather more complicated than initially thought. Over the past 20 years, various approaches have been developed and tested to search for genes and mutations underlying genetic traits in dogs, depending on the availability of genetic tools and sample resources. Candidate gene, linkage analysis, and genome-wide association studies have so far identified 24 mutations in 18 genes underlying retinal diseases in at least 58 dog breeds. Many of these genes have been associated with retinal diseases in humans, thus providing opportunities to study the role in pathogenesis and in normal vision. Application in therapeutic interventions such as gene therapy has proven successful initially in a naturally occurring dog model followed by trials in human patients. Other genes whose human homologs have not been associated with retinal diseases are potential candidates to explain equivalent human diseases and contribute to the understanding of their function in vision.

Taste phenotype associates with cardiovascular disease risk factors via diet quality in multivariate modeling.

PubMed

Sharafi, Mastaneh; Rawal, Shristi; Fernandez, Maria Luz; Huedo-Medina, Tania B; Duffy, Valerie B

2018-05-08

Sensations from foods and beverages drive dietary choices, which in turn, affect risk of diet-related diseases. Perception of these sensation varies with environmental and genetic influences. This observational study aimed to examine associations between chemosensory phenotype, diet and cardiovascular disease (CVD) risk. Reportedly healthy women (n = 110, average age 45 ± 9 years) participated in laboratory-based measures of chemosensory phenotype (taste and smell function, propylthiouracil (PROP) bitterness) and CVD risk factors (waist circumference, blood pressure, serum lipids). Diet variables included preference and intake of sweet/high-fat foods, dietary restraint, and diet quality based on reported preference (Healthy Eating Preference Index-HEPI) and intake (Healthy Eating Index-HEI). We found that females who reported high preference yet low consumption of sweet/high-fat foods had the highest dietary restraint and depressed quinine taste function. PROP nontasters were more likely to report lower diet quality; PROP supertasters more likely to consume but not like a healthy diet. Multivariate structural models were fitted to identify predictors of CVD risk factors. Reliable latent taste (quinine taste function, PROP tasting) and smell (odor intensity) variables were identified, with taste explaining more variance in the CVD risk factors. Lower bitter taste perception was associated with elevated risk. In multivariate models, the HEPI completely mediated the taste-adiposity and taste-HDL associations and partially mediated the taste-triglyceride or taste-systolic blood pressure associations. The taste-LDL pathway was significant and direct. The HEI could not replace HEPI in adequate models. However, using a latent diet quality variable with HEPI and HEI, increased the strength of association between diet quality and adiposity or CVD risk factors. In conclusion, bitter taste phenotype was associated with CVD risk factors via diet quality

Aggressive Regimens for Multidrug-Resistant Tuberculosis Reduce Recurrence

PubMed Central

Franke, Molly F.; Appleton, Sasha C.; Mitnick, Carole D.; Furin, Jennifer J.; Bayona, Jaime; Chalco, Katiuska; Shin, Sonya; Murray, Megan; Becerra, Mercedes C.

2013-01-01

Background. Recurrent tuberculosis disease occurs within 2 years in as few as 1% and as many as 29% of individuals successfully treated for multidrug-resistant (MDR) tuberculosis. A better understanding of treatment-related factors associated with an elevated risk of recurrent tuberculosis after cure is urgently needed to optimize MDR tuberculosis therapy. Methods. We conducted a retrospective cohort study among adults successfully treated for MDR tuberculosis in Peru. We used multivariable Cox proportional hazards regression analysis to examine whether receipt of an aggressive MDR tuberculosis regimen for ≥18 months following sputum conversion from positive to negative was associated with a reduced rate of recurrent tuberculosis. Results. Among 402 patients, the median duration of follow-up was 40.5 months (interquartile range, 21.2–53.4). Receipt of an aggressive MDR tuberculosis regimen for ≥18 months following sputum conversion was associated with a lower risk of recurrent tuberculosis (hazard ratio, 0.40 [95% confidence interval, 0.17–0.96]; P = .04). A baseline diagnosis of diabetes mellitus also predicted recurrent tuberculosis (hazard ratio, 10.47 [95% confidence interval, 2.17–50.60]; P = .004). Conclusions. Individuals who received an aggressive MDR tuberculosis regimen for ≥18 months following sputum conversion experienced a lower rate of recurrence after cure. Efforts to ensure that an aggressive regimen is accessible to all patients with MDR tuberculosis, such as minimization of sequential ineffective regimens, expanded drug access, and development of new MDR tuberculosis compounds, are critical to reducing tuberculosis recurrence in this population. Patients with diabetes mellitus should be carefully managed during initial treatment and followed closely for recurrent disease. PMID:23223591

Thalamic modulation of aggression.

PubMed

Andy, O J; Giurintano, L; Giurintano, S; McDonald, T

1975-01-01

This experiment extends Pavlov's method of contrasts for 8 components of aggression were quantitatively evaluated in 11 freely moving adult cats. Aggression was elicited from the perifornix septohypothalamic areas by a series of progressively increasing and decreasing stimulation parameters. Three levels of thalamic stimulation (low, medium, and high) were combined with the perifornix stimulations. High level thalamic stimulation tended to facilitate the aggressive response elicited by low level perifornix stimulation. Thalamic lesions attenuated the aggression response, especially those elicited during high level perifornix stimulation. It was suggested that within the hypothalamic induced aggression circuitry the center median nucleus modulates the excitatory state of the system. The discussion concerns anatomic and physiologic pathways through which the center median nucleus may modulate the sensory, motor, and affective-autonomic subsystems into a well integrated aggressive state. These experimental findings are supported by the clinically established treatment of aggression by stereotaxic lesions placed in the center median nucleus.

Tolerating increases in the serum creatinine following aggressive treatment of chronic kidney disease, hypertension and proteinuria: pre-renal success.

PubMed

Hirsch, Sheldon; Hirsch, Jackie; Bhatt, Udayan; Rovin, Brad H

2012-01-01

Blood pressure (BP) reduction in patients with chronic kidney disease (CKD), particularly with a renin-angiotensin system inhibitor (RASI), commonly leads to an initial decrease in glomerular filtration rate. The current clinical guideline, based on studies with single RASIs, is to tolerate an increase in the serum creatinine only up to 30%. This guideline has aptly guided CKD care for over a decade, but should be updated in the contemporary context of more aggressive RASI and diuretic use. This study is a retrospective review of 48 mostly African-American patients with CKD treated with multiple and/or high-dose renin-angiotensin system (RAS) inhibition and diuretics, targeting both low BP and reduction of urine protein. RASI was not reduced in response to initial increases in serum creatinine greater than 30%. A clinically well-tolerated increase in serum creatinine over 30% during the first year occurred in 41% of the patients. Treatment was unaltered, and target goals for BP and urine protein were typically achieved. After the point of maximal serum creatinine in the first year, these patients had minimal progression of disease over the next 6 years, with a long-term estimated glomerular filtration rate slope of only -0.52 ml/min/year/1.73 m(2). Only 25% progressed to end-stage renal disease or death. The 30% limitation to initial increases in the serum creatinine still pertains for single RASI at usual doses. However, favorable long-term outcomes suggest that initial increases over 30% should be tolerated in the context of dual goal-directed, more aggressive RASI and diuretic use. Copyright © 2012 S. Karger AG, Basel.

Aggression in children with behavioural/emotional difficulties: seeing aggression on television and video games.

PubMed

Mitrofan, Oana; Paul, Moli; Weich, Scott; Spencer, Nicholas

2014-11-18

Mental health professionals are often asked to give advice about managing children's aggression. Good quality evidence on contributory environmental factors such as seeing aggression on television and in video games is relatively lacking, although societal and professional concerns are high. This study investigated possible associations between seeing aggression in such media and the aggressive behaviour of children attending specialist outpatient child and adolescent mental health services (CAMHS). In this mixed methods study, forty-seven British children aged 7-11 years with behavioural/emotional difficulties attending CAMHS and their carers participated in a survey; twenty purposively-selected children and a parent/carer of theirs participated in a qualitative study, involving semi-structured interviews, analysed using the Framework Analysis Approach; findings were integrated. Children attending CAMHS exhibit clinically significant aggression, of varying types and frequency. They see aggression in multiple real and virtual settings. Verbal aggression was often seen, frequently exhibited and strongly associated with poor peer relationships and low prosocial behaviour. Children did not think seeing aggression influences their own behaviour but believed it influences others. Carers regarded aggression as resulting from a combination of inner and environmental factors and seeing aggression in real-life as having more impact than television/video games. There is yet no definitive evidence for or against a direct relationship between aggression seen in the media and aggression in children with behavioural/emotional difficulties. Future research should take an ecological perspective, investigating individual, developmental and environmental factors. Carers, professional organisations and policy makers should address aggression seen in all relevant area of children's lives, primarily real-life and secondly virtual environments.

Surgical care of the pediatric Crohn's disease patient.

PubMed

Stewart, Dylan

2017-12-01

Despite the significant advances in the medical management of inflammatory bowel disease over the last decade, surgery continues to play a major role in the management of pediatric Crohn's disease (CD). While adult and pediatric Crohn's disease may share many clinical characteristics, pediatric Crohn's patients often have a more aggressive phenotype, and the operative care given by the pediatric surgeon to the newly diagnosed Crohn's patient is very different in nature to the surgical needs of adult patients after decades of disease progression. Children also have the unique surgical indication of growth failure to consider in the overall clinical decision making. While surgery is never curative in CD, it has the ability to transform the disease process in children, and appropriately timed operations may have tremendous impact on a child's physical and mental maturation. This monograph aims to address the surgical care of Crohn's disease in general, with a specific emphasis on the surgical treatment of small intestinal and ileocecal involvement. Copyright © 2017 Elsevier Inc. All rights reserved.