Fructose-Containing Sugars and Cardiovascular Disease12

PubMed Central

Rippe, James M; Angelopoulos, Theodore J

2015-01-01

Cardiovascular disease (CVD) is the single largest cause of mortality in the United States and worldwide. Numerous risk factors have been identified for CVD, including a number of nutritional factors. Recently, attention has been focused on fructose-containing sugars and their putative link to risk factors for CVD. In this review, we focus on recent studies related to sugar consumption and cardiovascular risk factors including lipids, blood pressure, obesity, insulin resistance, diabetes, and the metabolic syndrome. We then examine the scientific basis for competing recommendations for sugar intake. We conclude that although it appears prudent to avoid excessive consumption of fructose-containing sugars, levels within the normal range of human consumption are not uniquely related to CVD risk factors with the exception of triglycerides, which may rise when simple sugars exceed 20% of energy per day, particularly in hypercaloric settings. PMID:26178027

Risk profiles of Alzheimer disease.

PubMed

Bilbul, Melanie; Schipper, Hyman M

2011-07-01

Alzheimer disease (AD) is a dementing, neurodegenerative disorder that affects approximately 500,000 Canadians and its prevalence is expected to double over the next 30 years. Although several medications may temporarily augment cognitive abilities in AD, there presently exists no proven method to avoid the inevitable clinical deterioration in this devastating condition. The delineation of risk factors for the development of AD offers hope for the advent of effective prevention or interventions that might retard the onset of symptoms. In this article, we provide a comprehensive review of midlife risk factors implicated in the etiopathogenesis of sporadic AD. Although some risk factors are heritable and largely beyond our control, others are determined by lifestyle or environment and are potentially modifiable. In a companion paper, we introduce the concept of an Alzheimer Risk Assessment Clinic for ascertainment and mitigation of these and other putative dementia risk factors in middle-aged adults.

Genome-Wide Association Study of d-Amphetamine Response in Healthy Volunteers Identifies Putative Associations, Including Cadherin 13 (CDH13)

PubMed Central

Wardle, Margaret C.; Sokoloff, Greta; Stephens, Matthew; de Wit, Harriet; Palmer, Abraham A.

2012-01-01

Both the subjective response to d-amphetamine and the risk for amphetamine addiction are known to be heritable traits. Because subjective responses to drugs may predict drug addiction, identifying alleles that influence acute response may also provide insight into the genetic risk factors for drug abuse. We performed a Genome Wide Association Study (GWAS) for the subjective responses to amphetamine in 381 non-drug abusing healthy volunteers. Responses to amphetamine were measured using a double-blind, placebo-controlled, within-subjects design. We used sparse factor analysis to reduce the dimensionality of the data to ten factors. We identified several putative associations; the strongest was between a positive subjective drug-response factor and a SNP (rs3784943) in the 8th intron of cadherin 13 (CDH13; P = 4.58×10−8), a gene previously associated with a number of psychiatric traits including methamphetamine dependence. Additionally, we observed a putative association between a factor representing the degree of positive affect at baseline and a SNP (rs472402) in the 1st intron of steroid-5-alpha-reductase-α-polypeptide-1 (SRD5A1; P = 2.53×10−7), a gene whose protein product catalyzes the rate-limiting step in synthesis of the neurosteroid allopregnanolone. This SNP belongs to an LD-block that has been previously associated with the expression of SRD5A1 and differences in SRD5A1 enzymatic activity. The purpose of this study was to begin to explore the genetic basis of subjective responses to stimulant drugs using a GWAS approach in a modestly sized sample. Our approach provides a case study for analysis of high-dimensional intermediate pharmacogenomic phenotypes, which may be more tractable than clinical diagnoses. PMID:22952603

Genome-wide association study of d-amphetamine response in healthy volunteers identifies putative associations, including cadherin 13 (CDH13).

PubMed

Hart, Amy B; Engelhardt, Barbara E; Wardle, Margaret C; Sokoloff, Greta; Stephens, Matthew; de Wit, Harriet; Palmer, Abraham A

2012-01-01

Both the subjective response to d-amphetamine and the risk for amphetamine addiction are known to be heritable traits. Because subjective responses to drugs may predict drug addiction, identifying alleles that influence acute response may also provide insight into the genetic risk factors for drug abuse. We performed a Genome Wide Association Study (GWAS) for the subjective responses to amphetamine in 381 non-drug abusing healthy volunteers. Responses to amphetamine were measured using a double-blind, placebo-controlled, within-subjects design. We used sparse factor analysis to reduce the dimensionality of the data to ten factors. We identified several putative associations; the strongest was between a positive subjective drug-response factor and a SNP (rs3784943) in the 8(th) intron of cadherin 13 (CDH13; P = 4.58×10(-8)), a gene previously associated with a number of psychiatric traits including methamphetamine dependence. Additionally, we observed a putative association between a factor representing the degree of positive affect at baseline and a SNP (rs472402) in the 1(st) intron of steroid-5-alpha-reductase-α-polypeptide-1 (SRD5A1; P = 2.53×10(-7)), a gene whose protein product catalyzes the rate-limiting step in synthesis of the neurosteroid allopregnanolone. This SNP belongs to an LD-block that has been previously associated with the expression of SRD5A1 and differences in SRD5A1 enzymatic activity. The purpose of this study was to begin to explore the genetic basis of subjective responses to stimulant drugs using a GWAS approach in a modestly sized sample. Our approach provides a case study for analysis of high-dimensional intermediate pharmacogenomic phenotypes, which may be more tractable than clinical diagnoses.

Practitioner Review: What have we learnt about the causes of ADHD?

PubMed Central

Thapar, Anita; Cooper, Miriam; Eyre, Olga; Langley, Kate

2013-01-01

Background Attention deficit hyperactivity disorder (ADHD) and its possible causes still attract controversy. Genes, pre and perinatal risks, psychosocial factors and environmental toxins have all been considered as potential risk factors. Method This review (focussing on literature published since 1997, selected from a search of PubMed) critically considers putative risk factors with a focus on genetics and selected environmental risks, examines their relationships with ADHD and discusses the likelihood that these risks are causal as well as some of the main implications. Results No single risk factor explains ADHD. Both inherited and noninherited factors contribute and their effects are interdependent. ADHD is familial and heritable. Research into the inherited and molecular genetic contributions to ADHD suggest an important overlap with other neurodevelopmental problems, notably, autism spectrum disorders. Having a biological relative with ADHD, large, rare copy number variants, some small effect size candidate gene variants, extreme early adversity, pre and postnatal exposure to lead and low birth weight/prematurity have been most consistently found as risk factors, but none are yet known to be definitely causal. There is a large literature documenting associations between ADHD and a wide variety of putative environmental risks that can, at present, only be regarded as correlates. Findings from research designs that go beyond simply testing for association are beginning to contest the robustness of some environmental exposures previously thought to be ADHD risk factors. Conclusions The genetic risks implicated in ADHD generally tend to have small effect sizes or be rare and often increase risk of many other types of psychopathology. Thus, they cannot be used for prediction, genetic testing or diagnostic purposes beyond what is predicted by a family history. There is a need to consider the possibility of parents and siblings being similarly affected and how this might impact on engagement with families, influence interventions and require integration with adult services. Genetic contributions to disorder do not necessarily mean that medications are the treatment of choice. We also consider how findings might influence the conceptualisation of ADHD, public health policy implications and why it is unhelpful and incorrect to dichotomise genetic/biological and environmental explanations. It is essential that practitioners can interpret genetic and aetiological research findings and impart informed explanations to families. PMID:22963644

A multinational study to compare prevalence of atopic dermatitis in the first year of life.

PubMed

Draaisma, Eelco; Garcia-Marcos, Luis; Mallol, Javier; Solé, Dirceu; Pérez-Fernández, Virginia; Brand, Paul L P

2015-06-01

Atopic dermatitis (AD) is common in childhood, with peak prevalence in early childhood. However, international comparisons of prevalence have focused on older children. We analysed differences in prevalence rates of AD and the associations with putative risk and protective factors, among infants in two European and two Central American countries. In 1-yr old infants participating in the International Study of Wheezing in Infants (EISL), prevalence of AD and putative risk and protective factors were assessed by a questionnaire applied to parents. For each risk/protective factor summary, odds ratios with 95% confidence intervals were calculated by means of random effects meta-analysis. Data from 9803 infants were analysed. AD prevalence varied from 10.6% (Valencia, Spain) to 28.2% (San Pedro Sula, Honduras). Average AD prevalences were lower in Europe (14.2%) than in Central America (18.2%, p < 0.01). Consistent with older children, presence of siblings decreased (OR 0.82 [0.72-0.94]), whereas family history of asthma (OR 1.32 [1.10-1.59]), rhinitis (OR 1.33 [1.14-1.54]) and atopic dermatitis (OR 2.40 [1.89-3.05]) increased the risk of infantile AD. However, gender, family size, breastfeeding and socio-economic status were not associated with AD prevalence. This study shows almost threefold differences in the prevalence of AD in infancy between countries. Risk and protective factors involved in the expression of infantile AD differ from those in older children, possibly suggesting a different pathophysiology. There is a need for additional international epidemiological surveys on AD in young children, the peak prevalence age of this condition. © 2015 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

Informing aetiologic research priorities for squamous cell oesophageal cancer in Africa: A review of setting-specific exposures to known and putative risk factors

PubMed Central

McCormack, V; Menya, D; Munishi, MO; Dzamalala, C; Gasmelseed, N; Roux, M Leon; Assefa, M; Odipo, O; Watts, M; Mwasamwaja, AO; Mmbaga, BT; Murphy, G; Abnet, CC; Dawsey, SM; Schüz, J

2018-01-01

Oesophageal squamous cell carcinoma (ESCC) is one of the most common cancers in most Eastern and Southern African countries, but its aetiology has been understudied to date. To inform its research agenda, we undertook a review to identify, of the ESCC risk factors that have been established or strongly suggested worldwide, those with a high prevalence or high exposure levels in any ESCC-affected African setting and the sources thereof. We found that for almost all ESCC risk factors known to date, including tobacco, alcohol, hot beverage consumption, nitrosamines and both inhaled and ingested PAHs, there is evidence of population groups with raised exposures, the sources of which vary greatly between cultures across the ESCC corridor. Research encompassing these risk factors is warranted and is likely to identify primary prevention strategies. PMID:27466161

The Cycle of Schizoaffective Disorder, Cognitive Ability, Alcoholism, and Suicidality

ERIC Educational Resources Information Center

Goldstein, Gerald; Haas, Gretchen L.; Pakrashi, Manish; Novero, Ada M.; Luther, James F.

2006-01-01

In this study we investigated the putative role of cognitive dysfunction, diagnosis (schizoaffective versus schizophrenia disorder), and alcoholism as risk factors for suicidal behavior among individuals with DSM-IV schizophrenia or schizoaffective disorders. Subjects received cognitive tests and medical records were reviewed for evidence of a…

Frequency of viral infections and environmental factors in multiple sclerosis.

PubMed

Eftekharian, Mohammad Mahdi; Ghannad, Masoud Sabouri; Taheri, Mohammad; Roshanaei, Ghodratollah; Mazdeh, Mehrdokht; Musavi, Mehrnoosh; Hormoz, Mona Bahmani

2016-06-08

Multiple sclerosis (MS) is a complicated disease which occurs due to relationship between genes and environmental factors that causes tissue damage by autoimmune mechanisms.We investigated and illustrated the hypotheses correlated to the evidence of several putative environmental risk factors for MS onset and progression in this part of Iran. Univariate logistic regression was used to detect the effects of environmental factors on the risk of MS. Data were analyzed using SPSS version 16. The childhood history of patients with rubella, measles and chickenpox increased the risk of MS significantly. Moreover, low consumption of dairy products, avoidance of seafood consumption, cigarette smoking and exposure to tobacco smoke, stress, anxiety disorders, depress and disturbing thoughts, negative and disturbing thoughts, developing a sudden shock upon hearing bad news, having obsessive-compulsive and being depressed increased the risk of MS significantly. The results of the current research partially solved the puzzling question of complex interplay between environmental factors and MS disease in this part of Iran. Incorporating these factors enables more powerful and accurate detection of novel risk factors with diagnostic and prognostic methods.

Level of education and multiple sclerosis risk after adjustment for known risk factors: The EnvIMS study.

PubMed

Bjørnevik, Kjetil; Riise, Trond; Cortese, Marianna; Holmøy, Trygve; Kampman, Margitta T; Magalhaes, Sandra; Myhr, Kjell-Morten; Wolfson, Christina; Pugliatti, Maura

2016-01-01

Several recent studies have found a higher risk of multiple sclerosis (MS) among people with a low level of education. This has been suggested to reflect an effect of smoking and lower vitamin D status in the social class associated with lower levels of education. The objective of this paper is to investigate the association between level of education and MS risk adjusting for the known risk factors smoking, infectious mononucleosis, indicators of vitamin D levels and body size. Within the case-control study on Environmental Factors In MS (EnvIMS), 953 MS patients and 1717 healthy controls from Norway reported educational level and history of exposure to putative environmental risk factors. Higher level of education were associated with decreased MS risk (p trend = 0.001) with an OR of 0.53 (95% CI 0.41-0.68) when comparing those with the highest and lowest level of education. This association was only moderately reduced after adjusting for known risk factors (OR 0.61, 95% CI 0.44-0.83). The estimates remained similar when cases with disease onset before age 28 were excluded. These findings suggest that factors related to lower socioeconomic status other than established risk factors are associated with MS risk. © The Author(s), 2015.

Level of education and multiple sclerosis risk after adjustment for known risk factors: The EnvIMS study

PubMed Central

Bjørnevik, Kjetil; Riise, Trond; Cortese, Marianna; Holmøy, Trygve; Kampman, Margitta T; Magalhaes, Sandra; Myhr, Kjell-Morten; Wolfson, Christina; Pugliatti, Maura

2016-01-01

Background: Several recent studies have found a higher risk of multiple sclerosis (MS) among people with a low level of education. This has been suggested to reflect an effect of smoking and lower vitamin D status in the social class associated with lower levels of education. Objective: The objective of this paper is to investigate the association between level of education and MS risk adjusting for the known risk factors smoking, infectious mononucleosis, indicators of vitamin D levels and body size. Methods: Within the case-control study on Environmental Factors In MS (EnvIMS), 953 MS patients and 1717 healthy controls from Norway reported educational level and history of exposure to putative environmental risk factors. Results: Higher level of education were associated with decreased MS risk (p trend = 0.001) with an OR of 0.53 (95% CI 0.41–0.68) when comparing those with the highest and lowest level of education. This association was only moderately reduced after adjusting for known risk factors (OR 0.61, 95% CI 0.44–0.83). The estimates remained similar when cases with disease onset before age 28 were excluded. Conclusion: These findings suggest that factors related to lower socioeconomic status other than established risk factors are associated with MS risk. PMID:26014605

Toxoplasma gondii in sheep and goats: seroprevalence and potential risk factors under dairy husbandry practices.

PubMed

Tzanidakis, Nikolaos; Maksimov, Pavlo; Conraths, Franz J; Kiossis, Evaggelos; Brozos, Christos; Sotiraki, Smaragda; Schares, Gereon

2012-12-21

Sheep and goats are highly susceptible for infections with Toxoplasma gondii and may play a major role in the transmission of toxoplasmosis to humans. The aim of this study was to obtain up-to-date data on T. gondii infection in small ruminants and to identify putative risk factors in sheep and goats reared under dairy husbandry systems most commonly applied in Greece. To this end, ELISA tests were established for the examination of sheep and goat sera based on the use of TgSAG1, a major surface antigen of T. gondii tachyzoites. Serum samples from 2-4 years old small ruminants, 1501 from sheep and 541 from goats were examined. These samples had been collected on 69 farms in a mountainous and in a costal environment of Northern Greece from September 2008 to January 2009. In addition to farms containing only sheep (n=28) and farms containing only goats (n=9) also mixed farms with both animal species (n=32) were sampled. A standardized questionnaire was used to obtain information on putative risk factors. Sheep showed a higher seroprevalence (48.6% [729/1501]) for T. gondii than goats (30.7% [166/541]). Univariate multi-level modelling assuming random effects by the factor "farm" revealed that goats were statistically significantly less often seropositive than sheep (OR 0.475 [95% CI: 0.318-0.707]). No statistically significant regional differences in seroprevalence were observed. Risk factor analysis using univariate multi-level modelling revealed that sheep and goats that were kept under intensive (OR 4.30 [95% CI: 1.39-13.27]) or semi-intensive (OR 5.35 [95% CI: 2.33-12.28]) conditions had significantly higher odds of being seropositive. Further significant risk factors were "feeding concentrate" (OR 3.88 [95% CI: 1.81-8.29]) and providing "water from the public supply" (OR 1.67 [95% CI: 4.56-12.39]) to small ruminants. Copyright © 2012 Elsevier B.V. All rights reserved.

High genetic-risk individuals benefit less from resistance exercise intervention

PubMed Central

Klimentidis, Yann C.; Bea, Jennifer W.; Lohman, Timothy; Hsieh, Pei-Shan; Going, Scott; Chen, Zhao

2015-01-01

Background/Objectives Genetic factors play an important role in body mass index (BMI) variation, and also likely play a role in the weight-loss and body composition response to physical activity/exercise. With the recent identification of BMI–associated genetic variants, it is possible to investigate the interaction of these genetic factors with exercise on body composition outcomes. Subjects/Methods In a block-randomized clinical trial of resistance exercise among women (n=148), we examined whether the putative effect of exercise on weight and DXA-derived body composition measurements differs according to genetic risk for obesity. Approximately one-half of the sample was randomized to an intervention consisting of a supervised, intensive, resistance exercise program, lasting one year. Genetic risk for obesity was defined as a genetic risk score (GRS) comprised of 21 SNPs known to be associated with normal BMI variation. We examined the interaction of exercise intervention and the GRS on anthropometric and body composition measurements after one year of the exercise intervention. Results We found statistically significant interactions for body weight (p=0.01), body fat (p=0.01), body fat % (p=0.02), and abdominal fat (p=0.02), whereby the putative effect of exercise is greater among those with a lower level of genetic risk for obesity. No single SNP appears to be a major driver of these interactions. Conclusions The weight-loss response to resistance exercise, including changes in body composition, differs according to an individual’s genetic risk for obesity. PMID:25924711

Analysis of 60 reported glioma risk SNPs replicates published GWAS findings but fails to replicate associations from published candidate-gene studies.

PubMed

Walsh, Kyle M; Anderson, Erik; Hansen, Helen M; Decker, Paul A; Kosel, Matt L; Kollmeyer, Thomas; Rice, Terri; Zheng, Shichun; Xiao, Yuanyuan; Chang, Jeffrey S; McCoy, Lucie S; Bracci, Paige M; Wiemels, Joe L; Pico, Alexander R; Smirnov, Ivan; Lachance, Daniel H; Sicotte, Hugues; Eckel-Passow, Jeanette E; Wiencke, John K; Jenkins, Robert B; Wrensch, Margaret R

2013-02-01

Genomewide association studies (GWAS) and candidate-gene studies have implicated single-nucleotide polymorphisms (SNPs) in at least 45 different genes as putative glioma risk factors. Attempts to validate these associations have yielded variable results and few genetic risk factors have been consistently replicated. We conducted a case-control study of Caucasian glioma cases and controls from the University of California San Francisco (810 cases, 512 controls) and the Mayo Clinic (852 cases, 789 controls) in an attempt to replicate previously reported genetic risk factors for glioma. Sixty SNPs selected from the literature (eight from GWAS and 52 from candidate-gene studies) were successfully genotyped on an Illumina custom genotyping panel. Eight SNPs in/near seven different genes (TERT, EGFR, CCDC26, CDKN2A, PHLDB1, RTEL1, TP53) were significantly associated with glioma risk in the combined dataset (P < 0.05), with all associations in the same direction as in previous reports. Several SNP associations showed considerable differences across histologic subtype. All eight successfully replicated associations were first identified by GWAS, although none of the putative risk SNPs from candidate-gene studies was associated in the full case-control sample (all P values > 0.05). Although several confirmed associations are located near genes long known to be involved in gliomagenesis (e.g., EGFR, CDKN2A, TP53), these associations were first discovered by the GWAS approach and are in noncoding regions. These results highlight that the deficiencies of the candidate-gene approach lay in selecting both appropriate genes and relevant SNPs within these genes. © 2012 WILEY PERIODICALS, INC.

Brain Protection and Cognitive Function: Cocoa Flavonoids as Nutraceuticals.

PubMed

Grassi, Davide; Ferri, Claudio; Desideri, Giovambattista

2016-01-01

Cognitive decline and dementia are major public health social problems, suggesting the specific need to provide research into risk factors for cognitive decline as priority topic. Increasing evidence supports the hypothesis that oxidative stress and neuroinflammation might play a crucial role in the pathophysiology of cognitive decline. Further, cognitive dysfunction and dementia in Alzheimer's disease as well as in vascular dementia seem to be also the consequence of cerebral blood flow decrease and deregulation, also suggesting a putative pathophysiological convergence of mechanisms between atherosclerosis and Alzheimer's disease. In keeping with this, a growing interest has been addressed to flavonoids as potential nutraceuticals with neuroprotective effects. Of interest, cocoa beans have been described as a fundamental source of anti-oxidant flavonoids with the flavan-3-ols and their derivatives being present in high concentrations. Therefore, recent studies specifically focused on the favorable effects of flavonoid-rich cocoa and chocolate on cerebrovascular risk factors and cognitive function. Aim of this review is to summarize new findings concerning the cocoa effects on cognitive function, particularly focusing on some putative mechanisms of vascular and antioxidant action involved in preventing dementia.

Developmental vitamin D deficiency and autism: Putative pathogenic mechanisms.

PubMed

Ali, Asad; Cui, Xiaoying; Eyles, Darryl

2018-01-01

Autism is a neurodevelopmental disease that presents in early life. Despite a considerable amount of studies, the neurobiological mechanisms underlying autism remain obscure. Both genetic and environmental factors are involved in the development of autism. Vitamin D deficiency is emerging as a consistently reported risk factor in children. One reason for the prominence now being given to this risk factor is that it would appear to interact with several other epidemiological risk factors for autism. Vitamin D is an active neurosteroid and plays crucial neuroprotective roles in the developing brain. It has important roles in cell proliferation and differentiation, immunomodulation, regulation of neurotransmission and steroidogenesis. Animal studies have suggested that transient prenatal vitamin D deficiency is associated with altered brain development. Here we review the potential neurobiological mechanisms linking prenatal vitamin D deficiency and autism and also discuss what future research targets must now be addressed. Crown Copyright © 2017. Published by Elsevier Ltd. All rights reserved.

CHOLESTEROL-RELATED GENETIC RISK SCORES ARE ASSOCIATED WITH HYPOMETABOLISM IN ALZHEIMER’S-AFFECTED BRAIN REGIONS

PubMed Central

Reiman, Eric M.; Chen, Kewei; Caselli, Richard J.; Alexander, Gene E.; Bandy, Daniel; Adamson, Jennifer L.; Lee, Wendy; Cannon, Ashley; Stephan, Elizabeth A.; Stephan, Dietrich A.; Papassotiropoulos, Andreas

2008-01-01

We recently implicated a cluster of nine single nucleotide polymorphisms from seven cholesterol-related genes in the risk of Alzheimer’s disease (AD) in a European cohort, and we proposed calculating an aggregate cholesterol-related genetic score (CREGS) to characterize a person’s risk. In a separate study, we found that apolipoprotein E (APOE) ε4 gene dose, an established AD risk factor, was correlated with fluorodeoxyglucose (FDG) positron emission tomography (PET) measurements of hypometabolism in AD-affected brain regions in a cognitively normal American cohort, and we proposed using PET as a presymptomatic endophenotype to help assess putative modifiers of AD risk. Thus, the objective in the present study is to determine whether CREGS is related to PET measurements of hypometabolism in AD-affected brain regions. DNA and PET data from 141 cognitively normal late middle-aged APOE ε4 homozygotes, heterozygotes and non-carriers were analyzed to evaluate the relationship between CREGS and regional PET measurements. Cholesterol-related genetic risk scores were associated with hypometabolism in AD-affected brain regions, even when controlling for the effects of APOE ε4 gene dose. The results support the role of cholesterol-related genes in the predisposition to AD, and support the value of neuroimaging in the presymptomatic assessment of putative modifiers of AD risk. PMID:18280754

Genetic susceptibility to lung cancer—light at the end of the tunnel?

PubMed Central

Christiani, David C.

2013-01-01

Lung cancer is one of the most common and deadliest cancers in the world. The major socio-environmental risk factor involved in the development of lung cancer is cigarette smoking. Additionally, there are multiple genetic factors, which may also play a role in lung cancer risk. Early work focused on the presence of relatively prevalent but low-penetrance alterations in candidate genes leading to increased risk of lung cancer. Development of new technologies such as genomic profiling and genome-wide association studies has been helpful in the detection of new genetic variants likely involved in lung cancer risk. In this review, we discuss the role of multiple genetic variants and review their putative role in the risk of lung cancer. Identifying genetic biomarkers and patterns of genetic risk may be useful in the earlier detection and treatment of lung cancer patients. PMID:23349013

Prevalence and putative risk markers of challenging behavior in students with intellectual disabilities.

PubMed

Dworschak, Wolfgang; Ratz, Christoph; Wagner, Michael

2016-11-01

Numerous studies have reported a high prevalence of challenging behavior among students with intellectual disabilities (ID). They discuss different putative risk markers as well as their influence on the occurrence of challenging behavior. The study investigates the prevalence of challenging behavior and evaluates in terms of a replication study well-known putative risk markers among a representative sample of students with ID (N=1629) in Bavaria, one of the largest regions in Germany. The research is based on a modified version of the Developmental Behavior Checklist (DBC). Findings indicate a prevalence rate of 52% for challenging behavior. The following putative risk markers are associated with challenging behavior: intense need for care, male gender, lack of communication skills, and residential setting. These risk markers explain 8.4% of the variance concerning challenging behavior. These results reveal that challenging behavior either is to a large extent determined by situations and interactions between individuals and environment and cannot be explained by the measured individual and social risk markers alone, or it is determined by further risk markers that were not measured. Copyright © 2016 Elsevier Ltd. All rights reserved.

Differential Susceptibility to Effects of the Home Environment on Motor Developmental Outcomes of Preschool Children: Low Birthweight Status as a Susceptibility Factor

ERIC Educational Resources Information Center

Wu, Jennifer Chun-Li; Chiang, Tung-liang

2016-01-01

Low birthweight (LBW) children tend to have higher risks of developmental problems. According to differential susceptibility hypothesis, these putatively vulnerable children may also disproportionately benefit from positive environmental exposure. This study aimed to examine whether LBW status moderates home environmental influences on…

Poverty and Behavior Problems during Early Childhood: The Mediating Role of Maternal Depression Symptoms and Parenting

ERIC Educational Resources Information Center

Mazza, Julia Rachel; Pingault, Jean-Baptiste; Booij, Linda; Boivin, Michel; Tremblay, Richard; Lambert, Jean; Zunzunegui, Maria Victoria; Côté, Sylvana

2017-01-01

Poverty is a well-established risk factor for behavior problems, yet our understanding of putative family mediators during early childhood (i.e., before age 5 years) is limited. The present study investigated whether the association between poverty and behavior problems during early childhood is mediated simultaneously by perceived parenting,…

Etiological aspect of left-handedness in adolescents.

PubMed

Dragović, Milan; Milenković, Sanja; Kocijancić, Dusica; Zlatko, Sram

2013-01-01

Lateralization of brain functions such as language and manual dominance (hand preferences and fine motor control) are most likely under genetic control. However, this does not preclude the effect of various environmental factors on functional brain lateralization. A strong association of non-right-handedness (left- and mixed-handedness) with various neurodevelopmental conditions (e.g. schizophrenia, autism, Rett syndrome) implies that in some cases, non-right-handedness may be acquired rather than inherited (i.e., pathologically determined). The aim of the study was: (a) re-investigation of several known risk factors for left-handedness (age of mother and/or father, twin pregnancies, and birth order), and (b) examination of hitherto uninvestigated factors (type of birth, Apgar score, maternal smoking during pregnancy). Putative, causative environmental agents for this shift in manual distributions are explored in a sample of 1031 high school students (404 males and 627 females) from Belgrade. Both pre-existing (age of parents, twin pregnancy, and birth order) and new (Apgar score, maternal smoking, type of birth) putative agents are examined. We found that maternal smoking and low Apgar score (2-6) can significantly increase risk for left-handedness (p=0.046 and p=0.042, respectively).The remaining factors showed no significant association with left-handedness in adolescents. Our study clearly demonstrates that left-handedness may be related to maternal smoking during pregnancy and a low Apgar score on birth.

Aspergillus otitis in small animals--a retrospective study of 17 cases.

PubMed

Goodale, Elizabeth C; Outerbridge, Catherine A; White, Stephen D

2016-02-01

Aspergillus spp. are saprophytic opportunistic fungal organisms and are a common cause of otomycosis in humans. Although there have been case reports of Aspergillus otitis externa in dogs, to the best of the authors' knowledge, this is the first retrospective case series describing Aspergillus otitis in dogs and cats. To characterize signalment, putative risk factors, treatments and outcomes of a case series of dogs and cats with Aspergillus otitis. Eight dogs and nine cats diagnosed with Aspergillus otitis. A retrospective review of medical records from 1989 to 2014 identified animals diagnosed with Aspergillus otitis based on culture. All dogs weighed greater than 23 kg. The most common putative risk factors identified in this study were concurrent diseases, therapy causing immunosuppression or a history of an otic foreign body. Aspergillus otitis was unilateral in all study dogs and most cats. Concurrent otitis media was confirmed in three dogs and one cat, and suspected in two additional cats. Aspergillus fumigatus was the most common isolate overall and was the dominant isolate in cats. Aspergillus niger and A. terreus were more commonly isolated from dogs. Animals received various topical and systemic antifungal medications; however, otic lavage under anaesthesia and/or surgical intervention increased the likelihood of resolution of the fungal infection. Aspergillus otitis is uncommon, typically seen as unilateral otitis externa in cats and larger breed dogs with possible risk factors that include immunosuppression and otic foreign bodies; previous antibiotic usage was common. © 2015 ESVD and ACVD.

Current Understanding of Lifestyle and Environmental Factors and Risk of Non-Hodgkin Lymphoma: An Epidemiological Update

PubMed Central

Bassig, Bryan A.; Lan, Qing; Rothman, Nathaniel; Zhang, Yawei; Zheng, Tongzhang

2012-01-01

The incidence rates of non-Hodgkin lymphoma (NHL) have steadily increased over the last several decades in the United States, and the temporal trends in incidence can only be partially explained by the HIV epidemic. In 1992, an international workshop sponsored by the United States National Cancer Institute concluded that there was an “emerging epidemic” of NHL and emphasized the need to investigate the factors responsible for the increasing incidence of this disease. Over the past two decades, numerous epidemiological studies have examined the risk factors for NHL, particularly for putative environmental and lifestyle risk factors, and international consortia have been established in order to investigate rare exposures and NHL subtype-specific associations. While few consistent risk factors for NHL aside from immunosuppression and certain infectious agents have emerged, suggestive associations with several lifestyle and environmental factors have been reported in epidemiologic studies. Further, increasing evidence has suggested that the effects of these and other exposures may be limited to or stronger for particular NHL subtypes. This paper examines the progress that has been made over the last twenty years in elucidating the etiology of NHL, with a primary emphasis on lifestyle factors and environmental exposures. PMID:23008714

Environmental Risk Factors and Type 1 Diabetes: Past, Present, and Future.

PubMed

Butalia, Sonia; Kaplan, Gilaad G; Khokhar, Bushra; Rabi, Doreen M

2016-12-01

Type 1 diabetes is an autoimmune condition that results from the destruction of the insulin-producing beta cells of the pancreas. The excess morbidity and mortality resulting from its complications, coupled with its increasing incidence, emphasize the importance of better understanding the causes of this condition. Over the past several decades, a substantive amount of work has been done and, although many advances have occurred in identifying disease-susceptibility genes, there has been a lag in understanding the environmental triggers. Several putative environmental risk factors have been proposed, including infections, dietary factors, air pollution, vaccines, location of residence, family environment and stress. However, most of these factors have been inconclusive, thus supporting the need for further study into the causes of type 1 diabetes. Copyright © 2016 Canadian Diabetes Association. Published by Elsevier Inc. All rights reserved.

Neighbourhood level social deprivation and the risk of psychotic disorders: a systematic review.

PubMed

O'Donoghue, Brian; Roche, Eric; Lane, Abbie

2016-07-01

The incidence of psychotic disorders varies according to the geographical area, and it has been investigated whether neighbourhood level factors may be associated with this variation. The aim of this systematic review is to collate and appraise the literature on the association between social deprivation and the incidence or risk for psychotic disorders. A systematic review was conducted, and studies were included if they were in English, provided a measure of social deprivation for more than one geographically defined area and examined either the correlation, rate ratio or risk of psychotic disorder. A defined search strategy was undertaken with Medline, CINAHL Plus and PsychInfo databases. A total of 409 studies were identified in the search, of which 28 fulfilled the inclusion criteria. Of these, four examined the association between social deprivation at the time of birth, three examined the putative prodrome of psychosis or those at ultra-high risk (UHR) for psychosis, and 23 examined the time at presentation with a first episode of psychosis (FEP) (one study examined two time points and one study included both UHR and FEP). Three of the studies that examined the level of social deprivation at birth found an association with a higher risk for psychotic disorders and increased social deprivation. Seventeen of the 23 studies found that there was a higher risk or rate of psychotic disorders in more deprived neighbourhoods at the time of presentation; however, adjusting for individual factors tended to weaken this association. Limited research has been conducted in the putative prodromal stage and has resulted in conflicting findings. Research conducted to date has not definitively identified whether the association is a result of social causation or social drift; however, the findings do have significant implications for service provision, such as the location and access of services.

Ethnic diversity in the genetics of venous thromboembolism.

PubMed

Tang, Liang; Hu, Yu

2015-11-01

Genetic susceptibility is considered as a crucial factor for the development of venous thromboembolism (VTE). Epidemiologic and genetic studies have revealed clear disparities in the incidence of VTE and the distribution of genetic factors for VTE in populations stratified by ethnicity worldwide. While gain-of-function polymorphisms in the procoagulant genes are common inherited factors in European-origin populations, the most prevalent molecular basis for venous thrombosis in Asians is confirmed to be dysfunctional variants in the anticoagulant genes. With the breakthrough of genomic technologies, a set of novel common alleles and rare mutations associated with VTE have also been identified, in different ethnic groups. Several putative pathways contributing to the pathogenesis of thrombophilia in populations of African-ancestry are largely unknown, as current knowledge of hereditary and acquired risk factors do not fully explain the highest risk of VTE in Black groups. In-depth studies across diverse ethnic populations are needed to unravel the whole genetics of VTE, which will help developing individual risk prediction models and strategies to minimise VTE in all populations.

A Blood Spot Method for Detecting Fumonisin-Induced Changes in Putative Sphingolipid Biomarkers in LM/Bc Mice and Humans

USDA-ARS?s Scientific Manuscript database

Fumonisin B1 (FB1) is a toxic chemical produced by molds. The molds that produce fumonisin are common in corn. Consumption of contaminated corn by farm animals has been shown to be the cause of disease. Fumonisin has been hypothesized to be an environmental risk factor for diseases in humans in c...

Genetic Differences in the Immediate Transcriptome Response to Stress Predict Risk-Related Brain Function and Psychiatric Disorders

PubMed Central

Arloth, Janine; Bogdan, Ryan; Weber, Peter; Frishman, Goar; Menke, Andreas; Wagner, Klaus V.; Balsevich, Georgia; Schmidt, Mathias V.; Karbalai, Nazanin; Czamara, Darina; Altmann, Andre; Trümbach, Dietrich; Wurst, Wolfgang; Mehta, Divya; Uhr, Manfred; Klengel, Torsten; Erhardt, Angelika; Carey, Caitlin E.; Conley, Emily Drabant; Ripke, Stephan; Wray, Naomi R.; Lewis, Cathryn M.; Hamilton, Steven P.; Weissman, Myrna M.; Breen, Gerome; Byrne, Enda M.; Blackwood, Douglas H.R.; Boomsma, Dorret I.; Cichon, Sven; Heath, Andrew C.; Holsboer, Florian; Lucae, Susanne; Madden, Pamela A.F.; Martin, Nicholas G.; McGuffin, Peter; Muglia, Pierandrea; Noethen, Markus M.; Penninx, Brenda P.; Pergadia, Michele L.; Potash, James B.; Rietschel, Marcella; Lin, Danyu; Müller-Myhsok, Bertram; Shi, Jianxin; Steinberg, Stacy; Grabe, Hans J.; Lichtenstein, Paul; Magnusson, Patrik; Perlis, Roy H.; Preisig, Martin; Smoller, Jordan W.; Stefansson, Kari; Uher, Rudolf; Kutalik, Zoltan; Tansey, Katherine E.; Teumer, Alexander; Viktorin, Alexander; Barnes, Michael R.; Bettecken, Thomas; Binder, Elisabeth B.; Breuer, René; Castro, Victor M.; Churchill, Susanne E.; Coryell, William H.; Craddock, Nick; Craig, Ian W.; Czamara, Darina; De Geus, Eco J.; Degenhardt, Franziska; Farmer, Anne E.; Fava, Maurizio; Frank, Josef; Gainer, Vivian S.; Gallagher, Patience J.; Gordon, Scott D.; Goryachev, Sergey; Gross, Magdalena; Guipponi, Michel; Henders, Anjali K.; Herms, Stefan; Hickie, Ian B.; Hoefels, Susanne; Hoogendijk, Witte; Hottenga, Jouke Jan; Iosifescu, Dan V.; Ising, Marcus; Jones, Ian; Jones, Lisa; Jung-Ying, Tzeng; Knowles, James A.; Kohane, Isaac S.; Kohli, Martin A.; Korszun, Ania; Landen, Mikael; Lawson, William B.; Lewis, Glyn; MacIntyre, Donald; Maier, Wolfgang; Mattheisen, Manuel; McGrath, Patrick J.; McIntosh, Andrew; McLean, Alan; Middeldorp, Christel M.; Middleton, Lefkos; Montgomery, Grant M.; Murphy, Shawn N.; Nauck, Matthias; Nolen, Willem A.; Nyholt, Dale R.; O’Donovan, Michael; Oskarsson, Högni; Pedersen, Nancy; Scheftner, William A.; Schulz, Andrea; Schulze, Thomas G.; Shyn, Stanley I.; Sigurdsson, Engilbert; Slager, Susan L.; Smit, Johannes H.; Stefansson, Hreinn; Steffens, Michael; Thorgeirsson, Thorgeir; Tozzi, Federica; Treutlein, Jens; Uhr, Manfred; van den Oord, Edwin J.C.G.; Van Grootheest, Gerard; Völzke, Henry; Weilburg, Jeffrey B.; Willemsen, Gonneke; Zitman, Frans G.; Neale, Benjamin; Daly, Mark; Levinson, Douglas F.; Sullivan, Patrick F.; Ruepp, Andreas; Müller-Myhsok, Bertram; Hariri, Ahmad R.; Binder, Elisabeth B.

2015-01-01

Summary Depression risk is exacerbated by genetic factors and stress exposure; however, the biological mechanisms through which these factors interact to confer depression risk are poorly understood. One putative biological mechanism implicates variability in the ability of cortisol, released in response to stress, to trigger a cascade of adaptive genomic and non-genomic processes through glucocorticoid receptor (GR) activation. Here, we demonstrate that common genetic variants in long-range enhancer elements modulate the immediate transcriptional response to GR activation in human blood cells. These functional genetic variants increase risk for depression and co-heritable psychiatric disorders. Moreover, these risk variants are associated with inappropriate amygdala reactivity, a transdiagnostic psychiatric endophenotype and an important stress hormone response trigger. Network modeling and animal experiments suggest that these genetic differences in GR-induced transcriptional activation may mediate the risk for depression and other psychiatric disorders by altering a network of functionally related stress-sensitive genes in blood and brain. Video Abstract PMID:26050039

Toddlers' Duration of Attention toward Putative Threat

ERIC Educational Resources Information Center

Kiel, Elizabeth J.; Buss, Kristin A.

2011-01-01

Although individual differences in reactions to novelty in the toddler years have been consistently linked to risk of developing anxious behavior, toddlers' attention toward a novel, putatively threatening stimulus while in the presence of other enjoyable activities has rarely been examined as a precursor to such risk. The current study examined…

Thirty years of Alzheimer's disease genetics: the implications of systematic meta-analyses.

PubMed

Bertram, Lars; Tanzi, Rudolph E

2008-10-01

The genetic underpinnings of Alzheimer's disease (AD) remain largely elusive despite early successes in identifying three genes that cause early-onset familial AD (those that encode amyloid precursor protein (APP) and the presenilins (PSEN1 and PSEN2)), and one genetic risk factor for late-onset AD (the gene that encodes apolipoprotein E (APOE)). A large number of studies that aimed to help uncover the remaining disease-related loci have been published in recent decades, collectively proposing or refuting the involvement of over 500 different gene candidates. Systematic meta-analyses of these studies currently highlight more than 20 loci that have modest but significant effects on AD risk. This Review discusses the putative pathogenetic roles and common biochemical pathways of some of the most genetically and biologically compelling of these potential AD risk factors.

Epidemiology of Gout

PubMed Central

Choi, Hyon

2014-01-01

Synopsis Gout is the most prevalent inflammatory arthritis in men. The findings of several epidemiological studies from a diverse range of countries suggest that the prevalence of gout has risen over the last few decades. Whilst incidence data are scarce, data from the US suggests that the incidence of gout is also rising. Evidence from prospective epidemiological studies has confirmed dietary factors (animal purines, alcohol and fructose), obesity, the metabolic syndrome, hypertension, diuretic use, and chronic kidney disease as clinically relevant risk factors for hyperuricemia and gout. Low-fat dairy products, coffee, and vitamin C appear to have a protective effect. Further prospective studies are required to examine other proposed risk factors for hyperuricaemia and gout such as the use of β-blockers and angiotension-II receptor antagonists (other than losartan), obstructive sleep apnoea, and osteoarthritis, and putative protective factors such as calcium-channel blockers and losartan. PMID:24703341

Schizophrenia and cannabis use.

PubMed

Kumra, Sanjiv

2007-01-01

Genetic predisposition and environmental risk factors are thought to play a role in the pathophysiology of schizophrenia. Exposure to cannabis is one environmental factor that's being studied for its possible link to development of schizophrenia in adolescents. This article presents evidence that supports the hypothesis that repeated cannabis use could interfere with the development of frontal white matter in some adolescents and may exacerbate anatomic pathology in those with schizophrenia. This putative mechanism may explain the deficits in working memory and worsening in the severity of clinical symptoms in adolescents with schizophrenia who use cannabis.

Risk Factors for Mosquito House Entry in the Lao PDR

PubMed Central

Hiscox, Alexandra; Khammanithong, Phasouk; Kaul, Surinder; Sananikhom, Pany; Luthi, Ruedi; Brey, Paul T.; Lindsay, Steve W.

2013-01-01

Background Construction of the Nam Theun 2 hydroelectric project and flooding of a 450 km2 area of mountain plateau in south-central Lao PDR resulted in the resettlement of 6,300 people to newly built homes. We examined whether new houses would have altered risk of house entry by mosquitoes compared with traditional homes built from poorer construction materials. Methodology/Principal Findings Surveys were carried out in the Nam Theun 2 resettlement area and a nearby traditional rice farming area in 2010. Mosquitoes were sampled in bedrooms using CDC light traps in 96 resettlement houses and 96 traditional houses and potential risk factors for mosquito house entry were recorded. Risk of mosquito house entry was more than twice as high in traditional bamboo houses compared with those newly constructed from wood (Putative Japanese Encephalitis (JE) vector incidence rate ratio (IRR) = 2.26, 95% CI 1.38–3.70, P = 0.001; Anopheline IRR = 2.35, 95% CI: 1.30–4.23, P = 0.005). Anophelines were more common in homes with cattle compared against those without (IRR = 2.32, 95% CI: 1.29–4.17, P = 0.005).Wood smoke from cooking fires located under the house or indoors was found to be protective against house entry by both groups of mosquito, compared with cooking in a separate room beside the house (Putative JE vector IRR = 0.43, 95% CI: 0.26–0.73, P = 0.002; Anopheline IRR = 0.22, 95% CI: 0.10–0.51, P<0.001). Conclusions/Significance Construction of modern wooden homes should help reduce human-mosquito contact in the Lao PDR. Reduced mosquito contact rates could lead to reduced transmission of diseases such as JE and malaria. Cattle ownership was associated with increased anopheline house entry, so zooprophylaxis for malaria control is not recommended in this area. Whilst wood smoke was protective against putative JE vector and anopheline house entry we do not recommend indoor cooking since smoke inhalation can enhance respiratory disease. PMID:23700411

Systematic meta-analysis of childhood social withdrawal in schizophrenia, and comparison with data from at-risk children aged 9-14 years.

PubMed

Matheson, Sandra L; Vijayan, Hena; Dickson, Hannah; Shepherd, Alana M; Carr, Vaughan J; Laurens, Kristin R

2013-08-01

Social withdrawal is a robust childhood risk factor for later schizophrenia. The aims of this paper were to assess the evidence for childhood social withdrawal among adults with schizophrenia and, comparatively, in children aged 9-14 years who are putatively at-risk of developing schizophrenia. We conducted a meta-analysis, including cohort and case-control studies reporting social withdrawal measured by the Child Behavior Checklist (CBCL) in adults with schizophrenia vs. controls. Further, an experimental study compared CBCL withdrawal scores from typically-developing children with scores from two groups of putatively at-risk children: (i) children displaying a triad of replicated antecedents for schizophrenia, and (ii) children with at least one first- or second-degree relative with schizophrenia or schizoaffective disorder. Six studies met inclusion criteria for the meta-analysis (N = 3828), which demonstrated a large effect of increased childhood social withdrawal in adults with schizophrenia (standardized mean difference [SMD] score = 1.035, 95% CI = 0.304-1.766, p = 0.006), with no indication of publication bias, but considerable heterogeneity (I(2) = 91%). Results from the experimental study also indicated a large effect of increased social withdrawal in children displaying the antecedent triad (SMD = 0.743, p = 0.001), and a weaker effect in children with a family history of schizophrenia (SMD = 0.442, p = 0.051). Childhood social withdrawal may constitute a vulnerability marker for schizophrenia in the presence of other antecedents and/or genetic risk factors for schizophrenia. Copyright © 2013 Elsevier Ltd. All rights reserved.

A Murine Model of Genetic and Environmental Neurotoxicant Action

DTIC Science & Technology

2001-09-01

toniatoes (Wilhoit et al., 1999)]. The geographical overlap in has emerged as a putative risk factor on the basis of its structural use patterns and the...terminals. Either of these outcomes couldofurther elevate DA and metabolite levels. Although the striatumT Tcontains serotonergic and cholinergic neurons...foods. Thus, there is clearly a basis brain, because PQ is structurally similar to MPP+. PQ injected to suppose that supramixtures of agricultural

Identification of risk factors associated with onset and progression of amyotrophic lateral sclerosis using systematic review and meta-analysis.

PubMed

Wang, Ming-Dong; Little, Julian; Gomes, James; Cashman, Neil R; Krewski, Daniel

2017-07-01

Although amyotrophic lateral sclerosis (ALS) was identified as a neurological condition 150 years ago, risk factors related to the onset and progression of ALS remain largely unknown. Monogenic mutations in over 30 genes are associated with about 10% of ALS cases. The age at onset of ALS and disease types has been found to influence ALS progression. The present study was designed to identify additional putative risk factors associated with the onset and progression of ALS using systematic review and meta-analysis of observational studies. Risk factors that may be associated with ALS include: 1) genetic mutations, including the intermediate CAG repeat expansion in ATXN2; 2) previous exposure to heavy metals such as lead and mercury; 3) previous exposure to organic chemicals, such as pesticides and solvents; 4) history of electric shock; 5) history of physical trauma/injury (including head trauma/injury); 6) smoking (a weak risk factor for ALS in women); and 6) other risk factors, such as participating in professional sports, lower body mass index, lower educational attainment, or occupations requiring repetitive/strenuous work, military service, exposure to Beta-N-methylamino-l-alanin and viral infections. Risk factors that may be associated with ALS progression rate include: 1) nutritional status, including vitamin D deficiency; 2) comorbidities; 3) ethnicity and genetic factors; 4) lack of supportive care; and 4) smoking. The extent to which these associations may be causal is discussed, with further research recommended to strengthen the evidence on which determinations of causality may be based. Copyright © 2016. Published by Elsevier B.V.

Metabolic factors and genetic risk mediate familial type 2 diabetes risk in the Framingham Heart Study

PubMed Central

Raghavan, Sridharan; Porneala, Bianca; McKeown, Nicola; Fox, Caroline S.; Dupuis, Josée; Meigs, James B.

2015-01-01

Aims/hypothesis Type 2 diabetes mellitus in parents is a strong determinant of diabetes risk in their offspring. We hypothesise that offspring diabetes risk associated with parental diabetes is mediated by metabolic risk factors. Methods We studied initially non-diabetic participants of the Framingham Offspring Study. Metabolic risk was estimated using beta cell corrected insulin response (CIR), HOMA-IR or a count of metabolic syndrome components (metabolic syndrome score [MSS]). Dietary risk and physical activity were estimated using questionnaire responses. Genetic risk score (GRS) was estimated as the count of 62 type 2 diabetes risk alleles. The outcome of incident diabetes in offspring was examined across levels of parental diabetes exposure, accounting for sibling correlation and adjusting for age, sex and putative mediators. The proportion mediated was estimated by comparing regression coefficients for parental diabetes with (βadj) and without (βunadj) adjustments for CIR, HOMA-IR, MSS and GRS (percentage mediated = 1 – βadj / βunadj). Results Metabolic factors mediated 11% of offspring diabetes risk associated with parental diabetes, corresponding to a reduction in OR per diabetic parent from 2.13 to 1.96. GRS mediated 9% of risk, corresponding to a reduction in OR per diabetic parent from 2.13 to 1.99. Conclusions/interpretation Metabolic risk factors partially mediated offspring type 2 diabetes risk conferred by parental diabetes to a similar magnitude as genetic risk. However, a substantial proportion of offspring diabetes risk associated with parental diabetes remains unexplained by metabolic factors, genetic risk, diet and physical activity, suggesting that important familial influences on diabetes risk remain undiscovered. PMID:25619168

Difficulties in deciding whether to ablate patients with putatively "low-intermediate-risk" differentiated thyroid carcinoma: do guidelines mainly apply in the centres that produce them? Results of a retrospective, two-centre quality assurance study.

PubMed

Frangos, Savvas; Iakovou, Ioannis P; Marlowe, Robert J; Eftychiou, Nicolaos; Patsali, Loukia; Vanezi, Anna; Savva, Androulla; Mpalaris, Vassilis; Giannoula, Evanthia I

2015-12-01

We determined the reasons for radioiodine thyroid remnant ablation, and the procedure's necessity based on postsurgical remnant size, in patients with putatively "low-intermediate-risk" differentiated thyroid carcinoma (DTC). We identified key clinicopathological, treatment and remnant characteristics, and factors associated with remnant size in 336 patients with pT1/2, M0 DTC ablated during the period September 2010 to October 2013 at one Cypriot or one Greek referral centre. Clinicopathological/treatment characteristics were compiled from charts. Experienced nuclear medicine physicians rated the numbers/intensities of uptake foci in the thyroid bed on postablation planar scintigrams using scales of 0-4 points and 0-3 points, respectively. The product of these scores was taken as the "remnant score" that ranged from 0 (no remnant) to 12 (multiple remnants, intense uptake). DTC was predominantly papillary. The median [25th-75th percentile] longest primary tumour diameter was 1.0 cm [0.7-1.5 cm]. Despite favourable histotypes and primary tumour classifications, patients often had preablation characteristics suggesting elevated or uncertain risk: 31.0% of patients (104 of 336) had primary tumour multifocality, 22.0% (74) had confirmed cervical lymph node metastases, 37.2% (125) had unknown nodal status, and 38.1% (128) had antithyroglobulin antibody seropositivity. The median [25th-75th percentile] remnant score was 4 [2-6]; 39.9% of patients (134 of 336) had scores ≥6. For the entire cohort, T or N stages (r ≤ 0.174, P ≤ 0.05) correlated positively with the remnant score in a univariate Spearman analysis. The numbers of patients referred by the surgeon, cervical lymph nodes excised and metastatic nodes excised correlated negatively (r ≤ 0.243, P ≤ 0.038) with the remnant score, and the first two factors independently predicted the remnant score (P ≤ 0.037) in a multivariate analysis. Patients with putatively "low-intermediate-risk" DTC frequently had disease characteristics denoting high or uncertain risk, suggesting that "selective" radioiodine ablation in such patients may seldom be applicable outside international centres of excellence. Proxies for surgeon experience and surgical completeness correlated with remnant number/uptake intensity and may aid ablation-related decision-making.

Anxiety and Anxiety Disorders in Children and Adolescents: Developmental Issues and Implications for DSM-V

PubMed Central

Beesdo, Katja; Knappe, Susanne; Pine, Daniel S.

2010-01-01

This review summarizes findings on the epidemiology and etiology of anxiety disorders among children and adolescents including separation anxiety disorder, specific phobia, social phobia, agoraphobia, panic disorder, and generalized anxiety disorder, also highlighting critical aspects of diagnosis, assessment, and treatment. Childhood and adolescence is the core risk phase for the development of anxiety symptoms and syndromes, ranging from transient mild symptoms to full-blown anxiety disorders. This article critically reviews epidemiological evidence covering prevalence, incidence, course, and risk factors. The core challenge in this age span is the derivation of developmentally more sensitive assessment methods. Identification of characteristics that could serve as solid predictors for onset, course, and outcome will require prospective designs that assess a wide range of putative vulnerability and risk factors. This type of information is important for improved early recognition and differential diagnosis as well as prevention and treatment in this age span. PMID:19716988

Relative Risks of Thrombosis and Bleeding in Different ABO Blood Groups.

PubMed

Franchini, Massimo; Lippi, Giuseppe

2016-03-01

The ABO blood group system is composed of complex carbohydrate molecules (i.e., the A, B, and H determinants) that are widely expressed on the surface of red blood cells and in a variety of other cell and tissues. Along with their pivotal role in transfusion and transplantation medicine, the ABO antigens participate in many other physiological processes and, in particular, are important determinants of von Willebrand factor and factor VIII circulating plasma levels. The precise influence of the ABO system on hemostasis has led the way to the investigation of a putative implication in the risk of developing cardiovascular disorders. Along with the underlying molecular mechanisms, the current knowledge on the role of ABO blood group antigens in both the thrombotic and hemorrhagic risk will be summarized in this narrative review. Thieme Medical Publishers 333 Seventh Avenue, New York, NY 10001, USA.

Diet and caries-associated bacteria in severe early childhood caries.

PubMed

Palmer, C A; Kent, R; Loo, C Y; Hughes, C V; Stutius, E; Pradhan, N; Dahlan, M; Kanasi, E; Arevalo Vasquez, S S; Tanner, A C R

2010-11-01

Frequent consumption of cariogenic foods and bacterial infection are risk factors for early childhood caries (ECC). This study hypothesized that a short diet survey focused on frequency of foods, categorized by putative cariogenicity, would differentiate severe ECC (S-ECC) from caries-free children. Children's diets were obtained by survey and plaque bacteria detected by PCR from 72 S-ECC and 38 caries-free children. S-ECC children had higher scores for between-meal juice (p < 0.01), solid-retentive foods (p < 0.001), eating frequency (p < 0.005), and estimated food cariogenicity (p < 0.0001) than caries-free children. S-ECC children with lesion recurrence ate fewer putative caries-protective foods than children without new lesions. Streptococcus mutans (p < 0.005), Streptococcus sobrinus (p < 0.005), and Bifidobacteria (p < 0.0001) were associated with S-ECC, and S. mutans with S. sobrinus was associated with lesion recurrence (p < 0.05). S. mutans-positive children had higher food cariogenicity scores. Food frequency, putative cariogenicity, and S. mutans were associated with S-ECC individually and in combination.

Diet and Caries-associated Bacteria in Severe Early Childhood Caries

PubMed Central

Palmer, C.A.; Kent, R.; Loo, C.Y.; Hughes, C.V.; Stutius, E.; Pradhan, N.; Dahlan, M.; Kanasi, E.; Arevalo Vasquez, S.S.; Tanner, A.C.R.

2010-01-01

Frequent consumption of cariogenic foods and bacterial infection are risk factors for early childhood caries (ECC). This study hypothesized that a short diet survey focused on frequency of foods, categorized by putative cariogenicity, would differentiate severe ECC (S-ECC) from caries-free children. Children’s diets were obtained by survey and plaque bacteria detected by PCR from 72 S-ECC and 38 caries-free children. S-ECC children had higher scores for between-meal juice (p < 0.01), solid-retentive foods (p < 0.001), eating frequency (p < 0.005), and estimated food cariogenicity (p < 0.0001) than caries-free children. S-ECC children with lesion recurrence ate fewer putative caries-protective foods than children without new lesions. Streptococcus mutans (p < 0.005), Streptococcus sobrinus (p < 0.005), and Bifidobacteria (p < 0.0001) were associated with S-ECC, and S. mutans with S. sobrinus was associated with lesion recurrence (p < 0.05). S. mutans-positive children had higher food cariogenicity scores. Food frequency, putative cariogenicity, and S. mutans were associated with S-ECC individually and in combination. PMID:20858780

Orbitofrontal sulcogyral patterns are related to temperamental risk for psychopathology.

PubMed

Whittle, Sarah; Bartholomeusz, Cali; Yücel, Murat; Dennison, Meg; Vijayakumar, Nandita; Allen, Nicholas B

2014-02-01

There are marked individual differences in the pattern of cortical (sulcogyral) folding in the orbitofrontal cortex (OFC), and there is a growing literature suggesting that these individual differences are associated with risk for psychotic disorders. To date, however, no study has investigated whether OFC folding patterns are associated with broader risk factors relevant to a range of psychopathology. This study helps address this knowledge gap by examining whether OFC sulcogyral folding patterns are associated with putative risk factors, specifically affective temperament and psychiatric symptoms, in a large community sample (N = 152) of adolescents. Results showed that the most common pattern of folding ('Type I', marked by discontinuity of the medial orbital sulcus and continuity of the lateral orbital sulcus) was associated with low levels of Surgency, high levels of Negative Affectivity (in girls) and higher depressive symptoms. This pattern was also associated with reduced thickness of OFC gray matter. Overall, the findings, combined with previous work, suggest some specificity of neurodevelopmental risk for different types of psychopathology. Thus, these results have the potential to inform the early identification of at-risk individuals.

Do dimensional psychopathology measures relate to creative achievement or divergent thinking?

PubMed Central

Zabelina, Darya L.; Condon, David; Beeman, Mark

2014-01-01

Previous research provides disparate accounts of the putative association between creativity and psychopathology, including schizotypy, psychoticism, hypomania, bipolar disorder, ADHD, and autism spectrum disorders. To examine these association, healthy, non-clinical participants completed several psychopathology-spectrum measures, often postulated to associate with creativity: the Schizotypal Personality Questionnaire, the Psychoticism scale, the Personality Inventory for DSM-5, the Hypomanic Personality Scale, the Attention Deficit/Hyperactivity Disorder scale, the Beck Depression Inventory, and the Autism-Spectrum Quotient. The goal of Study 1 was to evaluate the factor structure of these dimensional psychopathology measures and, in particular, to evaluate the case for a strong general factor(s). None of the factor solutions between 1 and 10 factors provided a strong fit with the data based on the most commonly used metrics. The goal of Study 2 was to determine whether these psychopathology scales predict, independently, two measures of creativity: 1. a measure of participants' real-world creative achievements, and 2. divergent thinking, a laboratory measure of creative cognition. After controlling for academic achievement, psychoticism and hypomania reliably predicted real-world creative achievement and divergent thinking scored with the consensual assessment technique. None of the psychopathology-spectrum scales reliably predicted divergent thinking scored with the manual scoring method. Implications for the potential links between several putative creative processes and risk factors for psychopathology are discussed. PMID:25278919

Do dimensional psychopathology measures relate to creative achievement or divergent thinking?

PubMed

Zabelina, Darya L; Condon, David; Beeman, Mark

2014-01-01

Previous research provides disparate accounts of the putative association between creativity and psychopathology, including schizotypy, psychoticism, hypomania, bipolar disorder, ADHD, and autism spectrum disorders. To examine these association, healthy, non-clinical participants completed several psychopathology-spectrum measures, often postulated to associate with creativity: the Schizotypal Personality Questionnaire, the Psychoticism scale, the Personality Inventory for DSM-5, the Hypomanic Personality Scale, the Attention Deficit/Hyperactivity Disorder scale, the Beck Depression Inventory, and the Autism-Spectrum Quotient. The goal of Study 1 was to evaluate the factor structure of these dimensional psychopathology measures and, in particular, to evaluate the case for a strong general factor(s). None of the factor solutions between 1 and 10 factors provided a strong fit with the data based on the most commonly used metrics. The goal of Study 2 was to determine whether these psychopathology scales predict, independently, two measures of creativity: 1. a measure of participants' real-world creative achievements, and 2. divergent thinking, a laboratory measure of creative cognition. After controlling for academic achievement, psychoticism and hypomania reliably predicted real-world creative achievement and divergent thinking scored with the consensual assessment technique. None of the psychopathology-spectrum scales reliably predicted divergent thinking scored with the manual scoring method. Implications for the potential links between several putative creative processes and risk factors for psychopathology are discussed.

[Tumors of the central nervous system].

PubMed

Alegría-Loyola, Marco Antonio; Galnares-Olalde, Javier Andrés; Mercado, Moisés

2017-01-01

Central nervous system (CNS) tumors constitute a heterogeneous group of neoplasms that share a considerable morbidity and mortality rate. Recent advances in the underlying oncogenic mechanisms of these tumors have led to new classification systems, which, in turn, allow for a better diagnostic approach and therapeutic planning. Most of these neoplasms occur sporadically and several risk factors have been found to be associated with their development, such as exposure to ionizing radiation or electromagnetic fields and the concomitant presence of conditions like diabetes, hypertension and Parkinson's disease. A relatively minor proportion of primary CNS tumors occur in the context of hereditary syndromes. The purpose of this review is to analyze the etiopathogenesis, clinical presentation, diagnosis and therapy of CNS tumors with particular emphasis in the putative risk factors mentioned above.

Factors associated with elevated blood pressure or hypertension in Afro-Caribbean youth: a cross-sectional study.

PubMed

Ferguson, Trevor S; Younger-Coleman, Novie O M; Tulloch-Reid, Marshall K; Bennett, Nadia R; Rousseau, Amanda E; Knight-Madden, Jennifer M; Samms-Vaughan, Maureen E; Ashley, Deanna E; Wilks, Rainford J

2018-01-01

Although several studies have identified risk factors for high blood pressure (BP), data from Afro-Caribbean populations are limited. Additionally, less is known about how putative risk factors operate in young adults and how social factors influence the risk of high BP. In this study, we estimated the relative risk for elevated BP or hypertension (EBP/HTN), defined as BP ≥ 120/80 mmHg, among young adults with putative cardiovascular disease (CVD) risk factors in Jamaica and evaluated whether relative risks differed by sex. Data from 898 young adults, 18-20 years old, were analysed. BP was measured with a mercury sphygmomanometer after participants had been seated for 5 min. Anthropometric measurements were obtained, and glucose, lipids and insulin measured from a fasting venous blood sample. Data on socioeconomic status (SES) were obtained via questionnaire. CVD risk factor status was defined using standard cut-points or the upper quintile of the distribution where the numbers meeting standard cut-points were small. Relative risks were estimated using odds ratios (OR) from logistic regression models. Prevalence of EBP/HTN was 30% among males and 13% among females ( p  < 0.001 for sex difference). There was evidence for sex interaction in the relationship between EBP/HTN and some of risk factors (obesity and household possessions), therefore we report sex-specific analyses. In multivariable logistic regression models, factors independently associated with EBP/HTN among men were obesity (OR 8.48, 95% CI [2.64-27.2], p  < 0.001), and high glucose (OR 2.01, CI [1.20-3.37], p  = 0.008), while high HOMA-IR did not achieve statistical significance (OR 2.08, CI [0.94-4.58], p  = 0.069). In similar models for women, high triglycerides (OR 1.98, CI [1.03-3.81], p  = 0.040) and high HOMA-IR (OR 2.07, CI [1.03-4.12], p  = 0.039) were positively associated with EBP/HTN. Lower SES was also associated with higher odds for EBP/HTN (OR 4.63, CI [1.31-16.4], p  = 0.017, for moderate vs. high household possessions; OR 2.61, CI [0.70-9.77], p  = 0.154 for low vs. high household possessions). Alcohol consumption was associated with lower odds of EBP/HTN among females only; OR 0.41 (CI [0.18-0.90], p  = 0.026) for drinking <1 time per week vs. never drinkers, and OR 0.28 (CI [0.11-0.76], p  = 0.012) for drinking ≥3 times per week vs. never drinkers. Physical activity was inversely associated with EBP/HTN in both males and females. Factors associated with EBP/HTN among Jamaican young adults include obesity, high glucose, high triglycerides and high HOMA-IR, with some significant differences by sex. Among women lower SES was positively associated with EBP/HTN, while moderate alcohol consumption was associated lower odds of EBP/HTN.

Intrinsic and extrinsic risk factors for nonunion after nonoperative treatment of midshaft clavicle fractures.

PubMed

Liu, W; Xiao, J; Ji, F; Xie, Y; Hao, Y

2015-04-01

The optimal treatment of midshaft clavicle fractures remains controversial. Nonunion is usually considered to be an uncommon complication following a nonoperatively treated clavicle fracture. Not every midshaft clavicular fractures shares the same risk of developing nonunion after nonoperative treatment. The present study was performed to identify the intrinsic and extrinsic independent factors that are independently predictive of nonunion in patients with midshaft clavicular fractures after nonoperative treatment. We performed a retrospective study of a series of 804 patients (391 men and 413 women with a median age of 51.3 years) with a radiographically confirmed midshaft clavicle fracture, which was treated nonoperatively. There were 96 patients who underwent nonunion. Putative intrinsic (patient-related) and extrinsic (injured-related) risk factors associated with nonunion were determined with the use of bivariate and multivariate statistical analyses. By bivariate analysis, the risk of nonunion was significantly increased by several intrinsic risk factors including age, sex, and smoking and extrinsic risk factors including displacement of the fracture and the presence of comminution (P<0.05 for all). On multivariate analysis, smoking (OR=4.16, 95% CI: 1.01-14.16), fracture displacement (OR=7.81, 95% CI: 2.27-25.38) and comminution of fracture (OR=3.86, 95% CI: 1.16-13.46) were identified as independent predictive factors. The risk factors for nonunion after nonoperative treatment of midshaft clavicle fractures are multifactorial. Smoking, fracture displacement and comminution of fracture are independent predictors for an individual likelihood of nonunion. Further studies are still required to evaluate these factors in the future. Level III, case-control study. Copyright © 2015 Elsevier Masson SAS. All rights reserved.

A 6-year longitudinal study of predictors for suicide attempts in major depressive disorder.

PubMed

Eikelenboom, Merijn; Beekman, Aartjan T F; Penninx, Brenda W J H; Smit, Johannes H

2018-06-13

Major depressive disorder (MDD), represent a major source of risk for suicidality. However, knowledge about risk factors for future suicide attempts (SAs) within MDD is limited. The present longitudinal study examined a wide range of putative non-clinical risk factors (demographic, social, lifestyle, personality) and clinical risk factors (depressive and suicidal indicators) for future SAs among persons with MDD. Furthermore, we examined the relationship between a number of significant predictors and the incidence of a future SA. Data are from 1713 persons (18-65 years) with a lifetime MDD at the baseline measurement of the Netherlands Study of Depression and Anxiety who were subsequently followed up 2, 4 and 6 years. SAs were assessed in the face-to-face measurements. Cox proportional hazard regression analyses were used to examine a wide range of possible non-clinical and clinical predictors for subsequent SAs during 6-year follow-up. Over a period of 6 years, 3.4% of the respondents attempted suicide. Younger age, lower education, unemployment, insomnia, antidepressant use, a previous SA and current suicidal thoughts independently predicted a future SA. The number of significant risk factors (ranging from 0 to 7) linearly predicted the incidence of future SAs: in those with 0 predictors the SA incidence was 0%, which increased to 32% incidence in those with 6+ predictors. Of the non-clinical factors, particularly socio-economic factors predicted a SA independently. Furthermore, preexisting suicidal ideation and insomnia appear to be important clinical risk factors for subsequent SA that are open to preventative intervention.

Advantages and limitations of web-based surveys: evidence from a child mental health survey.

PubMed

Heiervang, Einar; Goodman, Robert

2011-01-01

Web-based surveys may have advantages related to the speed and cost of data collection as well as data quality. However, they may be biased by low and selective participation. We predicted that such biases would distort point-estimates such as average symptom level or prevalence but not patterns of associations with putative risk-factors. A structured psychiatric interview was administered to parents in two successive surveys of child mental health. In 2003, parents were interviewed face-to-face, whereas in 2006 they completed the interview online. In both surveys, interviews were preceded by paper questionnaires covering child and family characteristics. The rate of parents logging onto the web site was comparable to the response rate for face-to-face interviews, but the rate of full response (completing all sections of the interview) was much lower for web-based interviews. Full response was less frequent for non-traditional families, immigrant parents, and less educated parents. Participation bias affected point estimates of psychopathology but had little effect on associations with putative risk factors. The time and cost of full web-based interviews was only a quarter of that for face-to-face interviews. Web-based surveys may be performed faster and at lower cost than more traditional approaches with personal interviews. Selective participation seems a particular threat to point estimates of psychopathology, while patterns of associations are more robust.

Putative Human and Avian Risk Factors for Avian Influenza Virus Infections in Backyard Poultry in Egypt

PubMed Central

Sheta, Basma M.; Fuller, Trevon L.; Larison, Brenda; Njabo, Kevin Y.; Ahmed, Ahmed Samy; Harrigan, Ryan; Chasar, Anthony; Aziz, Soad Abdel; Khidr, Abdel-Aziz A.; Elbokl, Mohamed M.; Habbak, Lotfy Z.; Smith, Thomas B.

2014-01-01

Highly pathogenic influenza A virus subtype H5N1 causes significant poultry mortality in the six countries where it is endemic and can also infect humans. Egypt has reported the third highest number of poultry outbreaks (n=1,084) globally. The objective of this cross-sectional study was to identify putative risk factors for H5N1 infections in backyard poultry in 16 villages in Damietta, El Gharbia, Fayoum, and Menofia governorates from 2010–2012. Cloacal and tracheal swabs and serum samples from domestic (n=1242)and wild birds (n=807) were tested for H5N1 via RT-PCR and hemagglutination inhibition, respectively. We measured poultry rearing practices with questionnaires (n=306 households) and contact rates among domestic and wild bird species with scan sampling. Domestic birds (chickens, ducks, and geese, n = 51) in three governorates tested positive for H5N1 by PCR or serology. A regression model identified a significant correlation between H5N1 in poultry and the practice of disposing of dead poultry and poultry feces in the garbage (F = 15.7, p< 0.0001). In addition, contact between domestic and wild birds was more frequent in villages where we detected H5N1 in backyard flocks (F= 29.5, p< 0.0001). PMID:24315038

Early Risk Factors of Overweight Developmental Trajectories during Middle Childhood

PubMed Central

Pryor, Laura E.; Brendgen, Mara; Tremblay, Richard E.; Pingault, Jean-Baptiste; Liu, Xuecheng; Dubois, Lise; Touchette, Evelyne; Falissard, Bruno; Boivin, Michel; Côté, Sylvana M.

2015-01-01

Background Research is needed to identify early life risk factors associated with different developmental paths leading to overweight by adolescence. Objectives To model heterogeneity in overweight development during middle childhood and identify factors associated with differing overweight trajectories. Methods Data was drawn from the Quebec Longitudinal Study of Child Development (QLSCD; 1998-2010). Trained research assistants measured height and weight according to a standardized protocol and conducted yearly home interviews with the child’s caregiver (mother in 98% of cases). Information on several putative early life risk factors for the development of overweight were obtained, including factors related to the child’s perinatal, early behavioral family and social environment. Group-based trajectories of the probability of overweight (6-12 years) were identified with a semiparametric method (n=1678). Logistic regression analyses were used to identify early risk factors (5 months- 5 years) associated with each trajectory. Results Three trajectories of overweight were identified: “early-onset overweight” (11.0 %), “late-onset overweight” (16.6%) and “never overweight” (72.5%). Multinomial analyses indicated that children in the early and late-onset group, compared to the never overweight group, had 3 common types of risk factors: parental overweight, preschool overweight history, and large size for gestational age. Maternal overprotection (OR= 1.12, CI: 1.01-1.25), short nighttime sleep duration (OR=1.66, CI: 1.07-2.57), and immigrant status (OR=2.01, CI: 1.05-3.84) were factors specific to the early-onset group. Finally, family food insufficiency (OR=1.81, CI: 1.00-3.28) was weakly associated with membership in the late-onset trajectory group. Conclusions The development of overweight in childhood follows two different trajectories, which have common and distinct risk factors that could be the target of early preventive interventions. PMID:26121682

Data-Driven Identification of Risk Factors of Patient Satisfaction at a Large Urban Academic Medical Center.

PubMed

Li, Li; Lee, Nathan J; Glicksberg, Benjamin S; Radbill, Brian D; Dudley, Joel T

2016-01-01

The Hospital Consumer Assessment of Healthcare Providers and Systems (HCAHPS) survey is the first publicly reported nationwide survey to evaluate and compare hospitals. Increasing patient satisfaction is an important goal as it aims to achieve a more effective and efficient healthcare delivery system. In this study, we develop and apply an integrative, data-driven approach to identify clinical risk factors that associate with patient satisfaction outcomes. We included 1,771 unique adult patients who completed the HCAHPS survey and were discharged from the inpatient Medicine service from 2010 to 2012. We collected 266 clinical features including patient demographics, lab measurements, medications, disease categories, and procedures. We developed and applied a data-driven approach to identify risk factors that associate with patient satisfaction outcomes. We identify 102 significant risk factors associating with 18 surveyed questions. The most significantly recurrent clinical risk factors were: self-evaluation of health, education level, Asian, White, treatment in BMT oncology division, being prescribed a new medication. Patients who were prescribed pregabalin were less satisfied particularly in relation to communication with nurses and pain management. Explanation of medication usage was associated with communication with nurses (q = 0.001); however, explanation of medication side effects was associated with communication with doctors (q = 0.003). Overall hospital rating was associated with hospital environment, communication with doctors, and communication about medicines. However, patient likelihood to recommend hospital was associated with hospital environment, communication about medicines, pain management, and communication with nurse. Our study identified a number of putatively novel clinical risk factors for patient satisfaction that suggest new opportunities to better understand and manage patient satisfaction. Hospitals can use a data-driven approach to identify clinical risk factors for poor patient satisfaction to support development of specific interventions to improve patients' experience of care.

Occupational Screening for Tuberculosis and the Use of a Borderline Zone for Interpretation of the IGRA in German Healthcare Workers

PubMed Central

Schablon, Anja; Nienhaus, Albert; Ringshausen, Felix C.; Preisser, Alexandra M.; Peters, Claudia

2014-01-01

Introduction Healthcare workers (HCWs) in low incidence countries with contact to patients with tuberculosis (TB) are considered a high-risk group for latent TB infection (LTBI) and therefore are routinely screened for LTBI. The German Occupational TB Network data is analyzed in order to estimate the prevalence and incidence of LTBI and to evaluate putative risk factors for a positive IGRA and the performance of IGRA in serial testing. Methods 3,823 HCWs were screened with the Quantiferon Gold in Tube (QFT) at least once; a second QFT was performed on 817 HCWs either in the course of contact tracing or serial examination. Risk factors for a positive QFT were assessed by a questionnaire. Results We observed a prevalence of LTBI of 8.3%. Putative risk factors for a positive QFT result were age >55 years (OR 6.89), foreign country of birth (OR 2.39), personal history of TB (OR 6.23) and workplace, e.g. internal medicine (OR 1.40), infection ward (OR 1.8) or geriatric care (OR 1.8). Of those repeatedly tested, 88.2% (721/817) tested consistently QFT-negative and 47 were consistently QFT-positive (5.8%). A conversion was observed in 2.8% (n = 21 of 742 with a negative first QFT) and a reversion occurred in 37.3% (n = 28 of 75 with a positive first QFT). Defining a conversion as an increase of the specific interferon concentration from <0.2 to >0.7 IU/ml, the conversion rate decreased to 1.2% (n = 8). Analogous to this, the reversion rate decreased to 18.8% (n = 9). Discussion In countries with a low incidence of TB and high hygiene standards, the LTBI infection risk for HCWs seems low. Introducing a borderline zone from 0.2 to ≤0.7 IU/ml may help to avoid unnecessary X-rays and preventive chemotherapy. No case of active TB was detected. Therefore, it might be reasonable to further restrict TB screening to HCWs who had unprotected contact with infectious patients or materials. PMID:25541947

A resource for characterizing genome-wide binding and putative target genes of transcription factors expressed during secondary growth and wood formation in Populus

Treesearch

Lijun Liu; Trevor Ramsay; Matthew S. Zinkgraf; David Sundell; Nathaniel Robert Street; Vladimir Filkov; Andrew Groover

2015-01-01

Identifying transcription factor target genes is essential for modeling the transcriptional networks underlying developmental processes. Here we report a chromatin immunoprecipitation sequencing (ChIP-seq) resource consisting of genome-wide binding regions and associated putative target genes for four Populus homeodomain transcription factors...

Characterization of clinical and genetic risk factors associated with dyslipidemia after kidney transplantation.

PubMed

Numakura, Kazuyuki; Kagaya, Hideaki; Yamamoto, Ryohei; Komine, Naoki; Saito, Mitsuru; Hiroshi, Tsuruta; Akihama, Susumu; Inoue, Takamitsu; Narita, Shintaro; Tsuchiya, Norihiko; Habuchi, Tomonori; Niioka, Takenori; Miura, Masatomo; Satoh, Shigeru

2015-01-01

We determined the prevalence of dyslipidemia in a Japanese cohort of renal allograft recipients and investigated clinical and genetic characteristics associated with having the disease. In total, 126 patients that received renal allograft transplants between February 2002 and August 2011 were studied, of which 44 recipients (34.9%) were diagnosed with dyslipidemia at 1 year after transplantation. Three clinical factors were associated with a risk of having dyslipidemia: a higher prevalence of disease observed among female than male patients (P = 0.021) and treatment with high mycophenolate mofetil (P = 0.012) and prednisolone (P = 0.023) doses per body weight at 28 days after transplantation. The genetic association between dyslipidemia and 60 previously described genetic polymorphisms in 38 putative disease-associated genes was analyzed. The frequency of dyslipidemia was significantly higher in patients with the glucocorticoid receptor (NR3C1) Bcl1 G allele than in those with the CC genotype (P = 0.001). A multivariate analysis revealed that the NR3C1 Bcl1 G allele was a significant risk factor for the prevalence of dyslipidemia (odds ratio = 4.6; 95% confidence interval = 1.8-12.2). These findings may aid in predicting a patient's risk of developing dyslipidemia.

Environmental risk factors for autism: an evidence-based review of systematic reviews and meta-analyses.

PubMed

Modabbernia, Amirhossein; Velthorst, Eva; Reichenberg, Abraham

2017-01-01

According to recent evidence, up to 40-50% of variance in autism spectrum disorder (ASD) liability might be determined by environmental factors. In the present paper, we conducted a review of systematic reviews and meta-analyses of environmental risk factors for ASD. We assessed each review for quality of evidence and provided a brief overview of putative mechanisms of environmental risk factors for ASD. Current evidence suggests that several environmental factors including vaccination, maternal smoking, thimerosal exposure, and most likely assisted reproductive technologies are unrelated to risk of ASD. On the contrary, advanced parental age is associated with higher risk of ASD. Birth complications that are associated with trauma or ischemia and hypoxia have also shown strong links to ASD, whereas other pregnancy-related factors such as maternal obesity, maternal diabetes, and caesarian section have shown a less strong (but significant) association with risk of ASD. The reviews on nutritional elements have been inconclusive about the detrimental effects of deficiency in folic acid and omega 3, but vitamin D seems to be deficient in patients with ASD. The studies on toxic elements have been largely limited by their design, but there is enough evidence for the association between some heavy metals (most important inorganic mercury and lead) and ASD that warrants further investigation. Mechanisms of the association between environmental factors and ASD are debated but might include non-causative association (including confounding), gene-related effect, oxidative stress, inflammation, hypoxia/ischemia, endocrine disruption, neurotransmitter alterations, and interference with signaling pathways. Compared to genetic studies of ASD, studies of environmental risk factors are in their infancy and have significant methodological limitations. Future studies of ASD risk factors would benefit from a developmental psychopathology approach, prospective design, precise exposure measurement, reliable timing of exposure in relation to critical developmental periods and should take into account the dynamic interplay between gene and environment by using genetically informed designs.

Emotional abuse of girls in Swaziland: prevalence, perpetrators, risk and protective factors and health outcomes.

PubMed

Meinck, Franziska; Fry, Deborah; Ginindza, Choice; Wazny, Kerri; Elizalde, Aldo; Spreckelsen, Thees F; Maternowska, M Catherine; Dunne, Michael P

2017-06-01

Research on emotional child abuse in sub-Saharan Africa is scarce. Few studies thus far have examined prevalence, risk and protective factors for emotional child abuse or the associations between emotional abuse and girls' health. A nationally representative two-stage, cluster-sampled, household survey of females aged 13-24 years (n = 1244) on childhood abuse victimisation was conducted. Participants completed interviewer-assisted questionnaires. Associations between emotional abuse and putative risk, and protective factors and health outcomes were analyzed using separate logistic regression models accounting for sampling design. Marginal effects of cumulative risk factors for emotional abuse victimisation were examined. Lifetime prevalence of emotional abuse was 28.5% with 58.3% of these girls reporting many abusive incidents. The most common perpetrators were female (27.8%) and male (16.7%) relatives and, more rarely, biological parents. Risk factors associated with emotional abuse were frequent caregiver changes (odds ratio (OR) 1.42, 95% confidence interval (CI) 1.03-1.970, poverty (OR 1.51, 95% CI 1.12-2.03), and physical abuse (OR 1.98, 95% CI 1.45-2.71) and sexual abuse (OR 2.22, 95% CI 1.57-3.10) victimisation. Being close to one's mother was a protective factor (OR 0.88, 95% CI 0.80-0.97). Risk for emotional abuse increased from 13% with no risk factors present to 58.4% -with all four risk factors present. Health outcomes associated with emotional child abuse were suicidal ideation (OR 1.85, 95% CI 1.30-2.63) and feeling depressed (OR 1.89, 95% CI 1.31-2.71). Girls in Swaziland experience high levels of emotional abuse victimisation. Emotional abuse is associated with economic disadvantage, family factors, other types of abuse victimisation and poor mental health. Therefore, a holistic approach to prevention is needed, incorporating poverty reduction and programmes to improve parent-child relationships, reduce the use of harsh criticism, and change parenting social norms.

Risk Factors for Human Salmonellosis Originating from Pigs, Cattle, Broiler Chickens and Egg Laying Hens: A Combined Case-Control and Source Attribution Analysis

PubMed Central

Mughini-Gras, Lapo; Enserink, Remko; Friesema, Ingrid; Heck, Max; van Duynhoven, Yvonne; van Pelt, Wilfrid

2014-01-01

Several case-control studies have investigated risk factors for human salmonellosis while others have used Salmonella subtyping to attribute human infections to different food and animal reservoirs. This study combined case-control and source attribution data into a single analysis to explore risk factors at the point of exposure for human salmonellosis originating from four putative food-producing animal reservoirs (pigs, cattle, broilers and layers/eggs) in the Netherlands. We confirmed that most human cases (∼90%) were attributable to layers/eggs and pigs. Layers/eggs and broilers were the most likely reservoirs of salmonellosis in adults, in urban areas, and in spring/summer, whereas pigs and cattle were the most likely reservoirs of salmonellosis in children, in rural areas, and in autumn/winter. Several reservoir-specific risk factors were identified. Not using a chopping board for raw meat only and consuming raw/undercooked meat were risk factors for infection with salmonellas originating from pigs, cattle and broilers. Consuming raw/undercooked eggs and by-products were risk factors for layer/egg-associated salmonellosis. Using antibiotics was a risk factor for pig- and cattle-associated salmonellosis and using proton-pump inhibitors for salmonellosis attributable to any reservoir. Pig- and cattle-associated infections were also linked to direct contact with animals and environmental exposure (e.g. playing in sandboxes). Eating fish, meat in pastry, and several non-meat foods (fruit, vegetables and pasteurized dairy products) were protective factors. Consuming pork and occupational exposure to animals and/or raw meats were protective against layer/egg-associated salmonellosis. We concluded that individuals acquiring salmonellosis from different reservoirs have different associated risk factors, suggesting that salmonellas may infect humans through various transmission pathways depending on their original reservoirs. The outcome of classical case-control studies can be enhanced by incorporating source attribution data and vice versa. PMID:24503703

Germ-line variants identified by next generation sequencing in a panel of estrogen and cancer associated genes correlate with poor clinical outcome in Lynch syndrome patients.

PubMed

Jóri, Balazs; Kamps, Rick; Xanthoulea, Sofia; Delvoux, Bert; Blok, Marinus J; Van de Vijver, Koen K; de Koning, Bart; Oei, Felicia Trups; Tops, Carli M; Speel, Ernst Jm; Kruitwagen, Roy F; Gomez-Garcia, Encarna B; Romano, Andrea

2015-12-01

The risk to develop colorectal and endometrial cancers among subjects testing positive for a pathogenic Lynch syndrome mutation varies, making the risk prediction difficult. Genetic risk modifiers alter the risk conferred by inherited Lynch syndrome mutations, and their identification can improve genetic counseling. We aimed at identifying rare genetic modifiers of the risk of Lynch syndrome endometrial cancer. A family based approach was used to assess the presence of genetic risk modifiers among 35 Lynch syndrome mutation carriers having either a poor clinical phenotype (early age of endometrial cancer diagnosis or multiple cancers) or a neutral clinical phenotype. Putative genetic risk modifiers were identified by Next Generation Sequencing among a panel of 154 genes involved in endometrial physiology and carcinogenesis. A simple pipeline, based on an allele frequency lower than 0.001 and on predicted non-conservative amino-acid substitutions returned 54 variants that were considered putative risk modifiers. The presence of two or more risk modifying variants in women carrying a pathogenic Lynch syndrome mutation was associated with a poor clinical phenotype. A gene-panel is proposed that comprehends genes that can carry variants with putative modifying effects on the risk of Lynch syndrome endometrial cancer. Validation in further studies is warranted before considering the possible use of this tool in genetic counseling.

Influence of methylenetetrahydrofolate reductase genotype, exercise and other risk factors on endothelial function in healthy individuals.

PubMed

Pullin, Catherine H; Wilson, John F; Ashfield-Watt, Pauline A L; Clark, Zoë E; Whiting, Jenny M; Lewis, Malcolm J; McDowell, Ian F W

2002-01-01

Cardiovascular disease has a multifactorial aetiology that is influenced by both genetic and environmental factors. Endothelial dysfunction is a key event in the pathogenesis of vascular disease that occurs before structural vascular changes or clinical symptoms are evident. Conventional risk factors, for example hypertension and diabetes mellitus, are associated with endothelial dysfunction, but the influence of other putative risk factors is not clear. The methylenetetrahydrofolate reductase (MTHFR) C677T genotype, a common polymorphism that induces hyperhomocysteinaemia, has been proposed as being a genetic risk factor for cardiovascular disease. A total of 126 healthy adults recruited by MTHFR C677T genotype (42 of each genotype, i.e. CC, CT and TT) underwent assessment of endothelial function. Brachial artery endothelium-dependent flow-mediated dilatation (FMD) was measured using high-resolution ultrasonic vessel "wall-tracking". Using multiple regression analysis, MTHFR genotype and 21 other subject and subject-lifestyle variables were investigated as potential predictors of endothelial function. FMD was influenced positively by frequency of aerobic exercise and by hormone replacement therapy, and negatively by increases in systolic blood pressure. MTHFR C677T genotype and the associated variation in plasma homocysteine levels did not influence FMD. Additionally, other factors, including plasma cholesterol and self-supplementation with either antioxidant vitamins or cod liver oil, showed no significant relationship with FMD, although these findings are compromised by the narrow range studied for cholesterol and the small number of subjects taking supplements. These observations have implications for risk factor management in the primary prevention of cardiovascular disease in healthy individuals.

Cigarette smoking and the pathogenesis of systemic lupus erythematosus.

PubMed

Speyer, Cameron B; Costenbader, Karen H

2018-06-01

Systemic lupus erythematosus (SLE) is a multi-system inflammatory autoimmune disease of incompletely understood etiology. It is thought that environmental exposures 'trigger' or accelerate the disease in genetically-predisposed individuals. Areas covered: Substantial epidemiological evidence exists to support the association between cigarette smoking and the risk of incident SLE. Recent evidence points to current smoking as the specific risk factor, with decreasing risk 5 years after smoking cessation, and the greatest risk for disease characterized by the presence of SLE-specific autoantibodies. Research has begun to search for possible explanations for the temporal nature of the relationship between current smoking and autoantibody positive-SLE. Here we review potential biologic mechanisms linking smoking and SLE risk, including effects upon T and B cells, inflammatory cytokines, oxidative stress, and the formation of short-lived DNA adducts. Expert commentary: The directions for future research in this field include studies of gene-environment interactions, epigenetics, metabolomics and putative biologic mechanisms.

Mindfulness and zest for life buffer the negative effects of experimentally-induced perceived burdensomeness and thwarted belongingness: Implications for theories of suicide.

PubMed

Collins, Khan R L; Best, Ida; Stritzke, Werner G K; Page, Andrew C

2016-07-01

Suicide research can be enhanced by an ability to safely manipulate putative causal variables. The present studies developed an experimental task to modify risk factors identified by the interpersonal theory of suicide (perceived burdensomeness and thwarted belongingness) and examine their hypothesized suppressive effect on persistence in adversity in undergraduate university students. Variables that may moderate the impact of these risk factors on persistence (zest for life and mindful awareness) were incorporated as potential resilience factors. Study 1 (N = 92) found elevated burdensomeness and diminished belongingness significantly impaired persistence. Additionally, these predicted effects were moderated by individual differences in zest for life. In Study 2 (N = 52), individuals trained in mindfulness prior to the experimental task displayed greater persistence relative to controls. Findings provide experimental support for the role of perceived burdensomeness and thwarted belongingness in the manner predicted by the interpersonal theory, and demonstrate a way to experimentally test the effects of resilience factors that reduce the impact of these interpersonal factors. (PsycINFO Database Record (c) 2016 APA, all rights reserved).

Risk factors for cryptorchidism

PubMed Central

Gurney, Jason K.; McGlynn, Katherine A.; Stanley, James; Merriman, Tony; Signal, Virginia; Shaw, Caroline; Edwards, Richard; Richiardi, Lorenzo; Hutson, John; Sarfati, Diana

2018-01-01

The condition known as cryptorchidism – undescended testis – is one of the most common congenital abnormalities found among males, and is one of the few known risk factors for testicular cancer (TC). Like testicular cancer, the key exposures in the occurrence of cryptorchidism remain elusive. Testicular descent is thought to occur during two hormonally-controlled phases – between 8–15 weeks and 25–35 weeks gestation – and while it is clear that a failure of testes to descend permanently is likely due to disruptions to one or both of these phases, the cause(s) and mechanism(s) of such disruption are still unclear. In this manuscript, we review the broad range of putative risk factors that have been evaluated in relation to the development of cryptorchidism to date, discuss their plausibility, and make suggestions regarding further approaches to understand aetiology. There are few exposures for which there is consistent evidence of an association with cryptorchidism; and in those cases where evidence appears unequivocal – for example, the relationship between cryptorchidism and gestational measures such as low birth weight – the measured exposure is likely to be a surrogate for the true causal exposure. The relative importance of each risk factor may vary considerably between mother/son pairs depending on an array of genetic, maternal, placental and foetal factors – all of which could vary between regions. PMID:28654092

Antioxidant and antiplatelet activity by polyphenol-rich nutrients: focus on extra virgin olive oil and cocoa.

PubMed

Loffredo, Lorenzo; Perri, Ludovica; Nocella, Cristina; Violi, Francesco

2017-01-01

Cardiovascular disease is the most common cause of death in the Western world. In the last decades nutraceutical approaches have been proposed to counteract atherosclerotic complications. In particular, polyphenols, a class of bio-active molecules prevalently contained in foods such as cocoa, fruits, vegetables, wine and tea, have been widely studied for their beneficial properties. Several epidemiological and interventional studies have shown that polyphenol-rich nutrients, as in extra virgin olive oil (EVOO) and cocoa, are associated with a risk reduction of cardiovascular events and/or modulation of cardiovascular risk factors. Definition of the mechanisms accounting for this putative cardio-protective effect is still elusive. This review focuses on the mechanisms that may be implicated in the beneficial effects of EVOO and cocoa, including down-regulation of oxidative stress and platelet aggregation, improvement of endothelial function and cardiovascular risk factor such as blood pressure, serum cholesterol and insulin sensitivity. © 2016 The British Pharmacological Society.

Alcohol consumption and all-cause mortality.

PubMed

Duffy, J C

1995-02-01

Prospective studies of alcohol and mortality in middle-aged men almost universally find a U-shaped relationship between alcohol consumption and risk of mortality. This review demonstrates the extent to which different studies lead to different risk estimates, analyses the putative influence of abstention as a risk factor and uses available data to produce point and interval estimates of the consumption level apparently associated with minimum risk from two studies in the UK. Data from a number of studies are analysed by means of logistic-linear modelling, taking account of the possible influence of abstention as a special risk factor. Separate analysis of British data is performed. Logistic-linear modelling demonstrates large and highly significant differences between the studies considered in the relationship between alcohol consumption and all-cause mortality. The results support the identification of abstention as a special risk factor for mortality, but do not indicate that this alone explains the apparent U-shaped relationship. Separate analysis of two British studies indicates minimum risk of mortality in this population at a consumption level of about 26 (8.5 g) units of alcohol per week. The analysis supports the view that abstention may be a specific risk factor for all-cause mortality, but is not an adequate explanation of the apparent protective effect of alcohol consumption against all-cause mortality. Future analyses might better be performed on a case-by-case basis, using a change-point model to estimate the parameters of the relationship. The current misinterpretation of the sensible drinking level of 21 units per week for men in the UK as a limit is not justified, and the data suggest that alcohol consumption is a net preventive factor against premature death in this population.

Establishing the role of rare coding variants in known Parkinson's disease risk loci.

PubMed

Jansen, Iris E; Gibbs, J Raphael; Nalls, Mike A; Price, T Ryan; Lubbe, Steven; van Rooij, Jeroen; Uitterlinden, André G; Kraaij, Robert; Williams, Nigel M; Brice, Alexis; Hardy, John; Wood, Nicholas W; Morris, Huw R; Gasser, Thomas; Singleton, Andrew B; Heutink, Peter; Sharma, Manu

2017-11-01

Many common genetic factors have been identified to contribute to Parkinson's disease (PD) susceptibility, improving our understanding of the related underlying biological mechanisms. The involvement of rarer variants in these loci has been poorly studied. Using International Parkinson's Disease Genomics Consortium data sets, we performed a comprehensive study to determine the impact of rare variants in 23 previously published genome-wide association studies (GWAS) loci in PD. We applied Prix fixe to select the putative causal genes underneath the GWAS peaks, which was based on underlying functional similarities. The Sequence Kernel Association Test was used to analyze the joint effect of rare, common, or both types of variants on PD susceptibility. All genes were tested simultaneously as a gene set and each gene individually. We observed a moderate association of common variants, confirming the involvement of the known PD risk loci within our genetic data sets. Focusing on rare variants, we identified additional association signals for LRRK2, STBD1, and SPATA19. Our study suggests an involvement of rare variants within several putatively causal genes underneath previously identified PD GWAS peaks. Copyright © 2017 Elsevier Inc. All rights reserved.

Update on causes of premature death in people with convulsive epilepsy in rural West China.

PubMed

Si, Yang; Chen, Deng; Tian, Linyu; Mu, Jie; Chen, Tao; Liu, Ling; Deng, Ying; He, Jun; Li, You; He, Li; Zhou, Dong

2016-06-01

This longitudinal prospective study updated a previous report on premature mortality and focused on the risk factors among patients with convulsive epilepsy in resource-poor settings. The present cohort size (7,231) and follow-up (mean 33.4 months) were expanded. The basic epidemiologic aspects of this cohort were similar to the original report (case fatality: 3.26% vs. 2.97%, respectively; injury contributed more than half of the deaths). Cox regression analysis suggested that male patients, late ages of onset (>45 years old), short duration of epilepsy (<10 years), and high convulsive seizure frequency (>2 per month) were independent risk factors for overall premature death. Male patients with late ages of onset and high seizure frequency had a higher risk of injury-specific death. This study emphasizes the preventable nature of injuries that are leading putative causes of death among people with convulsive epilepsy in rural West China. Education on specific populations and efficient seizure control are of paramount importance in reducing the risk of premature mortality. Wiley Periodicals, Inc. © 2016 International League Against Epilepsy.

Phylogenetic and comparative gene expression analysis of barley (Hordeum vulgare)WRKY transcription factor family reveals putatively retained functions betweenmonocots and dicots

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

Mangelsen, Elke; Kilian, Joachim; Berendzen, Kenneth W.

2008-02-01

WRKY proteins belong to the WRKY-GCM1 superfamily of zinc finger transcription factors that have been subject to a large plant-specific diversification. For the cereal crop barley (Hordeum vulgare), three different WRKY proteins have been characterized so far, as regulators in sucrose signaling, in pathogen defense, and in response to cold and drought, respectively. However, their phylogenetic relationship remained unresolved. In this study, we used the available sequence information to identify a minimum number of 45 barley WRKY transcription factor (HvWRKY) genes. According to their structural features the HvWRKY factors were classified into the previously defined polyphyletic WRKY subgroups 1 tomore » 3. Furthermore, we could assign putative orthologs of the HvWRKY proteins in Arabidopsis and rice. While in most cases clades of orthologous proteins were formed within each group or subgroup, other clades were composed of paralogous proteins for the grasses and Arabidopsis only, which is indicative of specific gene radiation events. To gain insight into their putative functions, we examined expression profiles of WRKY genes from publicly available microarray data resources and found group specific expression patterns. While putative orthologs of the HvWRKY transcription factors have been inferred from phylogenetic sequence analysis, we performed a comparative expression analysis of WRKY genes in Arabidopsis and barley. Indeed, highly correlative expression profiles were found between some of the putative orthologs. HvWRKY genes have not only undergone radiation in monocot or dicot species, but exhibit evolutionary traits specific to grasses. HvWRKY proteins exhibited not only sequence similarities between orthologs with Arabidopsis, but also relatedness in their expression patterns. This correlative expression is indicative for a putative conserved function of related WRKY proteins in mono- and dicot species.« less

Persistence of Clones of Coagulase-Negative Staphylococci among Premature Neonates in Neonatal Intensive Care Units: Two-Center Study of Bacterial Genotyping and Patient Risk Factors

PubMed Central

Vermont, Clementien L.; Hartwig, Nico G.; Fleer, André; de Man, Peter; Verbrugh, Henri; van den Anker, John; de Groot, Ronald; van Belkum, Alex

1998-01-01

From 1 January 1995 until 1 January 1996, we studied the molecular epidemiology of blood isolates of coagulase-negative staphylococci (CoNS) in the Neonatal Intensive Care Units (NICUs) of the Sophia Children’s Hospital (SCH; Rotterdam, The Netherlands) and the Wilhelmina Children’s Hospital (WCH; Utrecht, The Netherlands). The main goal of the present study was to detect putatively endemic clones of CoNS persisting in these NICUs. Pulsed-field gel electrophoresis was used to detect the possible presence of endemic clones of clinical significance. In addition, clinical data of patients in the SCH were analyzed retrospectively to identify risk factors for the acquisition of positive blood cultures. In both centers, endemic CoNS clones were persistently present. Thirty-three percent of the bacterial isolates derived from blood cultures in the SCH belonged to a single genotype. In the WCH, 45% of all bacterial strains belonged to a single clone. These clones were clearly different from each other, which implies that site specificity is involved. Interestingly, we observe that the clonal type in the SCH differed significantly from the incidentally occurring strains with respect to both the average pH and partial CO2 pressure of the patient’s blood at the time of bacterial culture. We found that the use of intravascular catheters, low gestational age, and a long hospital stay were important risk factors for the development of a putative CoNS infection. When the antibiotic susceptibility of the bacterial isolates was assessed, a clear correlation between the nature of the antibiotics most frequently used as a first line of defense versus the resistance profile was observed. We conclude that the intensive use of antibiotics in an NICU setting with highly susceptible patients causes selection of multiresistant clones of CoNS which subsequently become endemic. PMID:9705379

Integrated Post-GWAS Analysis Sheds New Light on the Disease Mechanisms of Schizophrenia

PubMed Central

Lin, Jhih-Rong; Cai, Ying; Zhang, Quanwei; Zhang, Wen; Nogales-Cadenas, Rubén; Zhang, Zhengdong D.

2016-01-01

Schizophrenia is a severe mental disorder with a large genetic component. Recent genome-wide association studies (GWAS) have identified many schizophrenia-associated common variants. For most of the reported associations, however, the underlying biological mechanisms are not clear. The critical first step for their elucidation is to identify the most likely disease genes as the source of the association signals. Here, we describe a general computational framework of post-GWAS analysis for complex disease gene prioritization. We identify 132 putative schizophrenia risk genes in 76 risk regions spanning 120 schizophrenia-associated common variants, 78 of which have not been recognized as schizophrenia disease genes by previous GWAS. Even more significantly, 29 of them are outside the risk regions, likely under regulation of transcriptional regulatory elements contained therein. These putative schizophrenia risk genes are transcriptionally active in both brain and the immune system, and highly enriched among cellular pathways, consistent with leading pathophysiological hypotheses about the pathogenesis of schizophrenia. With their involvement in distinct biological processes, these putative schizophrenia risk genes, with different association strengths, show distinctive temporal expression patterns, and play specific biological roles during brain development. PMID:27754856

End-stage renal disease in Taiwan: a case-control study.

PubMed

Tsai, Su-Ying; Tseng, Hung-Fu; Tan, Hsiu-Fen; Chien, Yu-Shu; Chang, Chia-Chu

2009-01-01

Taiwan has the highest incidence of end-stage renal disease (ESRD) in the world. The epidemiologic features of ESRD, however, have not been investigated. In this case-control study, we evaluated the risk of ESRD associated with a number of putative risk factors. We studied 200 patients among whom ESRD had been newly diagnosed between 1 January 2005 and 31 December 2005; 200 controls were selected from among relatives of patients treated in the general surgery unit. Using a structured questionnaire, we collected information related to socioeconomic factors, history of disease, regular blood or urine screening, lifestyle, environmental exposure, consumption of vitamin supplements, and regular drug use at 5 years before disease onset. Our primary multivariate risk models indicated that low socioeconomic status was a strong predictor of ESRD (education: odds ratio [OR], 2.78; 95% confidence interval [CI], 1.49-5.19; income: OR, 2.86, 95% CI, 1.48-5.52), even after adjusting for other risk factors. Other significant predictors for ESRD were a history of hypertension (OR, 3.63-3.90), history of diabetes (OR, 3.85-5.50), and regular intake of folk remedies or over-the-counter Chinese herbs (OR, 10.84-12.51). Regular intake of a multivitamin supplement 5 years before diagnosis was associated with a decreased risk of ESRD (OR, 0.12-0.14). Our findings indicate that low socioeconomic status, history of hypertension, diabetes, and regular use of folk remedies or over-the-counter Chinese herbs were significant risk factors for ESRD, while regular intake of a multivitamin supplement was associated with a decreased risk of ESRD.

Predictors of human papillomavirus infection in women undergoing routine cervical cancer screening in Spain: the CLEOPATRE study

PubMed Central

2012-01-01

Background Human papillomavirus (HPV) is a sexually transmitted infection that may lead to development of precancerous and cancerous lesions of the cervix. The aim of the current study was to investigate socio-demographic, lifestyle, and medical factors for potential associations with cervical HPV infection in women undergoing cervical cancer screening in Spain. Methods The CLEOPATRE Spain study enrolled 3 261 women aged 18–65 years attending cervical cancer screening across the 17 Autonomous Communities. Liquid-based cervical samples underwent cytological examination and HPV testing. HPV positivity was determined using the Hybrid Capture II assay, and HPV genotyping was conducted using the INNO-LiPA HPV Genotyping Extra assay. Multivariate logistic regression was used to identify putative risk factors for HPV infection. Results A lifetime number of two or more sexual partners, young age (18–25 years), a history of genital warts, and unmarried status were the strongest independent risk factors for HPV infection of any type. Living in an urban community, country of birth other than Spain, low level of education, and current smoking status were also independent risk factors for HPV infection. A weak inverse association between condom use and HPV infection was observed. Unlike monogamous women, women with two or more lifetime sexual partners showed a lower risk of infection if their current partner was circumcised (P for interaction, 0.005) and a higher risk of infection if they were current smokers (P for interaction, 0.01). Conclusion This is the first large-scale, country-wide study exploring risk factors for cervical HPV infection in Spain. The data strongly indicate that variables related to sexual behavior are the main risk factors for HPV infection. In addition, in non-monogamous women, circumcision of the partner is associated with a reduced risk and smoking with an increased risk of HPV infection. PMID:22734435

Predictors of human papillomavirus infection in women undergoing routine cervical cancer screening in Spain: the CLEOPATRE study.

PubMed

Roura, Esther; Iftner, Thomas; Vidart, José Antonio; Kjaer, Susanne Krüger; Bosch, F Xavier; Muñoz, Nubia; Palacios, Santiago; Rodriguez, Maria San Martin; Morillo, Carmen; Serradell, Laurence; Torcel-Pagnon, Laurence; Cortes, Javier; Castellsagué, Xavier

2012-06-26

Human papillomavirus (HPV) is a sexually transmitted infection that may lead to development of precancerous and cancerous lesions of the cervix. The aim of the current study was to investigate socio-demographic, lifestyle, and medical factors for potential associations with cervical HPV infection in women undergoing cervical cancer screening in Spain. The CLEOPATRE Spain study enrolled 3 261 women aged 18-65 years attending cervical cancer screening across the 17 Autonomous Communities. Liquid-based cervical samples underwent cytological examination and HPV testing. HPV positivity was determined using the Hybrid Capture II assay, and HPV genotyping was conducted using the INNO-LiPA HPV Genotyping Extra assay. Multivariate logistic regression was used to identify putative risk factors for HPV infection. A lifetime number of two or more sexual partners, young age (18-25 years), a history of genital warts, and unmarried status were the strongest independent risk factors for HPV infection of any type. Living in an urban community, country of birth other than Spain, low level of education, and current smoking status were also independent risk factors for HPV infection. A weak inverse association between condom use and HPV infection was observed. Unlike monogamous women, women with two or more lifetime sexual partners showed a lower risk of infection if their current partner was circumcised (P for interaction, 0.005) and a higher risk of infection if they were current smokers (P for interaction, 0.01). This is the first large-scale, country-wide study exploring risk factors for cervical HPV infection in Spain. The data strongly indicate that variables related to sexual behavior are the main risk factors for HPV infection. In addition, in non-monogamous women, circumcision of the partner is associated with a reduced risk and smoking with an increased risk of HPV infection.

Risk for Low Pathogenicity Avian Influenza Virus on Poultry Farms, the Netherlands, 2007-2013.

PubMed

Bouwstra, Ruth; Gonzales, Jose L; de Wit, Sjaak; Stahl, Julia; Fouchier, Ron A M; Elbers, Armin R W

2017-09-01

Using annual serologic surveillance data from all poultry farms in the Netherlands during 2007-2013, we quantified the risk for the introduction of low pathogenicity avian influenza virus (LPAIV) in different types of poultry production farms and putative spatial-environmental risk factors: distance from poultry farms to clay soil, waterways, and wild waterfowl areas. Outdoor-layer, turkey (meat and breeder), and duck (meat and breeder) farms had a significantly higher risk for LPAIV introduction than did indoor-layer farms. Except for outdoor-layer, all poultry types (i.e., broilers, chicken breeders, ducks, and turkeys) are kept indoors. For all production types, LPAIV risk decreased significantly with increasing distance to medium-sized waterways and with increasing distance to areas with defined wild waterfowl, but only for outdoor-layer and turkey farms. Future research should focus not only on production types but also on distance to waterways and wild bird areas. In addition, settlement of new poultry farms in high-risk areas should be discouraged.

Risk for Low Pathogenicity Avian Influenza Virus on Poultry Farms, the Netherlands, 2007–2013

PubMed Central

Bouwstra, Ruth; Gonzales, Jose L.; de Wit, Sjaak; Stahl, Julia; Fouchier, Ron A.M.

2017-01-01

Using annual serologic surveillance data from all poultry farms in the Netherlands during 2007–2013, we quantified the risk for the introduction of low pathogenicity avian influenza virus (LPAIV) in different types of poultry production farms and putative spatial-environmental risk factors: distance from poultry farms to clay soil, waterways, and wild waterfowl areas. Outdoor-layer, turkey (meat and breeder), and duck (meat and breeder) farms had a significantly higher risk for LPAIV introduction than did indoor-layer farms. Except for outdoor-layer, all poultry types (i.e., broilers, chicken breeders, ducks, and turkeys) are kept indoors. For all production types, LPAIV risk decreased significantly with increasing distance to medium-sized waterways and with increasing distance to areas with defined wild waterfowl, but only for outdoor-layer and turkey farms. Future research should focus not only on production types but also on distance to waterways and wild bird areas. In addition, settlement of new poultry farms in high-risk areas should be discouraged. PMID:28820139

Characterization of Clinical and Genetic Risk Factors Associated with Dyslipidemia after Kidney Transplantation

PubMed Central

Numakura, Kazuyuki; Kagaya, Hideaki; Yamamoto, Ryohei; Komine, Naoki; Saito, Mitsuru; Hiroshi, Tsuruta; Akihama, Susumu; Narita, Shintaro; Tsuchiya, Norihiko; Habuchi, Tomonori; Niioka, Takenori; Miura, Masatomo; Satoh, Shigeru

2015-01-01

We determined the prevalence of dyslipidemia in a Japanese cohort of renal allograft recipients and investigated clinical and genetic characteristics associated with having the disease. In total, 126 patients that received renal allograft transplants between February 2002 and August 2011 were studied, of which 44 recipients (34.9%) were diagnosed with dyslipidemia at 1 year after transplantation. Three clinical factors were associated with a risk of having dyslipidemia: a higher prevalence of disease observed among female than male patients (P = 0.021) and treatment with high mycophenolate mofetil (P = 0.012) and prednisolone (P = 0.023) doses per body weight at 28 days after transplantation. The genetic association between dyslipidemia and 60 previously described genetic polymorphisms in 38 putative disease-associated genes was analyzed. The frequency of dyslipidemia was significantly higher in patients with the glucocorticoid receptor (NR3C1) Bcl1 G allele than in those with the CC genotype (P = 0.001). A multivariate analysis revealed that the NR3C1 Bcl1 G allele was a significant risk factor for the prevalence of dyslipidemia (odds ratio = 4.6; 95% confidence interval = 1.8–12.2). These findings may aid in predicting a patient's risk of developing dyslipidemia. PMID:25944971

Potential Genetic Risk Factors for Chronic TMD: Genetic Associations from the OPPERA Case Control Study

PubMed Central

Smith, Shad B.; Maixner, Dylan; Greenspan, Joel; Dubner, Ron; Fillingim, Roger; Ohrbach, Richard; Knott, Charles; Slade, Gary; Bair, Eric; Gibson, Dustin G.; Zaykin, Dmitri V.; Weir, Bruce; Maixner, William; Diatchenko, Luda

2011-01-01

Genetic factors play a role in the etiology of persistent pain conditions, putatively by modulating underlying processes such as nociceptive sensitivity, psychological well-being, inflammation, and autonomic response. However, to date, only a few genes have been associated with temporomandibular disorders (TMD). This study evaluated 358 genes involved in pain processes, comparing allelic frequencies between 166 cases with chronic TMD and 1442 controls enrolled in the OPPERA (Orofacial Pain: Prospective Evaluation and Risk Assessment) study cooperative agreement. To enhance statistical power, 182 TMD cases and 170 controls from a similar study were included in the analysis. Genotyping was performed using the Pain Research Panel, an Affymetrix gene chip representing 3295 single nucleotide polymorphisms, including ancestry-informative markers that were used to adjust for population stratification. Adjusted associations between genetic markers and TMD case status were evaluated using logistic regression. The OPPERA findings provided evidence supporting previously-reported associations between TMD and two genes: HTR2A and COMT. Other genes were revealed as potential new genetic risk factors for TMD, including NR3C1, CAMK4, CHRM2, IFRD1, and GRK5. While these findings need to be replicated in independent cohorts, the genes potentially represent important markers of risk for TMD and they identify potential targets for therapeutic intervention. PMID:22074755

Risk of endometrial cancer in relation to medical conditions and medication use.

PubMed

Fortuny, Joan; Sima, Camelia; Bayuga, Sharon; Wilcox, Homer; Pulick, Katherine; Faulkner, Shameka; Zauber, Ann G; Olson, Sara H

2009-05-01

We studied the relation of medical conditions related to obesity and medications used for these conditions with endometrial cancer. We also investigated the association of other medical conditions and medications with risk. This U.S. population-based case-control study included 469 endometrial cancer cases and 467 controls. Information on putative risk factors for endometrial cancer was collected through personal interviews. We asked women about their medical history and medications used for six months or longer and the number of years each medication was taken. Risk was strongly associated with increasing obesity (P for trend < 0.001). Among the conditions related to obesity, and after adjustment for age, body mass index, and other risk factors and conditions, uterine fibroids were independently related to an increased cancer risk [adjusted odds ratio (OR), 1.8; 95% confidence interval (95% CI), 1.2-2.5]. Although hypertension was not significantly related to endometrial cancer after adjustment for age and body mass index, the use of thiazide diuretics was independently associated with increased risk (OR, 1.8; 95% CI, 1.1-3.0). Anemia was associated with decreased risk (OR, 0.6; 95% CI, 0.5-0.9). Use of nonsteroidal anti-inflammatory drugs was related to a decreased risk (OR, 0.7; 95% CI, 0.5-0.97). To our knowledge, the observation about thiazide diuretics is novel and requires confirmation in other studies and populations.

[Investigation on a group of autistic children: risk factors and medical social considerations].

PubMed

Troili, G M; Businaro, R; Massoni, F; Ricci, L; Petrone, L; Ricci, P; Ricci, S

2013-01-01

The aim of this work is to study the association between autism in a group of autistic children and risk factors for specific familiar diseases and developmental disease in the early years of life, through a medical social investigation. For this study, we have submitted an anamnestic questionnaire to 29 autistic children and their families in a South Italy region (Basilicata), collecting data about children and their parents. The results show that many children have a family history of autoimmune diseases (psoriasis, rheumatoid arthritis, celiac disease, Takayasu's arteritis), allergies and food intolerances, suggesting a putative involvement of the immune system in autism etiopathogenesis. Analyzing residences areas of patients, Potenza and Matera, with their environmental factors (radioactive waste repositories, incinerators, intensive farming), we demonstrate that the particular territorial characteristics don't affect autism. Autistic disorder is a spectrum of neurologic disorders complex both in etiopathogenesis and healthcare. So we aim to continue the study already undertaken on cytokines of autistic subjects serum and to extend it through biomolecular approaches assessing the presence of specific genetic polymorphisms in order to identify the physiopathogenetic mechanisms underlying the disease and to evaluate the predictive risk with the aim to improve care interventions.

Spatial clustering of malaria and associated risk factors during an epidemic in a highland area of western Kenya.

PubMed

Brooker, Simon; Clarke, Siân; Njagi, Joseph Kiambo; Polack, Sarah; Mugo, Benbolt; Estambale, Benson; Muchiri, Eric; Magnussen, Pascal; Cox, Jonathan

2004-07-01

The epidemiology of malaria over small areas remains poorly understood, and this is particularly true for malaria during epidemics in highland areas of Africa, where transmission intensity is low and characterized by acute within and between year variations. We report an analysis of the spatial distribution of clinical malaria during an epidemic and investigate putative risk factors. Active case surveillance was undertaken in three schools in Nandi District, Western Kenya for 10 weeks during a malaria outbreak in May-July 2002. Household surveys of cases and age-matched controls were conducted to collect information on household construction, exposure factors and socio-economic status. Household geographical location and altitude were determined using a hand-held geographical positioning system and landcover types were determined using high spatial resolution satellite sensor data. Among 129 cases identified during the surveillance, which were matched to 155 controls, we identified significant spatial clusters of malaria cases as determined using the spatial scan statistic. Conditional multiple logistic regression analysis showed that the risk of malaria was higher in children who were underweight, who lived at lower altitudes, and who lived in households where drugs were not kept at home. Copyright 2004 Blackwell Publishing Ltd

Triggers for an episode of sudden onset low back pain: study protocol

PubMed Central

2012-01-01

Background Most research on risk factors for low back pain has focused on long term exposures rather than factors immediately preceding the onset of low back pain. The aim of this study is to quantify the transient increase in risk of a sudden episode of low back pain associated with acute exposure to a range of common physical and psychological factors. Methods/design This study uses a case-crossover design. One thousand adults with a sudden onset of low back pain presenting to primary care clinicians will be recruited. Basic demographic and clinical information including exposure to putative triggers will be collected using a questionnaire. These triggers include exposure to hazardous manual tasks, physical activity, a slip/trip or fall, consumption of alcohol, sexual activity, being distracted, and being fatigued or tired. Exposures in the case window (0-2 hours from the time when participants first notice their back pain) will be compared to exposures in two control time-windows (one 24-26 hours and another 48-50 hours before the case window). Discussion The completion of this study will provide the first-research based estimates of the increase in risk of a sudden episode of acute low back pain associated with transient exposure to a range of common factors thought to trigger low back pain. PMID:22273001

Risk Factors for Campylobacteriosis of Chicken, Ruminant, and Environmental Origin: A Combined Case-Control and Source Attribution Analysis

PubMed Central

Wagenaar, Jaap A.; de Boer, Albert G.; Havelaar, Arie H.; Friesema, Ingrid H. M.; French, Nigel P.; Busani, Luca; van Pelt, Wilfrid

2012-01-01

Background Campylobacteriosis contributes strongly to the disease burden of food-borne pathogens. Case-control studies are limited in attributing human infections to the different reservoirs because they can only trace back to the points of exposure, which may not point to the original reservoirs because of cross-contamination. Human Campylobacter infections can be attributed to specific reservoirs by estimating the extent of subtype sharing between strains from humans and reservoirs using multilocus sequence typing (MLST). Methodology/Principal Findings We investigated risk factors for human campylobacteriosis caused by Campylobacter strains attributed to different reservoirs. Sequence types (STs) were determined for 696 C. jejuni and 41 C. coli strains from endemic human cases included in a case-control study. The asymmetric island model, a population genetics approach for modeling Campylobacter evolution and transmission, attributed these cases to four putative animal reservoirs (chicken, cattle, sheep, pig) and to the environment (water, sand, wild birds) considered as a proxy for other unidentified reservoirs. Most cases were attributed to chicken (66%) and cattle (21%), identified as the main reservoirs in The Netherlands. Consuming chicken was a risk factor for campylobacteriosis caused by chicken-associated STs, whereas consuming beef and pork were protective. Risk factors for campylobacteriosis caused by ruminant-associated STs were contact with animals, barbecuing in non-urban areas, consumption of tripe, and never/seldom chicken consumption. Consuming game and swimming in a domestic swimming pool during springtime were risk factors for campylobacteriosis caused by environment-associated STs. Infections with chicken- and ruminant-associated STs were only partially explained by food-borne transmission; direct contact and environmental pathways were also important. Conclusion/Significance This is the first case-control study in which risk factors for campylobacteriosis are investigated in relation to the attributed reservoirs based on MLST profiles. Combining epidemiological and source attribution data improved campylobacteriosis risk factor identification and characterization, generated hypotheses, and showed that genotype-based source attribution is epidemiologically sensible. PMID:22880049

Nutritional habits, risk, and progression of Parkinson disease.

PubMed

Erro, Roberto; Brigo, Francesco; Tamburin, Stefano; Zamboni, Mauro; Antonini, Angelo; Tinazzi, Michele

2018-01-01

Parkinson disease (PD) is a multifactorial disease, where a genetic predisposition combines with putative environmental risk factors. Mounting evidence suggests that the initial PD pathological manifestations may be located in the gut to subsequently affect brain areas. Moreover, several lines of research demonstrated that there are bidirectional connections between the central nervous system and the gut, the "gut-brain axis" that influences both brain and gastrointestinal function. This opens a potential therapeutic window suggesting that specific dietary strategies may interact with the disease process and influence the risk of PD or modify its course. Dietary components can also theoretically modulate the chronic activation of the inflammatory response that is associated with aging, the strongest risk factor for PD, that has been suggested to hasten the underlying neurodegenerative process in PD. Here, we reviewed the evidence supporting an association between certain dietary compound and either the risk or progression of PD and have provided an overview of the possible pathomechanisms linking nutrition and neurodegeneration. The results of our review would not support a clear role for any dietary components in reducing the risk or progression of PD. However, the evidence favouring a connection between gut abnormalities, inflammation, and neurodegeneration in PD have become too compelling to be ignored, so that further research, also in the field of nutritional genomics, is highly warranted.

Emotional abuse of girls in Swaziland: prevalence, perpetrators, risk and protective factors and health outcomes

PubMed Central

Meinck, Franziska; Fry, Deborah; Ginindza, Choice; Wazny, Kerri; Elizalde, Aldo; Spreckelsen, Thees F; Maternowska, M Catherine; Dunne, Michael P

2017-01-01

Background Research on emotional child abuse in sub–Saharan Africa is scarce. Few studies thus far have examined prevalence, risk and protective factors for emotional child abuse or the associations between emotional abuse and girls’ health. Methods A nationally representative two–stage, cluster–sampled, household survey of females aged 13–24 years (n = 1244) on childhood abuse victimisation was conducted. Participants completed interviewer–assisted questionnaires. Associations between emotional abuse and putative risk, and protective factors and health outcomes were analyzed using separate logistic regression models accounting for sampling design. Marginal effects of cumulative risk factors for emotional abuse victimisation were examined. Results Lifetime prevalence of emotional abuse was 28.5% with 58.3% of these girls reporting many abusive incidents. The most common perpetrators were female (27.8%) and male (16.7%) relatives and, more rarely, biological parents. Risk factors associated with emotional abuse were frequent caregiver changes (odds ratio (OR) 1.42, 95% confidence interval (CI) 1.03–1.970, poverty (OR 1.51, 95% CI 1.12–2.03), and physical abuse (OR 1.98, 95% CI 1.45–2.71) and sexual abuse (OR 2.22, 95% CI 1.57–3.10) victimisation. Being close to one’s mother was a protective factor (OR 0.88, 95% CI 0.80–0.97). Risk for emotional abuse increased from 13% with no risk factors present to 58.4% –with all four risk factors present. Health outcomes associated with emotional child abuse were suicidal ideation (OR 1.85, 95% CI 1.30–2.63) and feeling depressed (OR 1.89, 95% CI 1.31–2.71). Conclusions Girls in Swaziland experience high levels of emotional abuse victimisation. Emotional abuse is associated with economic disadvantage, family factors, other types of abuse victimisation and poor mental health. Therefore, a holistic approach to prevention is needed, incorporating poverty reduction and programmes to improve parent–child relationships, reduce the use of harsh criticism, and change parenting social norms. PMID:28607670

Enrichment of putative PAX8 target genes at serous epithelial ovarian cancer susceptibility loci.

PubMed

Kar, Siddhartha P; Adler, Emily; Tyrer, Jonathan; Hazelett, Dennis; Anton-Culver, Hoda; Bandera, Elisa V; Beckmann, Matthias W; Berchuck, Andrew; Bogdanova, Natalia; Brinton, Louise; Butzow, Ralf; Campbell, Ian; Carty, Karen; Chang-Claude, Jenny; Cook, Linda S; Cramer, Daniel W; Cunningham, Julie M; Dansonka-Mieszkowska, Agnieszka; Doherty, Jennifer Anne; Dörk, Thilo; Dürst, Matthias; Eccles, Diana; Fasching, Peter A; Flanagan, James; Gentry-Maharaj, Aleksandra; Glasspool, Rosalind; Goode, Ellen L; Goodman, Marc T; Gronwald, Jacek; Heitz, Florian; Hildebrandt, Michelle A T; Høgdall, Estrid; Høgdall, Claus K; Huntsman, David G; Jensen, Allan; Karlan, Beth Y; Kelemen, Linda E; Kiemeney, Lambertus A; Kjaer, Susanne K; Kupryjanczyk, Jolanta; Lambrechts, Diether; Levine, Douglas A; Li, Qiyuan; Lissowska, Jolanta; Lu, Karen H; Lubiński, Jan; Massuger, Leon F A G; McGuire, Valerie; McNeish, Iain; Menon, Usha; Modugno, Francesmary; Monteiro, Alvaro N; Moysich, Kirsten B; Ness, Roberta B; Nevanlinna, Heli; Paul, James; Pearce, Celeste L; Pejovic, Tanja; Permuth, Jennifer B; Phelan, Catherine; Pike, Malcolm C; Poole, Elizabeth M; Ramus, Susan J; Risch, Harvey A; Rossing, Mary Anne; Salvesen, Helga B; Schildkraut, Joellen M; Sellers, Thomas A; Sherman, Mark; Siddiqui, Nadeem; Sieh, Weiva; Song, Honglin; Southey, Melissa; Terry, Kathryn L; Tworoger, Shelley S; Walsh, Christine; Wentzensen, Nicolas; Whittemore, Alice S; Wu, Anna H; Yang, Hannah; Zheng, Wei; Ziogas, Argyrios; Freedman, Matthew L; Gayther, Simon A; Pharoah, Paul D P; Lawrenson, Kate

2017-02-14

Genome-wide association studies (GWAS) have identified 18 loci associated with serous ovarian cancer (SOC) susceptibility but the biological mechanisms driving these findings remain poorly characterised. Germline cancer risk loci may be enriched for target genes of transcription factors (TFs) critical to somatic tumorigenesis. All 615 TF-target sets from the Molecular Signatures Database were evaluated using gene set enrichment analysis (GSEA) and three GWAS for SOC risk: discovery (2196 cases/4396 controls), replication (7035 cases/21 693 controls; independent from discovery), and combined (9627 cases/30 845 controls; including additional individuals). The PAX8-target gene set was ranked 1/615 in the discovery (P GSEA <0.001; FDR=0.21), 7/615 in the replication (P GSEA =0.004; FDR=0.37), and 1/615 in the combined (P GSEA <0.001; FDR=0.21) studies. Adding other genes reported to interact with PAX8 in the literature to the PAX8-target set and applying an alternative to GSEA, interval enrichment, further confirmed this association (P=0.006). Fifteen of the 157 genes from this expanded PAX8 pathway were near eight loci associated with SOC risk at P<10 -5 (including six with P<5 × 10 -8 ). The pathway was also associated with differential gene expression after shRNA-mediated silencing of PAX8 in HeyA8 (P GSEA =0.025) and IGROV1 (P GSEA =0.004) SOC cells and several PAX8 targets near SOC risk loci demonstrated in vitro transcriptomic perturbation. Putative PAX8 target genes are enriched for common SOC risk variants. This finding from our agnostic evaluation is of particular interest given that PAX8 is well-established as a specific marker for the cell of origin of SOC.

LBH Gene Transcription Regulation by the Interplay of an Enhancer Risk Allele and DNA Methylation in Rheumatoid Arthritis.

PubMed

Hammaker, Deepa; Whitaker, John W; Maeshima, Keisuke; Boyle, David L; Ekwall, Anna-Karin H; Wang, Wei; Firestein, Gary S

2016-11-01

To identify nonobvious therapeutic targets for rheumatoid arthritis (RA), we performed an integrative analysis incorporating multiple "omics" data and the Encyclopedia of DNA Elements (ENCODE) database for potential regulatory regions. This analysis identified the limb bud and heart development (LBH) gene, which has risk alleles associated with RA/celiac disease and lupus, and can regulate cell proliferation in RA. We identified a novel LBH transcription enhancer with an RA risk allele (rs906868 G [Ref]/T) 6 kb upstream of the LBH gene with a differentially methylated locus. The confluence of 3 regulatory elements, rs906868, an RA differentially methylated locus, and a putative enhancer, led us to investigate their effects on LBH regulation in fibroblast-like synoviocytes (FLS). We cloned the 1.4-kb putative enhancer with either the rs906868 Ref allele or single-nucleotide polymorphism (SNP) variant into reporter constructs. The constructs were methylated in vitro and transfected into cultured FLS by nucleofection. We found that both variants increased transcription, thereby confirming the region's enhancer function. Unexpectedly, the transcriptional activity of the Ref risk allele was significantly lower than that of the SNP variant and is consistent with low LBH levels as a risk factor for aggressive FLS behavior. Using RA FLS lines with a homozygous Ref or SNP allele, we confirmed that homozygous Ref lines expressed lower LBH messenger RNA levels than did the SNP lines. Methylation significantly reduced enhancer activity for both alleles, indicating that enhancer function is dependent on its methylation status. This study shows how the interplay between genetics and epigenetics can affect expression of LBH in RA. © 2016, American College of Rheumatology.

Enrichment of putative PAX8 target genes at serous epithelial ovarian cancer susceptibility loci

PubMed Central

Kar, Siddhartha P; Adler, Emily; Tyrer, Jonathan; Hazelett, Dennis; Anton-Culver, Hoda; Bandera, Elisa V; Beckmann, Matthias W; Berchuck, Andrew; Bogdanova, Natalia; Brinton, Louise; Butzow, Ralf; Campbell, Ian; Carty, Karen; Chang-Claude, Jenny; Cook, Linda S; Cramer, Daniel W; Cunningham, Julie M; Dansonka-Mieszkowska, Agnieszka; Doherty, Jennifer Anne; Dörk, Thilo; Dürst, Matthias; Eccles, Diana; Fasching, Peter A; Flanagan, James; Gentry-Maharaj, Aleksandra; Glasspool, Rosalind; Goode, Ellen L; Goodman, Marc T; Gronwald, Jacek; Heitz, Florian; Hildebrandt, Michelle A T; Høgdall, Estrid; Høgdall, Claus K; Huntsman, David G; Jensen, Allan; Karlan, Beth Y; Kelemen, Linda E; Kiemeney, Lambertus A; Kjaer, Susanne K; Kupryjanczyk, Jolanta; Lambrechts, Diether; Levine, Douglas A; Li, Qiyuan; Lissowska, Jolanta; Lu, Karen H; Lubiński, Jan; Massuger, Leon F A G; McGuire, Valerie; McNeish, Iain; Menon, Usha; Modugno, Francesmary; Monteiro, Alvaro N; Moysich, Kirsten B; Ness, Roberta B; Nevanlinna, Heli; Paul, James; Pearce, Celeste L; Pejovic, Tanja; Permuth, Jennifer B; Phelan, Catherine; Pike, Malcolm C; Poole, Elizabeth M; Ramus, Susan J; Risch, Harvey A; Rossing, Mary Anne; Salvesen, Helga B; Schildkraut, Joellen M; Sellers, Thomas A; Sherman, Mark; Siddiqui, Nadeem; Sieh, Weiva; Song, Honglin; Southey, Melissa; Terry, Kathryn L; Tworoger, Shelley S; Walsh, Christine; Wentzensen, Nicolas; Whittemore, Alice S; Wu, Anna H; Yang, Hannah; Zheng, Wei; Ziogas, Argyrios; Freedman, Matthew L; Gayther, Simon A; Pharoah, Paul D P; Lawrenson, Kate

2017-01-01

Background: Genome-wide association studies (GWAS) have identified 18 loci associated with serous ovarian cancer (SOC) susceptibility but the biological mechanisms driving these findings remain poorly characterised. Germline cancer risk loci may be enriched for target genes of transcription factors (TFs) critical to somatic tumorigenesis. Methods: All 615 TF-target sets from the Molecular Signatures Database were evaluated using gene set enrichment analysis (GSEA) and three GWAS for SOC risk: discovery (2196 cases/4396 controls), replication (7035 cases/21 693 controls; independent from discovery), and combined (9627 cases/30 845 controls; including additional individuals). Results: The PAX8-target gene set was ranked 1/615 in the discovery (PGSEA<0.001; FDR=0.21), 7/615 in the replication (PGSEA=0.004; FDR=0.37), and 1/615 in the combined (PGSEA<0.001; FDR=0.21) studies. Adding other genes reported to interact with PAX8 in the literature to the PAX8-target set and applying an alternative to GSEA, interval enrichment, further confirmed this association (P=0.006). Fifteen of the 157 genes from this expanded PAX8 pathway were near eight loci associated with SOC risk at P<10−5 (including six with P<5 × 10−8). The pathway was also associated with differential gene expression after shRNA-mediated silencing of PAX8 in HeyA8 (PGSEA=0.025) and IGROV1 (PGSEA=0.004) SOC cells and several PAX8 targets near SOC risk loci demonstrated in vitro transcriptomic perturbation. Conclusions: Putative PAX8 target genes are enriched for common SOC risk variants. This finding from our agnostic evaluation is of particular interest given that PAX8 is well-established as a specific marker for the cell of origin of SOC. PMID:28103614

Sex Differences in Clinical Predictors of Suicidal Acts After Major Depression: A Prospective Study

PubMed Central

Oquendo, Maria A.; Bongiovi-Garcia, Mary E.; Galfalvy, Hanga; Goldberg, Pablo H.; Grunebaum, Michael F.; Burke, Ainsley K.; Mann, J. John

2013-01-01

Objective Whether sex differences exist in clinical risk factors associated with suicidal behavior is unknown. The authors postulated that among men with a major depressive episode, aggression, hostility, and history of substance misuse increase risk for future suicidal behavior, while depressive symptoms, childhood history of abuse, fewer reasons for living, and borderline personality disorder do so in depressed women. Method Patients with DSM-III-R major depression or bipolar disorder seeking treatment for a major depressive episode (N=314) were followed for 2 years. Putative predictors were tested with Cox proportional hazards regression analysis. Results During follow-up, 16.6% of the patients attempted or committed suicide. Family history of suicidal acts, past drug use, cigarette smoking, borderline personality disorder, and early parental separation each more than tripled the risk of future suicidal acts in men. For women, the risk for future suicidal acts was sixfold greater for prior suicide attempters; each past attempt increased future risk threefold. Suicidal ideation, lethality of past attempts, hostility, subjective depressive symptoms, fewer reasons for living, comorbid borderline personality disorder, and cigarette smoking also increased the risk of future suicidal acts for women. Conclusions These findings suggest that the importance of risk factors for suicidal acts differs in depressed men and women. This knowledge may improve suicide risk evaluation and guide future research on suicide assessment and prevention. PMID:17202555

The ACTTION-American Pain Society Pain Taxonomy (AAPT): an evidence-based and multidimensional approach to classifying chronic pain conditions.

PubMed

Fillingim, Roger B; Bruehl, Stephen; Dworkin, Robert H; Dworkin, Samuel F; Loeser, John D; Turk, Dennis C; Widerstrom-Noga, Eva; Arnold, Lesley; Bennett, Robert; Edwards, Robert R; Freeman, Roy; Gewandter, Jennifer; Hertz, Sharon; Hochberg, Marc; Krane, Elliot; Mantyh, Patrick W; Markman, John; Neogi, Tuhina; Ohrbach, Richard; Paice, Judith A; Porreca, Frank; Rappaport, Bob A; Smith, Shannon M; Smith, Thomas J; Sullivan, Mark D; Verne, G Nicholas; Wasan, Ajay D; Wesselmann, Ursula

2014-03-01

Current approaches to classification of chronic pain conditions suffer from the absence of a systematically implemented and evidence-based taxonomy. Moreover, existing diagnostic approaches typically fail to incorporate available knowledge regarding the biopsychosocial mechanisms contributing to pain conditions. To address these gaps, the Analgesic, Anesthetic, and Addiction Clinical Trial Translations Innovations Opportunities and Networks (ACTTION) public-private partnership with the U.S. Food and Drug Administration and the American Pain Society (APS) have joined together to develop an evidence-based chronic pain classification system called the ACTTION-APS Pain Taxonomy. This paper describes the outcome of an ACTTION-APS consensus meeting, at which experts agreed on a structure for this new taxonomy of chronic pain conditions. Several major issues around which discussion revolved are presented and summarized, and the structure of the taxonomy is presented. ACTTION-APS Pain Taxonomy will include the following dimensions: 1) core diagnostic criteria; 2) common features; 3) common medical comorbidities; 4) neurobiological, psychosocial, and functional consequences; and 5) putative neurobiological and psychosocial mechanisms, risk factors, and protective factors. In coming months, expert working groups will apply this taxonomy to clusters of chronic pain conditions, thereby developing a set of diagnostic criteria that have been consistently and systematically implemented across nearly all common chronic pain conditions. It is anticipated that the availability of this evidence-based and mechanistic approach to pain classification will be of substantial benefit to chronic pain research and treatment. The ACTTION-APS Pain Taxonomy is an evidence-based chronic pain classification system designed to classify chronic pain along the following dimensions: 1) core diagnostic criteria; 2) common features; 3) common medical comorbidities; 4) neurobiological, psychosocial, and functional consequences; and 5) putative neurobiological and psychosocial mechanisms, risk factors, and protective factors. Copyright © 2014 American Pain Society. Published by Elsevier Inc. All rights reserved.

CYP17 genetic polymorphism, breast cancer, and breast cancer risk factors.

PubMed

Ambrosone, Christine B; Moysich, Kirsten B; Furberg, Helena; Freudenheim, Jo L; Bowman, Elise D; Ahmed, Sabrina; Graham, Saxon; Vena, John E; Shields, Peter G

2003-01-01

Findings from previous studies regarding the association between the CYP17 genotype and breast cancer are inconsistent. We investigated the role of the MspAI genetic polymorphism in the 5' region of CYP17 on risk of breast cancer and as a modifier of reproductive risk factors. Questionnaire and genotyping data were obtained from a population-based, case-control study of premenopausal (n = 182) and postmenopausal (n = 214) European-American Caucasian women in western New York. Cases and controls were frequency matched by age and by county of residence. Odds ratios and 95% confidence intervals were used to estimate relative risks. The CYP17 genotype was not associated with breast cancer risk; however, controls with the A2/A2 genotype (associated with higher estrogens) had earlier menarche and earlier first full-term pregnancy. Premenopausal women with A1/A1 genotypes, but not with A2 alleles, were at significantly decreased risk with late age at menarche (odds ratio = 0.37, 95% confidence interval = 0.14-0.99), and at increased risk with late age at first full-term pregnancy (odds ratio = 4.30, 95% confidence interval = 1.46-12.67) and with use of oral contraceptives (odds ratio = 3.24, 95% confidence interval = 1.08-9.73). Associations were weaker among postmenopausal women. These results suggest that the effects of factors that may alter breast cancer risk through a hormonal mechanism may be less important among premenopausal women with putative higher lifetime exposures to circulating estrogens related to the CYP17 A2 allele.

Genome-wide association analyses identify 44 risk variants and refine the genetic architecture of major depression.

PubMed

Wray, Naomi R; Ripke, Stephan; Mattheisen, Manuel; Trzaskowski, Maciej; Byrne, Enda M; Abdellaoui, Abdel; Adams, Mark J; Agerbo, Esben; Air, Tracy M; Andlauer, Till M F; Bacanu, Silviu-Alin; Bækvad-Hansen, Marie; Beekman, Aartjan F T; Bigdeli, Tim B; Binder, Elisabeth B; Blackwood, Douglas R H; Bryois, Julien; Buttenschøn, Henriette N; Bybjerg-Grauholm, Jonas; Cai, Na; Castelao, Enrique; Christensen, Jane Hvarregaard; Clarke, Toni-Kim; Coleman, Jonathan I R; Colodro-Conde, Lucía; Couvy-Duchesne, Baptiste; Craddock, Nick; Crawford, Gregory E; Crowley, Cheynna A; Dashti, Hassan S; Davies, Gail; Deary, Ian J; Degenhardt, Franziska; Derks, Eske M; Direk, Nese; Dolan, Conor V; Dunn, Erin C; Eley, Thalia C; Eriksson, Nicholas; Escott-Price, Valentina; Kiadeh, Farnush Hassan Farhadi; Finucane, Hilary K; Forstner, Andreas J; Frank, Josef; Gaspar, Héléna A; Gill, Michael; Giusti-Rodríguez, Paola; Goes, Fernando S; Gordon, Scott D; Grove, Jakob; Hall, Lynsey S; Hannon, Eilis; Hansen, Christine Søholm; Hansen, Thomas F; Herms, Stefan; Hickie, Ian B; Hoffmann, Per; Homuth, Georg; Horn, Carsten; Hottenga, Jouke-Jan; Hougaard, David M; Hu, Ming; Hyde, Craig L; Ising, Marcus; Jansen, Rick; Jin, Fulai; Jorgenson, Eric; Knowles, James A; Kohane, Isaac S; Kraft, Julia; Kretzschmar, Warren W; Krogh, Jesper; Kutalik, Zoltán; Lane, Jacqueline M; Li, Yihan; Li, Yun; Lind, Penelope A; Liu, Xiaoxiao; Lu, Leina; MacIntyre, Donald J; MacKinnon, Dean F; Maier, Robert M; Maier, Wolfgang; Marchini, Jonathan; Mbarek, Hamdi; McGrath, Patrick; McGuffin, Peter; Medland, Sarah E; Mehta, Divya; Middeldorp, Christel M; Mihailov, Evelin; Milaneschi, Yuri; Milani, Lili; Mill, Jonathan; Mondimore, Francis M; Montgomery, Grant W; Mostafavi, Sara; Mullins, Niamh; Nauck, Matthias; Ng, Bernard; Nivard, Michel G; Nyholt, Dale R; O'Reilly, Paul F; Oskarsson, Hogni; Owen, Michael J; Painter, Jodie N; Pedersen, Carsten Bøcker; Pedersen, Marianne Giørtz; Peterson, Roseann E; Pettersson, Erik; Peyrot, Wouter J; Pistis, Giorgio; Posthuma, Danielle; Purcell, Shaun M; Quiroz, Jorge A; Qvist, Per; Rice, John P; Riley, Brien P; Rivera, Margarita; Saeed Mirza, Saira; Saxena, Richa; Schoevers, Robert; Schulte, Eva C; Shen, Ling; Shi, Jianxin; Shyn, Stanley I; Sigurdsson, Engilbert; Sinnamon, Grant B C; Smit, Johannes H; Smith, Daniel J; Stefansson, Hreinn; Steinberg, Stacy; Stockmeier, Craig A; Streit, Fabian; Strohmaier, Jana; Tansey, Katherine E; Teismann, Henning; Teumer, Alexander; Thompson, Wesley; Thomson, Pippa A; Thorgeirsson, Thorgeir E; Tian, Chao; Traylor, Matthew; Treutlein, Jens; Trubetskoy, Vassily; Uitterlinden, André G; Umbricht, Daniel; Van der Auwera, Sandra; van Hemert, Albert M; Viktorin, Alexander; Visscher, Peter M; Wang, Yunpeng; Webb, Bradley T; Weinsheimer, Shantel Marie; Wellmann, Jürgen; Willemsen, Gonneke; Witt, Stephanie H; Wu, Yang; Xi, Hualin S; Yang, Jian; Zhang, Futao; Arolt, Volker; Baune, Bernhard T; Berger, Klaus; Boomsma, Dorret I; Cichon, Sven; Dannlowski, Udo; de Geus, E C J; DePaulo, J Raymond; Domenici, Enrico; Domschke, Katharina; Esko, Tõnu; Grabe, Hans J; Hamilton, Steven P; Hayward, Caroline; Heath, Andrew C; Hinds, David A; Kendler, Kenneth S; Kloiber, Stefan; Lewis, Glyn; Li, Qingqin S; Lucae, Susanne; Madden, Pamela F A; Magnusson, Patrik K; Martin, Nicholas G; McIntosh, Andrew M; Metspalu, Andres; Mors, Ole; Mortensen, Preben Bo; Müller-Myhsok, Bertram; Nordentoft, Merete; Nöthen, Markus M; O'Donovan, Michael C; Paciga, Sara A; Pedersen, Nancy L; Penninx, Brenda W J H; Perlis, Roy H; Porteous, David J; Potash, James B; Preisig, Martin; Rietschel, Marcella; Schaefer, Catherine; Schulze, Thomas G; Smoller, Jordan W; Stefansson, Kari; Tiemeier, Henning; Uher, Rudolf; Völzke, Henry; Weissman, Myrna M; Werge, Thomas; Winslow, Ashley R; Lewis, Cathryn M; Levinson, Douglas F; Breen, Gerome; Børglum, Anders D; Sullivan, Patrick F

2018-05-01

Major depressive disorder (MDD) is a common illness accompanied by considerable morbidity, mortality, costs, and heightened risk of suicide. We conducted a genome-wide association meta-analysis based in 135,458 cases and 344,901 controls and identified 44 independent and significant loci. The genetic findings were associated with clinical features of major depression and implicated brain regions exhibiting anatomical differences in cases. Targets of antidepressant medications and genes involved in gene splicing were enriched for smaller association signal. We found important relationships of genetic risk for major depression with educational attainment, body mass, and schizophrenia: lower educational attainment and higher body mass were putatively causal, whereas major depression and schizophrenia reflected a partly shared biological etiology. All humans carry lesser or greater numbers of genetic risk factors for major depression. These findings help refine the basis of major depression and imply that a continuous measure of risk underlies the clinical phenotype.

Putative Prostate Cancer Risk SNP in an Androgen Receptor‐Binding Site of the Melanophilin Gene Illustrates Enrichment of Risk SNPs in Androgen Receptor Target Sites

PubMed Central

Bu, Huajie; Narisu, Narisu; Schlick, Bettina; Rainer, Johannes; Manke, Thomas; Schäfer, Georg; Pasqualini, Lorenza; Chines, Peter; Schweiger, Michal R.; Fuchsberger, Christian

2015-01-01

ABSTRACT Genome‐wide association studies have identified genomic loci, whose single‐nucleotide polymorphisms (SNPs) predispose to prostate cancer (PCa). However, the mechanisms of most of these variants are largely unknown. We integrated chromatin‐immunoprecipitation‐coupled sequencing and microarray expression profiling in TMPRSS2‐ERG gene rearrangement positive DUCaP cells with the GWAS PCa risk SNPs catalog to identify disease susceptibility SNPs localized within functional androgen receptor‐binding sites (ARBSs). Among the 48 GWAS index risk SNPs and 3,917 linked SNPs, 80 were found located in ARBSs. Of these, rs11891426:T>G in an intron of the melanophilin gene (MLPH) was within a novel putative auxiliary AR‐binding motif, which is enriched in the neighborhood of canonical androgen‐responsive elements. T→G exchange attenuated the transcriptional activity of the ARBS in an AR reporter gene assay. The expression of MLPH in primary prostate tumors was significantly lower in those with the G compared with the T allele and correlated significantly with AR protein. Higher melanophilin level in prostate tissue of patients with a favorable PCa risk profile points out a tumor‐suppressive effect. These results unravel a hidden link between AR and a functional putative PCa risk SNP, whose allele alteration affects androgen regulation of its host gene MLPH. PMID:26411452

Hallux Valgus, By Nature or Nurture? A Twin Study.

PubMed

Munteanu, Shannon E; Menz, Hylton B; Wark, John D; Christie, Jemma J; Scurrah, Katrina J; Bui, Minh; Erbas, Bircan; Hopper, John L; Wluka, Anita E

2017-09-01

To evaluate the contributions of shared but unmeasured genetic and environmental factors to hallux valgus (HV). Between 2011 and 2012, 74 monozygotic (MZ) and 56 dizygotic (DZ) female twin pairs self-reported HV and putative risk factors, including footwear use across their lifespan. Estimates of casewise concordance (P C ), correlation (ρ), and odds ratios (ORs) were calculated, adjusting for age and other risk factors, and compared between MZ and DZ pairs using logistic regression, generalized estimating equations, and a maximum likelihood-based method, respectively. A total of 70 participants (27%) reported HV, with 12 MZ and 7 DZ pairs being concordant. After adjusting for age, twins were correlated (ρ = 0.27 [95% confidence interval (95% CI) 0.08, 0.46]) and concordant (P C  = 0.45 [95% CI 0.29, 0.61]; mean age 58 years), with no difference between MZ and DZ pairs (P = 0.7). HV was associated with regularly wearing footwear with a constrictive toe-box during the fourth decade (adjusted OR 2.73 [95% CI 1.12, 6.67]). This risk factor was correlated in MZ (ρ = 0.38 [95% CI 0.15, 0.60]) but not DZ (ρ = -0.20 [95% CI -0.43, 0.03]) pairs. These correlations were significantly different (P = 0.002). Twins are correlated for HV, but we found no evidence that correlation was due to shared genetic factors. We identified an environmental risk factor, footwear with a constrictive toe-box, that is not shared to the same extent by MZ and DZ pairs, contrary to the assumption of the classic twin model. Footwear, and possibly genetic factors and unknown shared environmental factors, could contribute to developing HV. © 2016, American College of Rheumatology.

Exome sequencing of hepatocellular carcinomas identifies new mutational signatures and potential therapeutic targets

DOE PAGES

Schulze, Kornelius; Imbeaud, Sandrine; Letouzé, Eric; ...

2015-03-30

Our genomic analyses promise to improve tumor characterization to optimize personalized treatment for patients with hepatocellular carcinoma (HCC). Exome sequencing analysis of 243 liver tumors identified mutational signatures associated with specific risk factors, mainly combined alcohol and tobacco consumption and exposure to aflatoxin B1. We identified 161 putative driver genes associated with 11 recurrently altered pathways. Associations of mutations defined 3 groups of genes related to risk factors and centered on CTNNB1 (alcohol), TP53 (hepatitis B virus, HBV) and AXIN1. These analyses according to tumor stage progression identified TERT promoter mutation as an early event, whereasFGF3, FGF4, FGF19 or CCND1more » amplification and TP53 and CDKN2A alterations appeared at more advanced stages in aggressive tumors. In 28% of the tumors, we identified genetic alterations potentially targetable by US Food and Drug Administration (FDA)–approved drugs. Finally, we identified risk factor–specific mutational signatures and defined the extensive landscape of altered genes and pathways in HCC, which will be useful to design clinical trials for targeted therapy.« less

Exome sequencing of hepatocellular carcinomas identifies new mutational signatures and potential therapeutic targets

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

Schulze, Kornelius; Imbeaud, Sandrine; Letouzé, Eric

Our genomic analyses promise to improve tumor characterization to optimize personalized treatment for patients with hepatocellular carcinoma (HCC). Exome sequencing analysis of 243 liver tumors identified mutational signatures associated with specific risk factors, mainly combined alcohol and tobacco consumption and exposure to aflatoxin B1. We identified 161 putative driver genes associated with 11 recurrently altered pathways. Associations of mutations defined 3 groups of genes related to risk factors and centered on CTNNB1 (alcohol), TP53 (hepatitis B virus, HBV) and AXIN1. These analyses according to tumor stage progression identified TERT promoter mutation as an early event, whereasFGF3, FGF4, FGF19 or CCND1more » amplification and TP53 and CDKN2A alterations appeared at more advanced stages in aggressive tumors. In 28% of the tumors, we identified genetic alterations potentially targetable by US Food and Drug Administration (FDA)–approved drugs. Finally, we identified risk factor–specific mutational signatures and defined the extensive landscape of altered genes and pathways in HCC, which will be useful to design clinical trials for targeted therapy.« less

Common variation in PHACTR1 is associated with susceptibility to cervical artery dissection.

PubMed

Debette, Stéphanie; Kamatani, Yoichiro; Metso, Tiina M; Kloss, Manja; Chauhan, Ganesh; Engelter, Stefan T; Pezzini, Alessandro; Thijs, Vincent; Markus, Hugh S; Dichgans, Martin; Wolf, Christiane; Dittrich, Ralf; Touzé, Emmanuel; Southerland, Andrew M; Samson, Yves; Abboud, Shérine; Béjot, Yannick; Caso, Valeria; Bersano, Anna; Gschwendtner, Andreas; Sessa, Maria; Cole, John; Lamy, Chantal; Medeiros, Elisabeth; Beretta, Simone; Bonati, Leo H; Grau, Armin J; Michel, Patrik; Majersik, Jennifer J; Sharma, Pankaj; Kalashnikova, Ludmila; Nazarova, Maria; Dobrynina, Larisa; Bartels, Eva; Guillon, Benoit; van den Herik, Evita G; Fernandez-Cadenas, Israel; Jood, Katarina; Nalls, Michael A; De Leeuw, Frank-Erik; Jern, Christina; Cheng, Yu-Ching; Werner, Inge; Metso, Antti J; Lichy, Christoph; Lyrer, Philippe A; Brandt, Tobias; Boncoraglio, Giorgio B; Wichmann, Heinz-Erich; Gieger, Christian; Johnson, Andrew D; Böttcher, Thomas; Castellano, Maurizio; Arveiler, Dominique; Ikram, M Arfan; Breteler, Monique M B; Padovani, Alessandro; Meschia, James F; Kuhlenbäumer, Gregor; Rolfs, Arndt; Worrall, Bradford B; Ringelstein, Erich-Bernd; Zelenika, Diana; Tatlisumak, Turgut; Lathrop, Mark; Leys, Didier; Amouyel, Philippe; Dallongeville, Jean

2015-01-01

Cervical artery dissection (CeAD), a mural hematoma in a carotid or vertebral artery, is a major cause of ischemic stroke in young adults although relatively uncommon in the general population (incidence of 2.6/100,000 per year). Minor cervical traumas, infection, migraine and hypertension are putative risk factors, and inverse associations with obesity and hypercholesterolemia are described. No confirmed genetic susceptibility factors have been identified using candidate gene approaches. We performed genome-wide association studies (GWAS) in 1,393 CeAD cases and 14,416 controls. The rs9349379[G] allele (PHACTR1) was associated with lower CeAD risk (odds ratio (OR) = 0.75, 95% confidence interval (CI) = 0.69-0.82; P = 4.46 × 10(-10)), with confirmation in independent follow-up samples (659 CeAD cases and 2,648 controls; P = 3.91 × 10(-3); combined P = 1.00 × 10(-11)). The rs9349379[G] allele was previously shown to be associated with lower risk of migraine and increased risk of myocardial infarction. Deciphering the mechanisms underlying this pleiotropy might provide important information on the biological underpinnings of these disabling conditions.

End-stage Renal Disease in Taiwan: A Case–Control Study

PubMed Central

Tsai, Su-Ying; Tseng, Hung-Fu; Tan, Hsiu-Fen; Chien, Yu-Shu; Chang, Chia-Chu

2009-01-01

Background Taiwan has the highest incidence of end-stage renal disease (ESRD) in the world. The epidemiologic features of ESRD, however, have not been investigated. In this case–control study, we evaluated the risk of ESRD associated with a number of putative risk factors. Methods We studied 200 patients among whom ESRD had been newly diagnosed between 1 January 2005 and 31 December 2005; 200 controls were selected from among relatives of patients treated in the general surgery unit. Using a structured questionnaire, we collected information related to socioeconomic factors, history of disease, regular blood or urine screening, lifestyle, environmental exposure, consumption of vitamin supplements, and regular drug use at 5 years before disease onset. Results Our primary multivariate risk models indicated that low socioeconomic status was a strong predictor of ESRD (education: odds ratio [OR], 2.78; 95% confidence interval [CI], 1.49–5.19; income: OR, 2.86, 95% CI, 1.48–5.52), even after adjusting for other risk factors. Other significant predictors for ESRD were a history of hypertension (OR, 3.63–3.90), history of diabetes (OR, 3.85–5.50), and regular intake of folk remedies or over-the-counter Chinese herbs (OR, 10.84–12.51). Regular intake of a multivitamin supplement 5 years before diagnosis was associated with a decreased risk of ESRD (OR, 0.12–0.14). Conclusions Our findings indicate that low socioeconomic status, history of hypertension, diabetes, and regular use of folk remedies or over-the-counter Chinese herbs were significant risk factors for ESRD, while regular intake of a multivitamin supplement was associated with a decreased risk of ESRD. PMID:19542686

Major Depressive Disorder and Bipolar Disorder Predispose Youth to Accelerated Atherosclerosis and Early Cardiovascular Disease: A Scientific Statement From the American Heart Association.

PubMed

Goldstein, Benjamin I; Carnethon, Mercedes R; Matthews, Karen A; McIntyre, Roger S; Miller, Gregory E; Raghuveer, Geetha; Stoney, Catherine M; Wasiak, Hank; McCrindle, Brian W

2015-09-08

In the 2011 "Expert Panel on Integrated Guidelines for Cardiovascular Health and Risk Reduction in Children and Adolescents," several medical conditions among youth were identified that predispose to accelerated atherosclerosis and early cardiovascular disease (CVD), and risk stratification and management strategies for youth with these conditions were elaborated. Major depressive disorder (MDD) and bipolar disorder (BD) among youth satisfy the criteria set for, and therefore merit inclusion among, Expert Panel tier II moderate-risk conditions. The combined prevalence of MDD and BD among adolescents in the United States is ≈10%, at least 10 times greater than the prevalence of the existing moderate-risk conditions combined. The high prevalence of MDD and BD underscores the importance of positioning these diseases alongside other pediatric diseases previously identified as moderate risk for CVD. The overall objective of this statement is to increase awareness and recognition of MDD and BD among youth as moderate-risk conditions for early CVD. To achieve this objective, the primary specific aims of this statement are to (1) summarize evidence that MDD and BD are tier II moderate-risk conditions associated with accelerated atherosclerosis and early CVD and (2) position MDD and BD as tier II moderate-risk conditions that require the application of risk stratification and management strategies in accordance with Expert Panel recommendations. In this scientific statement, there is an integration of the various factors that putatively underlie the association of MDD and BD with CVD, including pathophysiological mechanisms, traditional CVD risk factors, behavioral and environmental factors, and psychiatric medications. © 2015 American Heart Association, Inc.

International Studies in Dementia With Particular Emphasis on Populations of African Origin

PubMed Central

Hendrie, Hugh C.; Murrell, Jill; Gao, Sujuan; Unverzagt, Fredrick W.; Ogunniyi, Adesola; Hall, Kathleen S.

2011-01-01

Epidemiologic studies on dementia generally have 2 major interacting objectives: descriptive, where rates of dementia and Alzheimer Disease (AD) are calculated for communities and selected populations, and analytic, which attempt to explain the observed phenotypic variations in communities and populations by identifying disease risk factors. The public health benefits derived from descriptive studies are exemplified by the recent published review of the global prevalence of dementia under the auspices of Alzheimer Disease International. This review emphasized the enormous and growing burden associated with dementia particularly for countries in the developing world and outlined strategies to influence policy making, planning, and healthcare allocation. One interesting feature of descriptive studies on dementia is that although the few epidemiologic studies conducted in Africa suggest that rates of dementia and AD are relatively low, rates of AD and dementia have been reported to be relatively high for African Americans. The Indianapolis-Ibadan Dementia Project has reported that the incidence rates for AD and dementia in Yoruba are less than half the incidence rates for AD and dementia in African Americans. Analytic studies are now underway to identify risk factors that may account for these rate differences. The risk factor model being applied, attempts to identify not only putative genetic and environmental factors but also their interactions. So far the major findings have included: apolipoprotein E e4, a major risk factor for AD in most populations, is also a risk factor for AD in African Americans but not for Yoruba; African Americans are at higher risk not only for AD, but also for diseases associated with increased cardiovascular risk such as hypertension, diabetes, and metabolic syndrome; African Americans have higher rates of hypercholesterolemia than Yoruba: there is an interaction between apolipoprotein E e4, cholesterol, and AD risk in both Yoruba and African Americans. We eventually hope to create a risk factor model that will not only account for the dementia rate differences between Yoruba and African Americans, but also help explain dementia rates in other developing and developed countries. PMID:16917194

International studies in dementia with particular emphasis on populations of African origin.

PubMed

Hendrie, Hugh C; Murrell, Jill; Gao, Sujuan; Unverzagt, Fredrick W; Ogunniyi, Adesola; Hall, Kathleen S

2006-01-01

Epidemiologic studies on dementia generally have 2 major interacting objectives: descriptive, where rates of dementia and Alzheimer Disease (AD) are calculated for communities and selected populations, and analytic, which attempt to explain the observed phenotypic variations in communities and populations by identifying disease risk factors. The public health benefits derived from descriptive studies are exemplified by the recent published review of the global prevalence of dementia under the auspices of Alzheimer Disease International. This review emphasized the enormous and growing burden associated with dementia particularly for countries in the developing world and outlined strategies to influence policy making, planning, and healthcare allocation. One interesting feature of descriptive studies on dementia is that although the few epidemiologic studies conducted in Africa suggest that rates of dementia and AD are relatively low, rates of AD and dementia have been reported to be relatively high for African Americans. The Indianapolis-Ibadan Dementia Project has reported that the incidence rates for AD and dementia in Yoruba are less than half the incidence rates for AD and dementia in African Americans. Analytic studies are now underway to identify risk factors that may account for these rate differences. The risk factor model being applied, attempts to identify not only putative genetic and environmental factors but also their interactions. So far the major findings have included: apolipoprotein E e4, a major risk factor for AD in most populations, is also a risk factor for AD in African Americans but not for Yoruba; African Americans are at higher risk not only for AD, but also for diseases associated with increased cardiovascular risk such as hypertension, diabetes, and metabolic syndrome; African Americans have higher rates of hypercholesterolemia than Yoruba: there is an interaction between apolipoprotein E e4, cholesterol, and AD risk in both Yoruba and African Americans. We eventually hope to create a risk factor model that will not only account for the dementia rate differences between Yoruba and African Americans, but also help explain dementia rates in other developing and developed countries.

IDENTIFYING AREAS WITH A HIGH RISK OF HUMAN INFECTION WITH THE AVIAN INFLUENZA A (H7N9) VIRUS IN EAST ASIA

PubMed Central

Fuller, Trevon; Havers, Fiona; Xu, Cuiling; Fang, Li-Qun; Cao, Wu-Chun; Shu, Yuelong; Widdowson, Marc-Alain; Smith, Thomas B.

2014-01-01

Summary Objectives The rapid emergence, spread, and disease severity of avian influenza A(H7N9) in China has prompted concerns about a possible pandemic and regional spread in the coming months. The objective of this study was to predict the risk of future human infections with H7N9 in China and neighboring countries by assessing the association between H7N9 cases at sentinel hospitals and putative agricultural, climatic, and demographic risk factors. Methods This cross-sectional study used the locations of H7N9 cases and negative cases from China’s influenza-like illness surveillance network. After identifying H7N9 risk factors with logistic regression, we used Geographic Information Systems (GIS) to construct predictive maps of H7N9 risk across Asia. Results Live bird market density was associated with human H7N9 infections reported in China from March-May 2013. Based on these cases, our model accurately predicted the virus’ spread into Guangxi autonomous region in February 2014. Outside China, we find there is a high risk that the virus will spread to northern Vietnam, due to the import of poultry from China. Conclusions Our risk map can focus efforts to improve surveillance in poultry and humans, which may facilitate early identification and treatment of human cases. PMID:24642206

Parental perspectives on the causes of an autism spectrum disorder in their children.

PubMed

Mercer, L; Creighton, S; Holden, J J A; Lewis, M E S

2006-02-01

Autism Spectrum Disorders (ASDs) are complex neurodevelopmental disorders with many biological causes, including genetic, syndromic and environmental. Such etiologic heterogeneity impacts considerably upon parents' needs for understanding their child's diagnosis. A descriptive survey was designed to investigate parental views on the cause(s) of ASD in their child. Among the 41 parents who replied to the questionnaire, genetic influences (90.2%), perinatal factors (68.3%), diet (51.2%), prenatal factors (43.9%) and vaccines (40.0%) were considered to be the most significant contributory factors. Parents reported inaccurately high recurrence risks, misperceptions of the contribution of various putative factors, feelings of guilt and blame regarding their child's diagnosis, as well as a lack of advocacy for genetic counseling by non-geneticist professionals. This study offers clinicians and researchers further insight into what parents believe contributed to their child's diagnosis of ASD and will help facilitate genetic counseling for these families.

Characterization of HIV Transmission in South-East Austria

PubMed Central

Kessler, Harald H.; Haas, Bernhard; Stelzl, Evelyn; Weninger, Karin; Little, Susan J.; Mehta, Sanjay R.

2016-01-01

To gain deeper insight into the epidemiology of HIV-1 transmission in South-East Austria we performed a retrospective analysis of 259 HIV-1 partial pol sequences obtained from unique individuals newly diagnosed with HIV infection in South-East Austria from 2008 through 2014. After quality filtering, putative transmission linkages were inferred when two sequences were ≤1.5% genetically different. Multiple linkages were resolved into putative transmission clusters. Further phylogenetic analyses were performed using BEAST v1.8.1. Finally, we investigated putative links between the 259 sequences from South-East Austria and all publicly available HIV polymerase sequences in the Los Alamos National Laboratory HIV sequence database. We found that 45.6% (118/259) of the sampled sequences were genetically linked with at least one other sequence from South-East Austria forming putative transmission clusters. Clustering individuals were more likely to be men who have sex with men (MSM; p<0.001), infected with subtype B (p<0.001) or subtype F (p = 0.02). Among clustered males who reported only heterosexual (HSX) sex as an HIV risk, 47% clustered closely with MSM (either as pairs or within larger MSM clusters). One hundred and seven of the 259 sequences (41.3%) from South-East Austria had at least one putative inferred linkage with sequences from a total of 69 other countries. In conclusion, analysis of HIV-1 sequences from newly diagnosed individuals residing in South-East Austria revealed a high degree of national and international clustering mainly within MSM. Interestingly, we found that a high number of heterosexual males clustered within MSM networks, suggesting either linkage between risk groups or misrepresentation of sexual risk behaviors by subjects. PMID:26967154

Characterization of HIV Transmission in South-East Austria.

PubMed

Hoenigl, Martin; Chaillon, Antoine; Kessler, Harald H; Haas, Bernhard; Stelzl, Evelyn; Weninger, Karin; Little, Susan J; Mehta, Sanjay R

2016-01-01

To gain deeper insight into the epidemiology of HIV-1 transmission in South-East Austria we performed a retrospective analysis of 259 HIV-1 partial pol sequences obtained from unique individuals newly diagnosed with HIV infection in South-East Austria from 2008 through 2014. After quality filtering, putative transmission linkages were inferred when two sequences were ≤1.5% genetically different. Multiple linkages were resolved into putative transmission clusters. Further phylogenetic analyses were performed using BEAST v1.8.1. Finally, we investigated putative links between the 259 sequences from South-East Austria and all publicly available HIV polymerase sequences in the Los Alamos National Laboratory HIV sequence database. We found that 45.6% (118/259) of the sampled sequences were genetically linked with at least one other sequence from South-East Austria forming putative transmission clusters. Clustering individuals were more likely to be men who have sex with men (MSM; p<0.001), infected with subtype B (p<0.001) or subtype F (p = 0.02). Among clustered males who reported only heterosexual (HSX) sex as an HIV risk, 47% clustered closely with MSM (either as pairs or within larger MSM clusters). One hundred and seven of the 259 sequences (41.3%) from South-East Austria had at least one putative inferred linkage with sequences from a total of 69 other countries. In conclusion, analysis of HIV-1 sequences from newly diagnosed individuals residing in South-East Austria revealed a high degree of national and international clustering mainly within MSM. Interestingly, we found that a high number of heterosexual males clustered within MSM networks, suggesting either linkage between risk groups or misrepresentation of sexual risk behaviors by subjects.

Etiologic Heterogeneity Among Non-Hodgkin Lymphoma Subtypes: The InterLymph Non-Hodgkin Lymphoma Subtypes Project

PubMed Central

Morton, Lindsay M.; Slager, Susan L.; Cerhan, James R.; Wang, Sophia S.; Vajdic, Claire M.; Skibola, Christine F.; Bracci, Paige M.; de Sanjosé, Silvia; Smedby, Karin E.; Chiu, Brian C. H.; Zhang, Yawei; Mbulaiteye, Sam M.; Monnereau, Alain; Turner, Jennifer J.; Clavel, Jacqueline; Adami, Hans-Olov; Chang, Ellen T.; Glimelius, Bengt; Hjalgrim, Henrik; Melbye, Mads; Crosignani, Paolo; di Lollo, Simonetta; Miligi, Lucia; Nanni, Oriana; Ramazzotti, Valerio; Rodella, Stefania; Costantini, Adele Seniori; Stagnaro, Emanuele; Tumino, Rosario; Vindigni, Carla; Vineis, Paolo; Becker, Nikolaus; Benavente, Yolanda; Boffetta, Paolo; Brennan, Paul; Cocco, Pierluigi; Foretova, Lenka; Maynadié, Marc; Nieters, Alexandra; Staines, Anthony; Colt, Joanne S.; Cozen, Wendy; Davis, Scott; de Roos, Anneclaire J.; Hartge, Patricia; Rothman, Nathaniel; Severson, Richard K.; Holly, Elizabeth A.; Call, Timothy G.; Feldman, Andrew L.; Habermann, Thomas M.; Liebow, Mark; Blair, Aaron; Cantor, Kenneth P.; Kane, Eleanor V.; Lightfoot, Tracy; Roman, Eve; Smith, Alex; Brooks-Wilson, Angela; Connors, Joseph M.; Gascoyne, Randy D.; Spinelli, John J.; Armstrong, Bruce K.; Kricker, Anne; Holford, Theodore R.; Lan, Qing; Zheng, Tongzhang; Orsi, Laurent; Dal Maso, Luigino; Franceschi, Silvia; La Vecchia, Carlo; Negri, Eva; Serraino, Diego; Bernstein, Leslie; Levine, Alexandra; Friedberg, Jonathan W.; Kelly, Jennifer L.; Berndt, Sonja I.; Birmann, Brenda M.; Clarke, Christina A.; Flowers, Christopher R.; Foran, James M.; Kadin, Marshall E.; Paltiel, Ora; Weisenburger, Dennis D.; Linet, Martha S.; Sampson, Joshua N.

2014-01-01

Background Non-Hodgkin lymphoma (NHL) comprises biologically and clinically heterogeneous subtypes. Previously, study size has limited the ability to compare and contrast the risk factor profiles among these heterogeneous subtypes. Methods We pooled individual-level data from 17 471 NHL cases and 23 096 controls in 20 case–control studies from the International Lymphoma Epidemiology Consortium (InterLymph). We estimated the associations, measured as odds ratios, between each of 11 NHL subtypes and self-reported medical history, family history of hematologic malignancy, lifestyle factors, and occupation. We then assessed the heterogeneity of associations by evaluating the variability (Q value) of the estimated odds ratios for a given exposure among subtypes. Finally, we organized the subtypes into a hierarchical tree to identify groups that had similar risk factor profiles. Statistical significance of tree partitions was estimated by permutation-based P values (P NODE). Results Risks differed statistically significantly among NHL subtypes for medical history factors (autoimmune diseases, hepatitis C virus seropositivity, eczema, and blood transfusion), family history of leukemia and multiple myeloma, alcohol consumption, cigarette smoking, and certain occupations, whereas generally homogeneous risks among subtypes were observed for family history of NHL, recreational sun exposure, hay fever, allergy, and socioeconomic status. Overall, the greatest difference in risk factors occurred between T-cell and B-cell lymphomas (P NODE < 1.0×10−4), with increased risks generally restricted to T-cell lymphomas for eczema, T-cell-activating autoimmune diseases, family history of multiple myeloma, and occupation as a painter. We further observed substantial heterogeneity among B-cell lymphomas (P NODE < 1.0×10−4). Increased risks for B-cell-activating autoimmune disease and hepatitis C virus seropositivity and decreased risks for alcohol consumption and occupation as a teacher generally were restricted to marginal zone lymphoma, Burkitt/Burkitt-like lymphoma/leukemia, diffuse large B-cell lymphoma, and/or lymphoplasmacytic lymphoma/Waldenström macroglobulinemia. Conclusions Using a novel approach to investigate etiologic heterogeneity among NHL subtypes, we identified risk factors that were common among subtypes as well as risk factors that appeared to be distinct among individual or a few subtypes, suggesting both subtype-specific and shared underlying mechanisms. Further research is needed to test putative mechanisms, investigate other risk factors (eg, other infections, environmental exposures, and diet), and evaluate potential joint effects with genetic susceptibility. PMID:25174034

Prevalence and risk factors of gestational diabetes in Punjab, North India: results from a population screening program.

PubMed

Arora, Geeti P; Thaman, Richa G; Prasad, Rashmi B; Almgren, Peter; Brøns, Charlotte; Groop, Leif C; Vaag, Allan A

2015-08-01

The World Health Organization (WHO) has in 2013 changed the diagnostic criteria for gestational diabetes mellitus (GDM) to acknowledge the putative effect of mildly elevated fasting plasma glucose (FPG) levels on pregnancy outcomes. We aimed to determine the prevalence and risk factors of GDM comparing the previous WHO 1999 criteria to the WHO 2013 criteria in North India. In a population-based screening programme, 5100 randomly selected North Indian women were studied using a cross-sectional design with a questionnaire, venous FPG and 2-h capillary plasma glucose (PG) after a 75 g oral glucose tolerance test performed between 24 and 28 weeks of pregnancy. The prevalence of GDM was 35% using WHO 2013 criteria vs 9% using WHO 1999 criteria. FPG measurements identified 94% of WHO 2013 GDM cases as opposed to 11% of WHO 1999 GDM cases. In contrast, 2-h PG measurements identified only 13% of WHO 2013 GDM cases compared with 96% of the WHO 1999 GDM cases. Using logistic regression with backward elimination, urban habitat, illiteracy, non-vegetarianism, increased BMI, Hindu religion and low adult height were all independent risk factors of GDM using the 1999 criteria, whereas only urban habitat, low adult height and increased age were independent risk factors of GDM using the 2013 criteria. Intervention studies are needed to justify the WHO 2013 GDM criteria increasing the prevalence four fold to include more than one third of North Indian pregnant women. © 2015 European Society of Endocrinology.

Study Protocol, Sample Characteristics, and Loss to Follow-Up: The OPPERA Prospective Cohort Study

PubMed Central

Bair, Eric; Brownstein, Naomi C.; Ohrbach, Richard; Greenspan, Joel D.; Dubner, Ron; Fillingim, Roger B.; Maixner, William; Smith, Shad; Diatchenko, Luda; Gonzalez, Yoly; Gordon, Sharon; Lim, Pei-Feng; Ribeiro-Dasilva, Margarete; Dampier, Dawn; Knott, Charles; Slade, Gary D.

2013-01-01

When studying incidence of pain conditions such as temporomandibular disorders (TMDs), repeated monitoring is needed in prospective cohort studies. However, monitoring methods usually have limitations and, over a period of years, some loss to follow-up is inevitable. The OPPERA prospective cohort study of first-onset TMD screened for symptoms using quarterly questionnaires and examined symptomatic participants to definitively ascertain TMD incidence. During the median 2.8-year observation period, 16% of the 3,263 enrollees completed no follow-up questionnaires, others provided incomplete follow-up, and examinations were not conducted for one third of symptomatic episodes. Although screening methods and examinations were found to have excellent reliability and validity, they were not perfect. Loss to follow-up varied according to some putative TMD risk factors, although multiple imputation to correct the problem suggested that bias was minimal. A second method of multiple imputation that evaluated bias associated with omitted and dubious examinations revealed a slight underestimate of incidence and some small biases in hazard ratios used to quantify effects of risk factors. Although “bottom line” statistical conclusions were not affected, multiply-imputed estimates should be considered when evaluating the large number of risk factors under investigation in the OPPERA study. Perspective These findings support the validity of the OPPERA prospective cohort study for the purpose of investigating the etiology of first-onset TMD, providing the foundation for other papers investigating risk factors hypothesized in the OPPERA project. PMID:24275220

The cycle of schizoaffective disorder, cognitive ability, alcoholism, and suicidality.

PubMed

Goldstein, Gerald; Haas, Gretchen L; Pakrashi, Manish; Novero, Ada M; Luther, James F

2006-02-01

In this study we investigated the putative role of cognitive dysfunction, diagnosis (schizoaffective versus schizophrenia disorder), and alcoholism as risk factors for suicidal behavior among individuals with DSM-TV schizophrenia or schizoaffective disorders. Subjects received cognitive tests and medical records were reviewed for evidence of a history of suicide attempts or suicidal ideation. Discriminant analysis was used to identify cognitive test performance measures that distinguished those with versus those without suicidal behavior. None of the cognitive measures discriminated between the two groups. The rates of suicidal behavior (suicidal ideation and suicide attempts) did not differ between participants with versus those without comorbid alcohol use. An association was found between suicidal behavior and the diagnosis of schizoaffective disorder. It was concluded that the history of prominent mood syndromes characteristic of schizoaffective disorder contributes to increased risk of suicidal behaviors. Cognitive dysfunction and/or alcoholism did not contribute additionally to risk in this study.

Factors associated with the risk of West Nile Virus among crows in New York State

PubMed Central

DeCarlo, C. H.; Clark, A. B.; McGowan, K. J.; Ziegler, P. E.; Glaser, A. L.; Szonyi, B.; Mohammed, H. O.

2010-01-01

West Nile virus (WNV) is transmitted between avian hosts in enzootic cycles by a mosquito vector. The virus has significant disease effects on humans and equines when it bridges into an epizootic cycle. Since the initial epidemic of WNV in 1999, perennial outbreaks in New York State suggest the local establishment of natural foci with perpetuation of the virus among susceptible hosts rather than reintroduction of the virus. The factors that play a role in the perpetuation of the virus are not fully understood. American crows (Corvus brachyrhynchos) are known to be highly susceptible to infection with the virus. We investigate the factors that put crows at risk of infection in Tompkins County, New York during the period of 2000 through 2008 in a case-control study. Cases were crow carcasses that were found dead and tested positive for WNV using real time reverse transcription (RT-PCR) or VecTestR. Data on putative risk factors were collected and assessed for significance of association with the presence of WNV using logistic regression analysis to evaluate the significance of each factor while simultaneously controlling for the effect of others. The risk of a crow carcass testing WNV positive varied with age, season of the year, and ecological area where the carcass was found. Crows that were more than one year old were 4 times more likely to be WNV positive in comparison to birds that were less than one year of age. It was three times more likely to find WNV positive carcasses in residential areas in comparison to rural areas. The risk of testing WNV positive did not vary by sex of the crow carcasses. PMID:20707862

Distress Tolerance and Psychopathological Symptoms and Disorders: A Review of the Empirical Literature among Adults

PubMed Central

Leyro, Teresa M.; Zvolensky, Michael J.; Bernstein, Amit

2010-01-01

In the present paper, we review theory and empirical study of distress tolerance, an emerging risk factor candidate for various forms of psychopathology. Despite the long-standing interest in, and promise of work on, distress tolerance for understanding adult psychopathology, there has not been a comprehensive review of the extant empirical literature focused on the construct. As a result, a comprehensive synthesis of theoretical and empirical scholarship on distress tolerance including integration of extant research on the relations between distress tolerance and psychopathology is lacking. Inspection of the scientific literature indicates that there are a number of promising ways to conceptualize and measure distress tolerance, as well as documented relations between distress tolerance factor(s) and psychopathological symptoms and disorders. Although promising, there also is notable conceptual and operational heterogeneity across the distress tolerance literature(s). Moreoever, a number of basic questions remain unanswered regarding the associations between distress tolerance and other risk and protective factors and processes, as well as its putative role(s) in vulnerability for, and resilience to, psychopathology. Thus, the current paper provides a comprehensive review of past and contemporary theory and research and proposes key areas for future empirical study of this construct. PMID:20565169

Childhood risk factors for lifetime bulimic or compulsive eating by age 30 years in a British national birth cohort.

PubMed

Nicholls, D; Statham, R; Costa, S; Micali, N; Viner, R M

2016-10-01

To examine whether previously identified childhood risk factors for bulimia or compulsive eating (BCE) predict self-reported lifetime BCE by age 30 years in a prospective birth cohort. Using data from the 1970 British Cohort Study at birth, 5, and 10 years, associations between 22 putative childhood risk factors and self-reported lifetime BCE at 30 years were examined, adjusting for sex and socioeconomic status. Only female sex (odds ratio (OR): 9.2; 95% confidence interval (CI): 1.9-43.7; p = 0.005), low self-esteem (OR:2.9; 95%CI: 1.1-7.5; p = 0.03) and high maternal education (OR:5.4; 95%CI: 2.0-14.8; p = 0.001) were significantly associated with higher risk of BCE, whereas high SES at 10 years was significantly protective (OR:0.2; 95%CI: 0.1-0.8; p = 0.022) of BCE in fully adjusted multivariable logistic regression analysis. Our findings do not support a strong role for childhood weight status and eating behaviours in the development of bulimia and compulsive eating pathology, rather suggesting a focus on self esteem may have greater relative importance. Findings in relation to maternal education and SES need further exploration. Copyright © 2016 Elsevier Ltd. All rights reserved.

Serological responses to Cryptosporidium antigens in inhabitants of Hungary using conventionally filtered surface water and riverbank filtered drinking water.

PubMed

Farkas, K; Plutzer, J; Moltchanova, E; Török, A; Varró, M J; Domokos, K; Frost, F; Hunter, P R

2015-10-01

In this study the putative protective seroprevalence (PPS) of IgG antibodies to the 27-kDa and 15/17-kDa Cryptosporidium antigens in sera of healthy participants who were and were not exposed to Cryptosporidium oocysts via surface water-derived drinking water was compared. The participants completed a questionnaire regarding risk factors that have been shown to be associated with infection. The PPS was significantly greater (49-61%) in settlements where the drinking water originated from surface water, than in the control city where riverbank filtration was used (21% and 23%). Logistic regression analysis on the risk factors showed an association between bathing/swimming in outdoor pools and antibody responses to the 15/17-kDa antigen complex. Hence the elevated responses were most likely due to the use of contaminated water. Results indicate that waterborne Cryptosporidium infections occur more frequently than reported but may derive from multiple sources.

Risk factors for eating disorder symptoms at 12 years of age: A 6-year longitudinal cohort study.

PubMed

Evans, Elizabeth H; Adamson, Ashley J; Basterfield, Laura; Le Couteur, Ann; Reilly, Jessica K; Reilly, John J; Parkinson, Kathryn N

2017-01-01

Eating disorders pose risks to health and wellbeing in young adolescents, but prospective studies of risk factors are scarce and this has impeded prevention efforts. This longitudinal study aimed to examine risk factors for eating disorder symptoms in a population-based birth cohort of young adolescents at 12 years. Participants from the Gateshead Millennium Study birth cohort (n = 516; 262 girls and 254 boys) completed self-report questionnaire measures of eating disorder symptoms and putative risk factors at age 7 years, 9 years and 12 years, including dietary restraint, depressive symptoms and body dissatisfaction. Body mass index (BMI) was also measured at each age. Within-time correlates of eating disorder symptoms at 12 years of age were greater body dissatisfaction for both sexes and, for girls only, higher depressive symptoms. For both sexes, higher eating disorder symptoms at 9 years old significantly predicted higher eating disorder symptoms at 12 years old. Dietary restraint at 7 years old predicted boys' eating disorder symptoms at age 12, but not girls'. Factors that did not predict eating disorder symptoms at 12 years of age were BMI (any age), girls' dietary restraint at 7 years and body dissatisfaction at 7 and 9 years of age for both sexes. In this population-based study, different patterns of predictors and correlates of eating disorder symptoms were found for girls and boys. Body dissatisfaction, a purported risk factor for eating disorder symptoms in young adolescents, developed concurrently with eating disorder symptoms rather than preceding them. However, restraint at age 7 and eating disorder symptoms at age 9 years did predict 12-year eating disorder symptoms. Overall, our findings suggest that efforts to prevent disordered eating might beneficially focus on preadolescent populations. Copyright © 2016 The Authors. Published by Elsevier Ltd.. All rights reserved.

No Association Between Variant N-acetyltransferase Genes, Cigarette Smoking and Prostate Cancer Susceptibility Among Men of African Descent

PubMed Central

Kidd, La Creis Renee; VanCleave, Tiva T.; Doll, Mark A.; Srivastava, Daya S.; Thacker, Brandon; Komolafe, Oyeyemi; Pihur, Vasyl; Brock, Guy N.; Hein, David W.

2011-01-01

Objective We evaluated the individual and combination effects of NAT1, NAT2 and tobacco smoking in a case-control study of 219 incident prostate cancer (PCa) cases and 555 disease-free men. Methods Allelic discriminations for 15 NAT1 and NAT2 loci were detected in germ-line DNA samples using Taqman polymerase chain reaction (PCR) assays. Single gene, gene-gene and gene-smoking interactions were analyzed using logistic regression models and multi-factor dimensionality reduction (MDR) adjusted for age and subpopulation stratification. MDR involves a rigorous algorithm that has ample statistical power to assess and visualize gene-gene and gene-environment interactions using relatively small samples sizes (i.e., 200 cases and 200 controls). Results Despite the relatively high prevalence of NAT1*10/*10 (40.1%), NAT2 slow (30.6%), and NAT2 very slow acetylator genotypes (10.1%) among our study participants, these putative risk factors did not individually or jointly increase PCa risk among all subjects or a subset analysis restricted to tobacco smokers. Conclusion Our data do not support the use of N-acetyltransferase genetic susceptibilities as PCa risk factors among men of African descent; however, subsequent studies in larger sample populations are needed to confirm this finding. PMID:21709725

Geographic variation of gallbladder cancer mortality and risk factors in Chile: a population-based ecologic study

PubMed Central

Andia, Marcelo E.; Hsing, Ann W.; Andreotti, Gabriella; Ferreccio, Catterina

2010-01-01

Chile’s gallbladder cancer rates are among the highest in the world, being the first cancer killer among Chilean women. To provide insights into the etiology of gallbladder cancer, we conducted an ecologic study examining the geographical variation of gallbladder cancer and several putative risk factors. The relative risk of dying from gallbladder cancer (relative to the national average mortality rate) between 1985 and 2003 was estimated for each of the 333 Chilean counties, using a hierarchical Poisson regression model, adjusting for age, sex, and geographical location. The risk of gallbladder cancer mortality was analyzed in relation to region (costal, inland, northern, and southern), poverty, Amerindian (Mapuche) population, typhoid fever, and access to cholecystectomy, using logistic regression analysis. There were 27,183 gallbladder cancer deaths, age-sex-adjusted county mortality rates ranging from 8.2 to 12.4 per 100,000 inhabitants, being higher in inland and southern regions; compare to the north-coastal, the northern-inland region had a 10-fold risk odds ratio (OR) (95% of confidence interval (95% CI): 2.4–42.2) and the southern-inland region had a 26-fold risk (OR 95%CI: 6.0–114.2). Independent risk factors for gallbladder cancer were: ethnicity (Mapuche) OR:3.9 (95%CI 1.8–8.7), typhoid fever OR:2.9 (95%CI 1.2–6.9), poverty OR:5.1 (95%CI 1.6–15.9), low access to cholecystectomy OR:3.9 (95%CI 1.5–10.1), low access to hospital care OR:14.2 (95%CI 4.2–48.7) and high urbanization OR:8.0 (95%CI 3.4–18.7). Our results suggest that gallbladder cancer in Chile may be related to both genetic factors and poor living conditions. Future analytic studies are needed to further clarify the role of these factors in gallbladder cancer etiology. PMID:18566990

IBD and Environment: Are There Differences between East and West.

PubMed

Gearry, Richard B

2016-01-01

The inflammatory bowel diseases (IBDs), Crohn's disease (CD) and ulcerative colitis (UC) occur worldwide with differences in epidemiology, etiology and phenotype between regions. Breakthroughs have occurred in IBD genetics, although the genes that predispose to IBD differ between racial groups. What do we know about the 'envirotype' of those who develop IBD, and are there differences between the East and the West? The strongest IBD risk factor identified to date is a family history of IBD. Whilst likely representing an underlying genetic predisposition, it may also reflect shared environmental factors amongst family members. Cigarette smoking increases the risk of developing CD, whilst smoking is less common in those who develop UC. Having ceased smoking increases the risk of developing UC subsequently. Unlike the West, cigarette smoking appears to play a lesser role in the East. Other environmental risk factors are inconsistent. Studies of migrant populations moving from regions of low to high IBD incidence point to early life as a key time for environmental triggers. In these populations, it is the second generation (those born in the high incidence region) with higher IBD incidence rates than their parents. Early life environmental exposures have been studied exhaustively but, except for having been breastfed, few putative early childhood environmental risk factors have been shown consistently to alter the risk of developing IBD. The identification of IBD environmental risk factors remains elusive in both the East and West. In the West, case-control studies are unlikely to move the field forward without multi-level (phenotype, genotype, diet history, 'envirotype' and microbiome) data, ideally collected prospectively. Cohort studies (such as the Genes, Environment, Microbiome project) may address some of these issues. However, in the East where IBD incidence is still increasing, well-designed comprehensive case-control studies may identify differences that give an insight into the 'envirotype' driving IBD incidence. © 2016 S. Karger AG, Basel.

Early interventions for youths at high risk for bipolar disorder: a developmental approach.

PubMed

Benarous, Xavier; Consoli, Angèle; Milhiet, Vanessa; Cohen, David

2016-03-01

In recent decades, ongoing research programmes on primary prevention and early identification of bipolar disorder (BD) have been developed. The aim of this article is to review the principal forms of evidence that support preventive interventions for BD in children and adolescents and the main challenges associated with these programmes. We performed a literature review of the main computerised databases (MEDLINE, PUBMED) and a manual search of the literature relevant to prospective and retrospective studies of prodromal symptoms, premorbid stages, risk factors, and early intervention programmes for BD. Genetic and environmental risk factors of BD were identified. Most of the algorithms used to measure the risk of developing BD and the early interventions programmes focused on the familial risk. The prodromal signs varied greatly and were age dependent. During adolescence, depressive episodes associated with genetic or environmental risk factors predicted the onset of hypomanic/manic episodes over subsequent years. In prepubertal children, the lack of specificity of clinical markers and difficulties in mood assessment were seen as impeding preventive interventions at these ages. Despite encouraging results, biomarkers have not thus far been sufficiently validated in youth samples to serve as screening tools for prevention. Additional longitudinal studies in youths at high risk of developing BD should include repeated measures of putative biomarkers. Staging models have been developed as an integrative approach to specify the individual level of risk based on clinical (e.g. prodromal symptoms and familial history of BD) and non-clinical (e.g. biomarkers and neuroimaging) data. However, there is still a lack of empirically validated studies that measure the benefits of using these models to design preventive intervention programmes.

Pre-Pregnancy BMI, Gestational Weight Gain, and the Risk of Hypertensive Disorders of Pregnancy: A Cohort Study in Wuhan, China

PubMed Central

Hu, Ronghua; Zhang, Yiming; Bassig, Bryan A.; Triche, Elizabeth; Yang, Shaoping; Qiu, Lin; Zhang, Yaqi; Yao, Cong; Xu, Shunqing; Wang, Youjie; Xia, Wei; Qian, Zhengmin; Zheng, Tongzhang; Zhang, Bin

2015-01-01

Background Hypertensive disorders of pregnancy (HDP) are major causes of maternal death worldwide and the risk factors are not fully understood. Few studies have investigated the risk factors for HDP among Chinese women. A cohort study involving 84,656 women was conducted to investigate pre-pregnancy BMI, total gestational weight gain (GWG), and GWG during early pregnancy as risk factors for HDP among Chinese women. Methods The study was conducted between 2011–2013 in Wuhan, China, utilizing data from the Maternal and Children Healthcare Information Tracking System of Wuhan. A total of 84,656 women with a live singleton pregnancy were included. Multiple unconditional logistic regression was conducted to evaluate associations between putative risk factors and HDP. Results Women who were overweight or obese before pregnancy had an elevated risk of developing HDP (overweight: OR = 2.66, 95% CI = 2.32–3.05; obese: OR = 5.53, 95% CI = 4.28–7.13) compared to their normal weight counterparts. Women with total GWG above the Institute of Medicine (IOM) recommendation had an adjusted OR of 1.72 (95% CI = 1.54–1.93) for HDP compared to women who had GWG within the IOM recommendation. Women with gestational BMI gain >10 kg/m2 during pregnancy had an adjusted OR of 3.35 (95% CI = 2.89–3.89) for HDP, compared to women with a gestational BMI gain <5 kg/m2. The increased risk of HDP was also observed among women with higher early pregnancy (up to 18 weeks of pregnancy) GWG (>600g/wk: adjusted OR = 1.48, 95% CI = 1.19–1.84). Conclusion The results from this study show that maternal pre-pregnancy BMI, early GWG, and total GWG are positively associated with the risk of HDP. Weight control efforts before and during pregnancy may help to reduce the risk of HDP. PMID:26305565

Pre-Pregnancy BMI, Gestational Weight Gain, and the Risk of Hypertensive Disorders of Pregnancy: A Cohort Study in Wuhan, China.

PubMed

Zhou, Aifen; Xiong, Chao; Hu, Ronghua; Zhang, Yiming; Bassig, Bryan A; Triche, Elizabeth; Yang, Shaoping; Qiu, Lin; Zhang, Yaqi; Yao, Cong; Xu, Shunqing; Wang, Youjie; Xia, Wei; Qian, Zhengmin; Zheng, Tongzhang; Zhang, Bin

2015-01-01

Hypertensive disorders of pregnancy (HDP) are major causes of maternal death worldwide and the risk factors are not fully understood. Few studies have investigated the risk factors for HDP among Chinese women. A cohort study involving 84,656 women was conducted to investigate pre-pregnancy BMI, total gestational weight gain (GWG), and GWG during early pregnancy as risk factors for HDP among Chinese women. The study was conducted between 2011-2013 in Wuhan, China, utilizing data from the Maternal and Children Healthcare Information Tracking System of Wuhan. A total of 84,656 women with a live singleton pregnancy were included. Multiple unconditional logistic regression was conducted to evaluate associations between putative risk factors and HDP. Women who were overweight or obese before pregnancy had an elevated risk of developing HDP (overweight: OR = 2.66, 95% CI = 2.32-3.05; obese: OR = 5.53, 95% CI = 4.28-7.13) compared to their normal weight counterparts. Women with total GWG above the Institute of Medicine (IOM) recommendation had an adjusted OR of 1.72 (95% CI = 1.54-1.93) for HDP compared to women who had GWG within the IOM recommendation. Women with gestational BMI gain >10 kg/m2 during pregnancy had an adjusted OR of 3.35 (95% CI = 2.89-3.89) for HDP, compared to women with a gestational BMI gain <5 kg/m2. The increased risk of HDP was also observed among women with higher early pregnancy (up to 18 weeks of pregnancy) GWG (>600g/wk: adjusted OR = 1.48, 95% CI = 1.19-1.84). The results from this study show that maternal pre-pregnancy BMI, early GWG, and total GWG are positively associated with the risk of HDP. Weight control efforts before and during pregnancy may help to reduce the risk of HDP.

What Factors Contribute to Headache-Related Disability in Teens?

PubMed

Kemper, Kathi J; Heyer, Geoffrey; Pakalnis, Ann; Binkley, Philip F

2016-03-01

Our aim was to describe the relationship between risk factors, such as stress, depression, and anxiety, and potentially protective factors against pediatric headache-related disability, such as mindfulness, resilience, and self-compassion, and to determine teens' interest in mind-body skills training to help reduce headache-related disability. This was a cross-sectional survey among adolescents seen in an academic neurology clinic reporting four or more headaches monthly using standardized instruments to determine the relationship between putative risk and protective factors as well as physiologic markers of inflammation and vagal tone and headache-related disability. Among the 29 participants, 31% were male, the average age was 14.8 years, average headache frequency was 11.6 per month, and the most commonly reported trigger was stress (86%). The only risk or protective factor significantly associated with headache-related disability was depression (r = 0.52, P = 0.004). Depression was negatively correlated with mindfulness, resilience, and self-compassion (P < 0.01 each) and positively correlated with stress, sleep disturbance, and anxiety (P < 0.01 each). Biomarkers of vagal tone and inflammation were correlated with each other but not with headache-related disability or depression. There was strong interest in learning skills like slow, deep breathing practices supported by a smart phone application to reduce stress and the negative impact of headaches on daily life. Among teens with frequent migraine headaches, depression is the strongest risk factor for headache-related disability. Stress is viewed as a headache trigger, and teens reported wanting to learn simple stress management strategies supported by a smart phone application to help reduce headache-related disability. Copyright © 2016 Elsevier Inc. All rights reserved.

A meta-analysis of multiple myeloma risk regions in African and European ancestry populations identifies putatively functional loci

PubMed Central

Rand, Kristin A.; Song, Chi; Dean, Eric; Serie, Daniel J.; Curtin, Karen; Sheng, Xin; Hu, Donglei; Huff, Carol Ann; Bernal-Mizrachi, Leon; Tomasson, Michael H.; Ailawadhi, Sikander; Singhal, Seema; Pawlish, Karen; Peters, Edward S.; Bock, Cathryn H.; Stram, Alex; Van Den Berg, David J; Edlund, Christopher K.; V.Conti, David; Zimmerman, Todd; Hwang, Amie E.; Huntsman, Scott; Graff, John; Nooka, Ajay; Kong, Yinfei; Pregja, Silvana L.; Berndt, Sonja I.; Blot, William J.; Carpten, John; Casey, Graham; Chu, Lisa; Diver, W. Ryan; Stevens, Victoria L.; Lieber, Michael R.; Goodman, Phyllis J.; Hennis, Anselm J.M.; Hsing, Ann W.; Mehta, Jayesh; Kittles, Rick A.; Kolb, Suzanne; Klein, Eric A.; Leske, Cristina; Murphy, Adam B.; Nemesure, Barbara; Neslund-Dudas, Christine; Strom, Sara S.; Vij, Ravi; Rybicki, Benjamin A.; Stanford, Janet L.; Signorello, Lisa B.; Witte, John S.; Ambrosone, Christine B.; Bhatti, Parveen; John, Esther M.; Bernstein, Leslie; Zheng, Wei; Olshan, Andrew F.; Hu, Jennifer J.; Ziegler, Regina G.; Nyante, Sarah J.; Bandera, Elisa V.; Birmann, Brenda M.; Ingles, Sue A.; Press, Michael F.; Atanackovic, Djordje; Glenn, Martha J.; Cannon-Albright, Lisa A.; Jones, Brandt; Tricot, Guido; Martin, Thomas G.; Kumar, Shaji K.; Wolf, Jeffrey L.; Deming, Sandra L.; Rothman, Nathaniel; Brooks-Wilson, Angela R.; Rajkumar, S. Vincent; Kolonel, Laurence N.; Chanock, Stephen J.; Slager, Susan L.; Severson, Richard K.; Janakiraman, Nalini; Terebelo, Howard R.; Brown, Elizabeth E.; De Roos, Anneclaire J.; Mohrbacher, Ann F.; Colditz, Graham A.; Giles, Graham G.; Spinelli, John J.; Chiu, Brian C.; Munshi, Nikhil C.; Anderson, Kenneth C.; Levy, Joan; Zonder, Jeffrey A.; Orlowski, Robert Z.; Lonial, Sagar; Camp, Nicola J.; Vachon, Celine M.; Ziv, Elad; Stram, Daniel O.; Hazelett, Dennis J.; Haiman, Christopher A.; Cozen, Wendy

2017-01-01

Background Genome-wide association studies (GWAS) in European populations have identified genetic risk variants associated with multiple myeloma (MM). Methods We performed association testing of common variation in eight regions in 1,264 MM patients and 1,479 controls of European ancestry (EA) and 1,305 MM patients and 7,078 controls of African ancestry (AA) and conducted a meta-analysis to localize the signals, with epigenetic annotation used to predict functionality. Results We found that variants in 7p15.3, 17p11.2, 22q13.1 were statistically significantly (p<0.05) associated with MM risk in AAs and EAs and the variant in 3p22.1 was associated in EAs only. In a combined AA-EA meta-analysis, variation in five regions (2p23.3, 3p22.1, 7p15.3, 17p11.2, 22q13.1) was statistically signficantly associated with MM risk. In 3p22.1, the correlated variants clustered within the gene body of ULK4. Correlated variants in 7p15.3 clustered around an enhancer at the 3′ end of the CDCA7L transcription termination site. A missense variant at 17p11.2 (rs34562254, Pro251Leu, OR=1.32, p=2.93×10−7) in TNFRSF13B, encodes a lymphocyte-specific protein in the tumor necrosis factor receptor family that interacts with the NF-κB pathway. SNPs correlated with the index signal in 22q13.1 cluster around the promoter and enhancer regions of CBX7. Conclusions We found that reported MM susceptibility regions contain risk variants important across populations supporting the use of multiple racial/ethnic groups with different underlying genetic architecture to enhance the localization and identification of putatively functional alleles. Impact A subset of reported risk loci for multiple myeloma have consistent affects across populations and are likely to be functional. PMID:27587788

Fibroblast growth factor-23: what we know, what we don't know, and what we need to know.

PubMed

Kovesdy, Csaba P; Quarles, Leigh Darryl

2013-09-01

Traditional risk factors of cardiovascular morbidity and mortality such as hypertension, hypercholesterolemia and obesity are paradoxically associated with better outcomes in dialysis patients, and the few trials of interventions targeting modifiable traditional risk factors have yielded disappointing results in this patient population. Non-traditional risk factors such as inflammation, anemia and abnormalities in bone and mineral metabolism have been proposed as potential explanations for the excess mortality seen in patients with chronic kidney disease (CKD) and end-stage renal disease (ESRD), but without clear understanding of what the most important pathophysiologic mechanisms of these risk factors are, which ones might be ideal treatment targets and which therapeutic interventions may be effective and safe in targeting them. Among the novel risk factors, fibroblast growth factor-23 (FGF23) has recently emerged as one of the most powerful predictors of adverse outcomes in patients with CKD and ESRD. FGF23 is a hormone produced by osteoblasts/osteocytes in bone that acts on the kidney to regulate phosphate and vitamin D metabolism through activation of FGF receptor/α-Klotho co-receptor complexes. It is possible that elevated FGF23 may exert its negative impact through distinct mechanisms of action independent from its role as a regulator of phosphorus homeostasis. Elevated circulating FGF23 concentrations have been associated with left ventricular hypertrophy (LVH), and it has been suggested that FGF23 exerts a direct effect on the myocardium. While it is possible that 'off target' effects of FGF23 present in very high concentrations could induce LVH, this possibility is controversial, since α-klotho is not expressed in the myocardium. Another possibility is that FGF23's effect on the heart is mediated indirectly, via 'on target' activation of other humoral pathways. We will review the physiology and pathophysiology of FGF23, the outcomes associated with elevated FGF23 levels, and describe putative mechanisms of action responsible for its negative effects and potential therapeutic strategies to treat these.

[Health and environment].

PubMed

Tubiana, M

2000-07-01

The impact of the environment (air, water, food pollution) on health is a major concern in contemporary society. Unfortunately, there are relatively few objective epidemiological data on this subject and their accuracy is limited. Risks are often not quantified, whereas in public health the quantitative assessment of the various risks and benefits must provide the bases for a global strategy. Actual risks should be distinguished from putative risks and, when the risks are putative, an effort should be made to ascertain the upper and lower limits of the risk. The validity of a linear no threshold relationship for assessing putative risks should be discussed and, whenever appropriate, other relationships should be considered. Since emotional reactions often pervade environmental issues, which in turn are exploited for political or commercial reasons, it is not surprising that any statement or action may provoke violent debate. It is serious to underestimate the importance of a risk, since appropriate measures may not be put in place. However, it is equally serious to overestimate it because this can provoke unjustified fears, a pervasive unease, and a rejection of certain technologies, even to the point of discrediting science. It can lead therefore to a questioning of progress by instilling fears about any innovation, as well as facilitating the manipulation of public opinion for financial or ideological reasons, and finally to distortions in budget allocations and public health actions. Confronted with this situation, the Academy's role should be threefold. a) Whenever necessary, point out the need for an increase in appropriate fundamental research. When epidemiological data are uncertain, analyse the cause of these uncertainties and advocate appropriate development in statistical methodologies and epidemiological research, which could ascertain the upper limit of the putative risk. The lack of knowledge often results in public anxiety; this reaction should be investigated and psychosociological research must be encouraged and supported. b) Inform the scientific community and the public; fight against misinformation and sensationalism in the news, and take advantage of the Internet to this end. Encourage openness and transparency in the preparation of scientific reports and dialogue with the stakeholders. c) Better define the role and the place of experts, ensure their independence, monitor their competence and make sure they represent the various fields involved. When reports are conflicting, the Academy should be ready to organize a forum for analysing the roots of these disagreements and to delineate the limits of the uncertainties.

Comparative Proteomics of Tandem Mass Spectrometry Analyses for Bacterial Strains Identification and Differentiation

DTIC Science & Technology

2012-02-01

risk, bio -terrorism utility, Homeland Security, agricultural monitoring, quality of foodstuffs, environmental monitoring, and biological warfare agents...CAL19717 Putative surface antigen CAL21872 Putative sigma 54 modulation protein NP_395233 Plasminogen activator protease precursor CAL19882 OMP...S. (2005). Chemical and biological weapons : current concepts for future defenses. Johns Hopkins APL Tech. Digest, 26, 321-333. Dworzanski, J.P

Anti-HCV immunoblot indeterminate results in blood donors: non-specific reactivity or past exposure to HCV?

PubMed

Kiely, P; Styles, C

2017-08-01

The significance of anti-HCV immunoblot (IB) indeterminate results can be difficult to determine. We analysed results for blood donors tested on the MP Diagnostics HCV Blot 3.0 IB assay to determine whether indeterminate results representing past exposure to HCV could be distinguished from those due to non-specific reactivity. Results for all donors tested by IB during the study period (July 2010 to December 2013) were included in this study. Of 131 donors tested by IB, 34 (26.0%) were negative, 38 (29.0%) were indeterminate, and 59 (45.0%) were positive. There was no significant difference in IB band reactivity strength between indeterminate and positive donors. The PRISM HCV chemiluminescent immunoassay (ChLIA) sample to cut-off (s/co) ratio distribution for the indeterminate donors was significantly higher than for those with biological false reactivity (P = 0·037), but significantly lower than for donors who were IB positive/HCV RNA negative (P < 0·001) or IB not tested/HCV RNA positive (P < 0·001). Of donors available for follow-up, 53.1% of the indeterminate group disclosed a putative risk factor for HCV infection compared to 39.4% (P < 0·001) for the IB-negative group, 76.6% (P = 0·065) for the IB-positive group and 83.4% (P < 0·001) for the HCV RNA-positive group. The results of this study indicate that PRISM ChLIA s/co ratios >2·00 with IB indeterminate results predict exposure to HCV, particularly in the presence of putative risk factors for HCV infection. These findings may be applied to optimizing counselling of donors with indeterminate HCV results. © 2017 International Society of Blood Transfusion.

A plausibly causal functional lupus-associated risk variant in the STAT1-STAT4 locus.

PubMed

Patel, Zubin; Lu, Xiaoming; Miller, Daniel; Forney, Carmy R; Lee, Joshua; Lynch, Arthur; Schroeder, Connor; Parks, Lois; Magnusen, Albert F; Chen, Xiaoting; Pujato, Mario; Maddox, Avery; Zoller, Erin E; Namjou, Bahram; Brunner, Hermine I; Henrickson, Michael; Huggins, Jennifer L; Williams, Adrienne H; Ziegler, Julie T; Comeau, Mary E; Marion, Miranda C; Glenn, Stuart B; Adler, Adam; Shen, Nan; Nath, Swapan K; Stevens, Anne M; Freedman, Barry I; Pons-Estel, Bernardo A; Tsao, Betty P; Jacob, Chaim O; Kamen, Diane L; Brown, Elizabeth E; Gilkeson, Gary S; Alarcón, Graciela S; Martin, Javier; Reveille, John D; Anaya, Juan-Manuel; James, Judith A; Sivils, Kathy L; Criswell, Lindsey A; Vilá, Luis M; Petri, Michelle; Scofield, R Hal; Kimberly, Robert P; Edberg, Jeffrey C; Ramsey-Goldman, Rosalind; Bang, So-Young; Lee, Hye-Soon; Bae, Sang-Cheol; Boackle, Susan A; Cunninghame Graham, Deborah; Vyse, Timothy J; Merrill, Joan T; Niewold, Timothy B; Ainsworth, Hannah C; Silverman, Earl D; Weisman, Michael H; Wallace, Daniel J; Raj, Prithvi; Guthridge, Joel M; Gaffney, Patrick M; Kelly, Jennifer A; Alarcón-Riquelme, Marta E; Langefeld, Carl D; Wakeland, Edward K; Kaufman, Kenneth M; Weirauch, Matthew T; Harley, John B; Kottyan, Leah C

2018-04-18

Systemic Lupus Erythematosus (SLE or lupus) (OMIM: 152700) is a chronic autoimmune disease with debilitating inflammation that affects multiple organ systems. The STAT1-STAT4 locus is one of the first and most highly-replicated genetic loci associated with lupus risk. We performed a fine-mapping study to identify plausible causal variants within the STAT1-STAT4 locus associated with increased lupus disease risk. Using complementary frequentist and Bayesian approaches in trans-ancestral Discovery and Replication cohorts, we found one variant whose association with lupus risk is supported across ancestries in both the Discovery and Replication cohorts: rs11889341. In B cell lines from patients with lupus and healthy controls, the lupus risk allele of rs11889341 was associated with increased STAT1 expression. We demonstrated that the transcription factor HMGA1, a member of the HMG transcription factor family with an AT-hook DNA-binding domain, has enriched binding to the risk allele compared to the non-risk allele of rs11889341. We identified a genotype-dependent repressive element in the DNA within the intron of STAT4 surrounding rs11889341. Consistent with expression quantitative trait locus (eQTL) analysis, the lupus risk allele of rs11889341 decreased the activity of this putative repressor. Altogether, we present a plausible molecular mechanism for increased lupus risk at the STAT1-STAT4 locus in which the risk allele of rs11889341, the most probable causal variant, leads to elevated STAT1 expression in B cells due to decreased repressor activity mediated by increased binding of HMGA1.

Common variation in PHACTR1 is associated with susceptibility to cervical artery dissection

PubMed Central

Debette, Stéphanie; Kamatani, Yoichiro; Metso, Tiina M; Kloss, Manja; Chauhan, Ganesh; Engelter, Stefan T; Pezzini, Alessandro; Thijs, Vincent; Markus, Hugh S; Dichgans, Martin; Wolf, Christiane; Dittrich, Ralf; Touzé, Emmanuel; Southerland, Andrew M; Samson, Yves; Abboud, Shérine; Béjot, Yannick; Caso, Valeria; Bersano, Anna; Gschwendtner, Andreas; Sessa, Maria; Cole, John; Lamy, Chantal; Medeiros, Elisabeth; Beretta, Simone; Bonati, Leo H; Grau, Armin J; Michel, Patrik; Majersik, Jennifer J; Sharma, Pankaj; Kalashnikova, Ludmila; Nazarova, Maria; Dobrynina, Larisa; Bartels, Eva; Guillon, Benoit; van den Herik, Evita G; Fernandez-Cadenas, Israel; Jood, Katarina; Nalls, Michael A; De Leeuw, Frank-Erik; Jern, Christina; Cheng, Yu-Ching; Werner, Inge; Metso, Antti J; Lichy, Christoph; Lyrer, Philippe A; Brandt, Tobias; Boncoraglio, Giorgio B; Wichmann, Heinz-Erich; Gieger, Christian; Johnson, Andrew D; Böttcher, Thomas; Castellano, Maurizio; Arveiler, Dominique; Ikram, M Arfan; Breteler, Monique M B; Padovani, Alessandro; Meschia, James F; Kuhlenbäumer, Gregor; Rolfs, Arndt; Worrall, Bradford B; Ringelstein, Erich-Bernd; Zelenika, Diana; Tatlisumak, Turgut; Lathrop, Mark; Leys, Didier; Amouyel, Philippe; Dallongeville, Jean

2018-01-01

Cervical artery dissection (CeAD), a mural hematoma in a carotid or vertebral artery, is a major cause of ischemic stroke in young adults although relatively uncommon in the general population (incidence of 2.6/100,000 per year)1. Minor cervical traumas, infection, migraine and hypertension are putative risk factors1–3, and inverse associations with obesity and hypercholesterolemia are described3,4. No confirmed genetic susceptibility factors have been identified using candidate gene approaches5. We performed genome-wide association studies (GWAS) in 1,393 CeAD cases and 14,416 controls. The rs9349379[G] allele (PHACTR1) was associated with lower CeAD risk (odds ratio (OR) = 0.75, 95% confidence interval (CI) = 0.69–0.82; P = 4.46 × 10−10), with confirmation in independent follow-up samples (659 CeAD cases and 2,648 controls; P = 3.91 × 10−3; combined P = 1.00 × 10−11). The rs9349379[G] allele was previously shown to be associated with lower risk of migraine and increased risk of myocardial infarction6–9. Deciphering the mechanisms underlying this pleiotropy might provide important information on the biological underpinnings of these disabling conditions. PMID:25420145

Discovery of extra-terrestrial life: assessment by scales of its importance and associated risks.

PubMed

Almár, Iván; Race, Margaret S

2011-02-13

The Rio Scale accepted by the SETI Committee of the International Academy of Astronautics in 2002 is intended for use in evaluating the impact on society of any announcement regarding the discovery of evidence of extra-terrestrial (ET) intelligence. The Rio Scale is mathematically defined using three parameters (class of phenomenon, type of discovery and distance) and a δ factor, the assumed credibility of a claim. This paper proposes a new scale applicable to announcements alleging evidence of ET life within or outside our Solar System. The London Scale for astrobiology has mathematical structure and logic similar to the Rio Scale, and uses four parameters (life form, nature of phenomenon, type of discovery and distance) as well as a credibility factor δ to calculate a London Scale index (LSI) with values ranging from 0 to 10. The level of risk or biohazard associated with a purported discovery is evaluated independently of the LSI value and may be ranked in four categories. The combined information is intended to provide a scalar assessment of the scientific importance, validity and potential risks associated with putative evidence of ET life discovered on Earth, on nearby bodies in the Solar System or in our Galaxy.

The effect of household poverty on tuberculosis.

PubMed

Siroka, A; Law, I; Macinko, J; Floyd, K; Banda, R P; Hoa, N B; Tsolmon, B; Chanda-Kapata, P; Gasana, M; Lwinn, T; Senkoro, M; Tupasi, T; Ponce, N A

2016-12-01

pSETTING: Households in Malawi, Mongolia, Myanmar, the Philippines, Rwanda, Tanzania, Viet Nam and Zambia.OBJECTIVE To assess the relationship between household socio-economic level, both relative and absolute, and individual tuberculosis (TB) disease. We analysed national TB prevalence surveys from eight countries individually and in pooled multicountry models. Socio-economic level (SEL) was measured in terms of both relative household position and absolute wealth. The outcome of interest was whether or not an individual had TB disease. Logistic regression models were used to control for putative risk factors for TB disease such as age, sex and previous treatment history. Overall, a strong and consistent association between household SEL and individual TB disease was not found. Significant results were found in four individual country models, with the lowest socio-economic quintile being associated with higher TB risk in Mongolia, Myanmar, Tanzania and Viet Nam. TB prevalence surveys are designed to assess prevalence of disease and, due to the small numbers of cases usually detected, may not be the most efficient means of investigating TB risk factors. Different designs are needed, including measuring the SEL of individuals in nested case-control studies within TB prevalence surveys or among TB patients seeking treatment in health care facilities.

Antimicrobial peptides as a possible interlink between periodontal diseases and its risk factors: A systematic review.

PubMed

Li, S; Schmalz, G; Schmidt, J; Krause, F; Haak, R; Ziebolz, D

2018-04-01

Antimicrobial peptides (AMPs) play a critical role in controlling innate and acquired immune responses. Local dysregulation of AMP is implicated in the pathogenesis of periodontal diseases as a response to periodontal pathogen challenge. Changes in AMP expression also characterize tobacco smoking, diabetes mellitus, obesity and rheumatoid arthritis, which are established risk factors of periodontal diseases, suggesting AMP may act as putative mechanistic links between these. The aim was to evaluate and summarize critically the current evidence pertaining to interrelationships between AMPs, periodontal diseases and selected periodontal disease risk factors. General and theme specific keywords were used to search the PUBMED database for studies relevant to AMP, periodontal diseases, smoking, diabetes mellitus, obesity and rheumatoid arthritis and critically reviewed. A total of 131 abstracts and 119 full text articles were screened for relevance; 13 studies were selected for inclusion after critical review. Local AMP dysregulation characteristic to periodontal diseases appears to occur within a broader landscape of complex systemic immune perturbations independently induced by smoking, metabolic and rheumatoid disease. The nature of these interactions and mechanistic pathways involved are inadequately understood. AMPs could be possible mechanistic interlinks between periodontal diseases and its risk factors. However, such evidence is very limited and more in vivo and in vitro studies are necessary to clarify the nature of such relationships. A greater understanding of AMPs as shared mediators is essential for unraveling their value as therapeutic or biomarker candidates. © 2017 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

Jiangsu Four Cancers Study: a large case-control study of lung, liver, stomach, and esophageal cancers in Jiangsu Province, China.

PubMed

Zhao, Jin-Kou; Wu, Ming; Kim, Claire H; Jin, Zi-Yi; Zhou, Jin-Yi; Han, Ren-Qiang; Yang, Jie; Zhang, Xiao-Feng; Wang, Xu-Shan; Liu, Ai-Ming; Gu, Xiaoping; Su, Ming; Hu, Xu; Sun, Zheng; Li, Gang; Li, Liming; Mu, Lina; Zhang, Zuo-Feng

2017-07-01

Cancer is a major public health burden both globally and in China. The most common cancer-related deaths in China are attributable to cancers of the lung, liver, stomach, and esophagus. Previous epidemiologic studies on cancer in China have often been limited by small sample sizes, inconsistent measurements, and lack of precise and accurate data. The Jiangsu Four Cancers (JFC) Study is a population-based case-control study carried out in an effort to obtain consistent and high-quality data to investigate the life style, behavioral, environmental, and genetic factors associated with the four major cancers in China. The aim of this paper is to describe the overall design of the JFC Study and report selected findings on the major risk factors for cancers. Epidemiologic data were collected from 2003 to 2010 through in-person interviews using a structured questionnaire and blood samples were drawn. Unconditional logistic regression was used to estimate the associations of putative risk factors with risks of cancers of the lung, liver, stomach, and esophagus. The study included 2871 lung cancer cases, 2018 liver cancer cases, 2969 esophageal cancer cases, 2216 stomach cancer cases, and 8019 community controls. Low educational level, low income level, tobacco smoking, alcohol drinking, and family history of cancer were confirmed as risk factors for these major cancers. The JFC Study is one of the largest case-control studies of cancers in the Chinese population and will serve as a rich resource for future research on the four major cancers in China.

Coronary heart disease risk factors in adult premenopausal white women with polycystic ovary syndrome compared with a healthy female population.

PubMed

Glueck, Charles J; Morrison, John A; Goldenberg, Naila; Wang, Ping

2009-05-01

Our specific aim was to determine whether coronary heart disease (CHD) risk factors in polycystic ovary syndrome (PCOS) patients were independent of their higher body mass index (BMI) and centripetal obesity. In adult, premenopausal, white women, CHD risk factors were compared between 488 patients with well-defined PCOS and 351 healthy free-living population controls from the Princeton Follow-up Study (PFS). After excluding women with irregular menses (putative PCOS phenotypes), comparisons were also made between the 261 PFS women with a history of regular menses and the 488 women with PCOS. Fasting lipids, insulin, glucose, homeostasis model assessment of insulin resistance (HOMA-IR), HOMA insulin secretion, blood pressure, BMI, and waist circumference were measured. Compared with both the full cohort of 351 PFS women and the subgroup of 261 PFS women with regular menses, women with PCOS had higher BMI, waist circumference, total and low-density lipoprotein cholesterol, triglyceride, systolic blood pressure, diastolic blood pressure, insulin, glucose, and HOMA-IR (all Ps < or = .005). After adjusting for age and BMI, women with PCOS, compared with the 351 and 261 PFS women, had lower high-density lipoprotein cholesterol (P < .0001, .0008) and higher systolic blood pressure (P = .0002, < .0001), insulin (P = .017, .039), HOMA-IR (P = .013, .032), and HOMA insulin secretion (P = .022, .037). The small subgroup of PCOS women with normal BMI (<25 kg/m(2)) (36/488, 7%) also had higher age-adjusted insulin, glucose, and HOMA-IR (all Ps < .005) than the subgroup of PFS women with BMI less than 25 kg/m(2) (123/261, 47%). Increased CHD risk factors and high HOMA-IR in PCOS cannot be exclusively attributed to their preponderant centripetal obesity. Identification of women with clinical features of PCOS should alert the clinician to potentially increased risk for CHD and prompt CHD risk factor testing.

Epidemiology of goblet cell and microvesicular hyperplastic polyps.

PubMed

Qazi, Taha M; O'Brien, Michael J; Farraye, Francis A; Gould, Ryan W; Chen, Clara A; Schroy, Paul C

2014-12-01

Serrated polyps compromise both typical hyperplastic polyps as well as sessile serrated adenomas and dysplastic serrated polyps. Hyperplastic polyps exhibit two histological patterns: microvesicular hyperplastic polyps (MVHPs) and goblet cell hyperplastic polyps (GCHPs). MVHPs and GCHPs differ in their molecular signature. MVHPs have been frequently found to have the BRAF(V600E) mutation as well as aberrant methylation. In contrast, GCHPs have been associated with the KRAS mutation (KRAS-mut), which are infrequently seen in dysplastic serrated sessile adenomas. The particular risk factors that are associated with development of the types of hyperplastic polyps have not been previously studied. The purpose of this study is to characterize the associations between particular risk factors and the development of goblet cell or microvesicular hyperplastic polyps. We conducted a cross-sectional analysis of 3,543 asymptomatic, mostly average risk patients 50 and 79 years of age undergoing open-access screening colonoscopy between March 2005 and January 2012. Each patient was given a survey regarding 25 reputed risk factors for colorectal neoplasia and the responses were correlated with findings at colonoscopy. Associations between putative risk factors for colorectal neoplasia and MVHPs and GSHPs were examined using multiple logistic regression. MVHPS and GCHPs were identified in 5.3% and 8.7% of patients, respectively. The results of the statistical analysis indicate that a history of smoking greater than 20 years is associated with an increased risk of MVHPs (P<0.005) and GCHPs (P<0.005). An elevated BMI >30 kg/m(2) was also associated with the presence of MVHP at colonoscopy (P<0.005). Blacks and Asians appear to be protected from the development of MVHPs. In contrast, there was a positive association with the presence of GCHP at colonoscopy in blacks. The study suggests that the development of the distinct histological types of hyperplastic polyps are associated with distinct modifiable and non-modifiable lifestyle factors.

Risk factors for development of incipient and overt diabetic nephropathy in patients with non-insulin dependent diabetes mellitus: prospective, observational study.

PubMed Central

Gall, M. A.; Hougaard, P.; Borch-Johnsen, K.; Parving, H. H.

1997-01-01

OBJECTIVE: To evaluate putative risk factors for the development of incipient diabetic nephropathy (persistent microalbuminuria) and overt diabetic nephropathy (persistent macroalbuminuria) in patients with non-insulin dependent diabetes. DESIGN: Prospective, observational study of a cohort of white, non-insulin dependent diabetic patients followed for a median period of 5.8 years. SETTING: Outpatient clinic in tertiary referral centre. SUBJECTS: 191 patients aged under 66 years with non-insulin dependent diabetes and normoalbuminuria (urinary albumin excretion rate < 30 mg/24 h) who attended the clinic during 1987. MAIN OUTCOME MEASURES: Incipient and overt diabetic nephropathy. RESULTS: Fifteen patients were lost to follow up. Thirty six of the 176 remaining developed persistent microalbuminuria (30-299 mg/24 h in two out of three consecutive 24 hour urine collections) and five developed persistent macroalbuminuria (> or = mg/24 h in two out of three consecutive collections) during follow up. The five year cumulative incidence of incipient diabetic nephropathy was 23% (95% confidence interval 17% to 30%). Cox's multiple stepwise regression analysis revealed the following risk factors for the development of incipient or overt diabetic nephropathy: increased baseline log urinary albumin excretion rate (relative risk 11.1 (3.4 to 35.9); P < 0.0001); male sex (2.6 (1.2 to 5.4); P < 0.02); presence of retinopathy (2.4 (1.3 to 4.7); P < 0.01); increased serum cholesterol concentration (1.4 (1.1 to 1.7); P < 0.01); haemoglobin A1c concentration (1.2 (1.0 to 1.4); P < 0.05); and age (1.07 (1.02 to 1.12); P < 0.01). Known duration of diabetes, body mass index, arterial blood pressure, serum creatinine concentration, pre-existing coronary heart disease, and history of smoking were not risk factors. CONCLUSION: Several potentially modifiable risk factors predict the development of incipient and overt diabetic nephropathy in normoalbuminuric patients with non-insulin dependent diabetes. PMID:9080995

12 CFR 956.4 - Risk-based capital requirement for investments.

Code of Federal Regulations, 2010 CFR

2010-01-01

... credit risk of all investments that are not rated by an NRSRO, or are rated or have a putative rating... 12 Banks and Banking 7 2010-01-01 2010-01-01 false Risk-based capital requirement for investments... OFF-BALANCE SHEET ITEMS FEDERAL HOME LOAN BANK INVESTMENTS § 956.4 Risk-based capital requirement for...

The MOBILIZE Boston Study: design and methods of a prospective cohort study of novel risk factors for falls in an older population.

PubMed

Leveille, Suzanne G; Kiel, Douglas P; Jones, Richard N; Roman, Anthony; Hannan, Marian T; Sorond, Farzaneh A; Kang, Hyun G; Samelson, Elizabeth J; Gagnon, Margaret; Freeman, Marcie; Lipsitz, Lewis A

2008-07-18

Falls are the sixth leading cause of death in elderly people in the U.S. Despite progress in understanding risk factors for falls, many suspected risk factors have not been adequately studied. Putative risk factors for falls such as pain, reductions in cerebral blood flow, somatosensory deficits, and foot disorders are poorly understood, in part because they pose measurement challenges, particularly for large observational studies. The MOBILIZE Boston Study (MBS), an NIA-funded Program Project, is a prospective cohort study of a unique set of risk factors for falls in seniors in the Boston area. Using a door-to-door population-based recruitment, we have enrolled 765 persons aged 70 and older. The baseline assessment was conducted in 2 segments: a 3-hour home interview followed within 4 weeks by a 3-hour clinic examination. Measures included pain, cerebral hemodynamics, and foot disorders as well as established fall risk factors. For the falls follow-up, participants return fall calendar postcards to the research center at the end of each month. Reports of falls are followed-up with a telephone interview to assess circumstances and consequences of each fall. A second assessment is performed 18 months following baseline. Of the 2382 who met all eligibility criteria at the door, 1616 (67.8%) agreed to participate and were referred to the research center for further screening. The primary reason for ineligibility was inability to communicate in English. Results from the first 600 participants showed that participants are largely representative of seniors in the Boston area in terms of age, sex, race and Hispanic ethnicity. The average age of study participants was 77.9 years (s.d. 5.5) and nearly two-thirds were women. The study cohort was 78% white and 17% black. Many participants (39%) reported having fallen at least once in the year before baseline. Our results demonstrate the feasibility of conducting comprehensive assessments, including rigorous physiologic measurements, in a diverse population of older adults to study non-traditional risk factors for falls and disability. The MBS will provide an important new data resource for examining novel risk factors for falls and mobility problems in the older population.

Identification of estrogen-responsive genes using a genome-wide analysis of promoter elements for transcription factor binding sites.

PubMed

Kamalakaran, Sitharthan; Radhakrishnan, Senthil K; Beck, William T

2005-06-03

We developed a pipeline to identify novel genes regulated by the steroid hormone-dependent transcription factor, estrogen receptor, through a systematic analysis of upstream regions of all human and mouse genes. We built a data base of putative promoter regions for 23,077 human and 19,984 mouse transcripts from National Center for Biotechnology Information annotation and 8793 human and 6785 mouse promoters from the Data Base of Transcriptional Start Sites. We used this data base of putative promoters to identify potential targets of estrogen receptor by identifying estrogen response elements (EREs) in their promoters. Our program correctly identified EREs in genes known to be regulated by estrogen in addition to several new genes whose putative promoters contained EREs. We validated six genes (KIAA1243, NRIP1, MADH9, NME3, TPD52L, and ABCG2) to be estrogen-responsive in MCF7 cells using reverse transcription PCR. To allow for extensibility of our program in identifying targets of other transcription factors, we have built a Web interface to access our data base and programs. Our Web-based program for Promoter Analysis of Genome, PAGen@UIC, allows a user to identify putative target genes for vertebrate transcription factors through the analysis of their upstream sequences. The interface allows the user to search the human and mouse promoter data bases for potential target genes containing one or more listed transcription factor binding sites (TFBSs) in their upstream elements, using either regular expression-based consensus or position weight matrices. The data base can also be searched for promoters harboring user-defined TFBSs given as a consensus or a position weight matrix. Furthermore, the user can retrieve putative promoter sequences for any given gene together with identified TFBSs located on its promoter. Orthologous promoters are also analyzed to determine conserved elements.

Cloning and characterization of prunus serotina AGAMOUS, a putative flower homeotic gene

Treesearch

Xiaomei Liu; Joseph Anderson; Paula Pijut

2010-01-01

Members of the AGAMOUS subfamily of MADS-box transcription factors play an important role in regulating the development of reproductive organs in flowering plants. To help understand the mechanism of floral development in black cherry (Prunus serotina), PsAG (a putative flower homeotic identity gene) was isolated...

Prostate cancer and industrial pollution Risk around putative focus in a multi-source scenario.

PubMed

Ramis, Rebeca; Diggle, Peter; Cambra, Koldo; López-Abente, Gonzalo

2011-04-01

Prostate cancer is the second most common type of cancer among men but its aetiology is still largely unknown. Different studies have proposed several risk factors such as ethnic origin, age, genetic factors, hormonal factors, diet and insulin-like growth factor, but the spatial distribution of the disease suggests that other environmental factors are involved. This paper studies the spatial distribution of prostate cancer mortality in an industrialized area using distances from each of a number of industrial facilities as indirect measures of exposure to industrial pollution. We studied the Gran Bilbao area (Spain) with a population of 791,519 inhabitants distributed in 657 census tracts. There were 20 industrial facilities within the area, 8 of them in the central axis of the region. We analysed prostate cancer mortality during the period 1996-2003. There were 883 deaths giving a crude rate of 14 per 100,000 inhabitants. We extended the standard Poisson regression model by the inclusion of a multiplicative non-linear function to model the effect of distance from an industrial facility. The function's shape combined an elevated risk close to the source with a neutral effect at large distance. We also included socio-demographic covariates in the model to control potential confounding. We aggregated the industrial facilities by sector: metal, mineral, chemical and other activities. Results relating to metal industries showed a significantly elevated risk by a factor of approximately 1.4 in the immediate vicinity, decaying with distance to a value of 1.08 at 12km. The remaining sectors did not show a statistically significant excess of risk at the source. Notwithstanding the limitations of this kind of study, we found evidence of association between the spatial distribution of prostate cancer mortality aggregated by census tracts and proximity to metal industrial facilities located within the area, after adjusting for socio-demographic characteristics at municipality level. Copyright © 2010 Elsevier Ltd. All rights reserved.

Workplace cluster of Bell’s palsy in Lima, Peru

PubMed Central

2014-01-01

Background We report on a workplace cluster of Bell’s palsy that occurred within a four-month period in 2011 among employees of a three-story office building in Lima, Peru and our investigation to determine the etiology and associated risk factors. Findings An outbreak investigation was conducted to identify possible common infectious or environmental exposures and included patient interviews, reviews of medical records, an epidemiologic survey, serological analysis for IgM and IgG antibodies to putative Bell’s palsy-inducing pathogens, and an environmental exposure assessment of the office building. Three cases of Bell’s palsy were reported among 65 at-risk employees, attack rate 4.6%. Although two patients had underlying risk factors, there was no clear association or common identifiable risk factor among all cases. Serologic analysis showed no evidence of recent infections, and air and water sample measures of all known chemical or neurotoxins were below maximum allowable concentrations for exposure. Conclusions An infection spread among workplace employees could not be excluded as a potential cause of this cluster; however, it was unlikely a pathogen commonly associated with individual cases of Bell’s palsy. Although a specific etiology was not identified among all cases, we believe this methodology will aid future outbreak investigations of Bell’s palsy and a better understanding of its etiology. While environmental assessments may be useful in their ability to ascertain the cause of clusters of Bell’s palsy, future investigations should prioritize focus on common infectious etiology. PMID:24885256

Integration of Population-Level Genotype Data with Functional Annotation Reveals Over-Representation of Long Noncoding RNAs at Ovarian Cancer Susceptibility Loci.

PubMed

Reid, Brett M; Permuth, Jennifer B; Chen, Y Ann; Teer, Jamie K; Monteiro, Alvaro N A; Chen, Zhihua; Tyrer, Jonathan; Berchuck, Andrew; Chenevix-Trench, Georgia; Doherty, Jennifer A; Goode, Ellen L; Iverson, Edwin S; Lawrenson, Kate; Pearce, Celeste L; Pharoah, Paul D; Phelan, Catherine M; Ramus, Susan J; Rossing, Mary Anne; Schildkraut, Joellen M; Cheng, Jin Q; Gayther, Simon A; Sellers, Thomas A

2017-01-01

Genome-wide association studies (GWAS) have identified multiple loci associated with epithelial ovarian cancer (EOC) susceptibility, but further progress requires integration of epidemiology and biology to illuminate true risk loci below genome-wide significance levels (P < 5 × 10 -8 ). Most risk SNPs lie within non-protein-encoding regions, and we hypothesize that long noncoding RNA (lncRNA) genes are enriched at EOC risk regions and represent biologically relevant functional targets. Using imputed GWAS data from about 18,000 invasive EOC cases and 34,000 controls of European ancestry, the GENCODE (v19) lncRNA database was used to annotate SNPs from 13,442 lncRNAs for permutation-based enrichment analysis. Tumor expression quantitative trait locus (eQTL) analysis was performed for sub-genome-wide regions (1 × 10 -5 > P > 5 × 10 -8 ) overlapping lncRNAs. Of 5,294 EOC-associated SNPs (P < 1.0 × 10 -5 ), 1,464 (28%) mapped within 53 unique lncRNAs and an additional 3,484 (66%) SNPs were correlated (r 2 > 0.2) with SNPs within 115 lncRNAs. EOC-associated SNPs comprised 130 independent regions, of which 72 (55%) overlapped with lncRNAs, representing a significant enrichment (P = 5.0 × 10 -4 ) that was more pronounced among a subset of 5,401 lncRNAs with active epigenetic regulation in normal ovarian tissue. EOC-associated lncRNAs and their putative promoters and transcription factors were enriched for biologically relevant pathways and eQTL analysis identified five novel putative risk regions with allele-specific effects on lncRNA gene expression. lncRNAs are significantly enriched at EOC risk regions, suggesting a mechanistic role for lncRNAs in driving predisposition to EOC. lncRNAs represent key candidates for integrative epidemiologic and functional studies. Further research on their biologic role in ovarian cancer is indicated. Cancer Epidemiol Biomarkers Prev; 26(1); 116-25. ©2016 AACR. ©2016 American Association for Cancer Research.

Neuroendocrine factors affecting the glycogen metabolism of purified Mytilus edulis glycogen cells: partial characterization of the putative glycogen mobilization hormone--demonstration of a factor that stimulates glycogen synthesis.

PubMed

Robbins, I; Lenoir, F; Mathieu, M

1991-04-01

A putative glycogen mobilizing hormone (GMH) from the marine mussel Mytilus edulis L. has been partially characterized. GMH activity is present in the cerebral ganglia and the hemolymph serum and promotes the mobilization of glycogen in isolated glycogen cells. The cerebral GMH is trypsin sensitive and partially heat labile and has an apparent molecular mass of greater than 20 kDa. Following fractionation of cerebral extracts by molecular mass, a second factor, with a molecular mass of ca. 1.5 kDa, was discovered. This factor stimulates post-incubation incorporation of 14C into glycogen in isolated glycogen cells.

A resource for characterizing genome-wide binding and putative target genes of transcription factors expressed during secondary growth and wood formation in Populus.

PubMed

Liu, Lijun; Ramsay, Trevor; Zinkgraf, Matthew; Sundell, David; Street, Nathaniel Robert; Filkov, Vladimir; Groover, Andrew

2015-06-01

Identifying transcription factor target genes is essential for modeling the transcriptional networks underlying developmental processes. Here we report a chromatin immunoprecipitation sequencing (ChIP-seq) resource consisting of genome-wide binding regions and associated putative target genes for four Populus homeodomain transcription factors expressed during secondary growth and wood formation. Software code (programs and scripts) for processing the Populus ChIP-seq data are provided within a publically available iPlant image, including tools for ChIP-seq data quality control and evaluation adapted from the human Encyclopedia of DNA Elements (ENCODE) project. Basic information for each transcription factor (including members of Class I KNOX, Class III HD ZIP, BEL1-like families) binding are summarized, including the number and location of binding regions, distribution of binding regions relative to gene features, associated putative target genes, and enriched functional categories of putative target genes. These ChIP-seq data have been integrated within the Populus Genome Integrative Explorer (PopGenIE) where they can be analyzed using a variety of web-based tools. We present an example analysis that shows preferential binding of transcription factor ARBORKNOX1 to the nearest neighbor genes in a pre-calculated co-expression network module, and enrichment for meristem-related genes within this module including multiple orthologs of Arabidopsis KNOTTED-like Arabidopsis 2/6. © 2015 Society for Experimental Biology and John Wiley & Sons Ltd This article has been contributed to by US Government employees and their work is in the public domain in the USA.

PHYSIOLOGIC BIOMARKERS AND HENDRA VIRUS INFECTION IN AUSTRALIAN BLACK FLYING FOXES (PTEROPUS ALECTO).

PubMed

McMichael, Lee; Edson, Daniel; Mayer, David; Broos, Alice; Kopp, Steven; Meers, Joanne; Field, Hume

2017-01-01

Bats of the genus Pteropus (Pteropodidae), colloquially known as flying foxes, are recognized as the natural reservoir of Hendra virus, a zoonotic paramyxovirus responsible for mortality in horses and humans. Some previous studies have suggested that physiologic and ecologic factors promote Hendra virus infection in flying foxes, and by extension, spillover to horses and humans. However, the impact of Hendra virus infection on relevant physiologic biomarkers in flying foxes has not been measured. Over 12 mo in eastern Australia, we captured and sampled 446 individual black flying foxes ( Pteropus alecto ), a putative primary reservoir host species, and measured a suite of hematologic, plasma biochemistry, and urinary biomarkers. All mean hematologic and biochemical values in both Hendra virus-positive and virus-negative cohorts were within the published reference ranges for black flying foxes. We found no association between Hendra virus infection (as indicated by PCR detection of Hendra virus RNA) and biomarkers for nutritional stress, reproductive stress, or extreme metabolic demand. However, we identified associations between several other biomarkers and Hendra virus infection, which may partly elucidate the physiologic effects of Hendra virus infection in flying foxes. Our findings highlight the need for critical evaluation of putative risk factors for infection in flying foxes and provide insights for future epidemiologic studies of Hendra virus and related viruses in the Pteropus species.

Dynamic Modulation of Expression of Lentiviral Restriction Factors in Primary CD4+ T Cells following Simian Immunodeficiency Virus Infection.

PubMed

Rahmberg, Andrew R; Rajakumar, Premeela A; Billingsley, James M; Johnson, R Paul

2017-04-01

Although multiple restriction factors have been shown to inhibit HIV/SIV replication, little is known about their expression in vivo Expression of 45 confirmed and putative HIV/SIV restriction factors was analyzed in CD4 + T cells from peripheral blood and the jejunum in rhesus macaques, revealing distinct expression patterns in naive and memory subsets. In both peripheral blood and the jejunum, memory CD4 + T cells expressed higher levels of multiple restriction factors compared to naive cells. However, relative to their expression in peripheral blood CD4 + T cells, jejunal CCR5 + CD4 + T cells exhibited significantly lower expression of multiple restriction factors, including APOBEC3G , MX2 , and TRIM25 , which may contribute to the exquisite susceptibility of these cells to SIV infection. In vitro stimulation with anti-CD3/CD28 antibodies or type I interferon resulted in upregulation of distinct subsets of multiple restriction factors. After infection of rhesus macaques with SIVmac239, the expression of most confirmed and putative restriction factors substantially increased in all CD4 + T cell memory subsets at the peak of acute infection. Jejunal CCR5 + CD4 + T cells exhibited the highest levels of SIV RNA, corresponding to the lower restriction factor expression in this subset relative to peripheral blood prior to infection. These results illustrate the dynamic modulation of confirmed and putative restriction factor expression by memory differentiation, stimulation, tissue microenvironment and SIV infection and suggest that differential expression of restriction factors may play a key role in modulating the susceptibility of different populations of CD4 + T cells to lentiviral infection. IMPORTANCE Restriction factors are genes that have evolved to provide intrinsic defense against viruses. HIV and simian immunodeficiency virus (SIV) target CD4 + T cells. The baseline level of expression in vivo and degree to which expression of restriction factors is modulated by conditions such as CD4 + T cell differentiation, stimulation, tissue location, or SIV infection are currently poorly understood. We measured the expression of 45 confirmed and putative restriction factors in primary CD4 + T cells from rhesus macaques under various conditions, finding dynamic changes in each state. Most dramatically, in acute SIV infection, the expression of almost all target genes analyzed increased. These are the first measurements of many of these confirmed and putative restriction factors in primary cells or during the early events after SIV infection and suggest that the level of expression of restriction factors may contribute to the differential susceptibility of CD4 + T cells to SIV infection. Copyright © 2017 American Society for Microbiology.

Alcohol outlet density, drinking contexts and intimate partner violence: a review of environmental risk factors.

PubMed

Cunradi, Carol B; Mair, Christina; Todd, Michael

2014-01-01

Alcohol use is a robust predictor of intimate partner violence (IPV). A critical barrier to progress in preventing alcohol-related IPV is that little is known about how an individual's specific drinking contexts (where, how often, and with whom one drinks) are related to IPV, or how these contexts are affected by environmental characteristics, such as alcohol outlet density and neighborhood disadvantage. The putative mechanism is the social environment in which drinking occurs that may promote or strengthen aggressive norms. Once these contexts are known, specific prevention measures can be put in place, including policy-oriented (e.g., regulating outlet density) and individually oriented (e.g., brief interventions to reduce risk for spousal aggression) measures targeting at-risk populations. This paper reviews applicable theories and empirical research evidence that links IPV to drinking contexts and alcohol outlet density, highlights research gaps, and makes recommendations for future research. © The Author(s) 2015 Reprints and permissions: sagepub.co.uk/journalsPermissions.nav.

Fire interest and antisociality as risk factors in the severity and persistence of juvenile firesetting.

PubMed

MacKay, Sherri; Henderson, Joanna; Del Bove, Giannetta; Marton, Peter; Warling, Diane; Root, Carol

2006-09-01

In the DSM-IV-TR, firesetting is included as a criterion for the diagnoses of conduct disorder and pyromania. The link between firesetting and antisocial behavior is well established in the empirical literature. Although theoretical models of firesetting often include fire interest as a putative risk factor, there is little research on the role of fire interest in firesetting or on the construct of pyromania. The present study evaluated a sample of children and adolescents referred to an outpatient specialty program for juvenile firesetters with firesetting as the primary presenting problem. By assessing fire interest and antisocial behavior concurrently, the contribution of fire interest to firesetting after controlling for the role of conduct problems was evaluated. Results revealed that fire interest and antisocial behavior were significantly and positively correlated. Moreover, variations in fire interest added to the prediction of firesetting severity at assessment and firesetting recidivism at 18-month follow-up above and beyond what was predicted by antisociality alone. These findings have implications for an empirically derived taxonomy of pathological firesetting.

Iatrogenic outbreak of M. chelonae skin abscesses.

PubMed Central

Camargo, D.; Saad, C.; Ruiz, F.; Ramirez, M. E.; Lineros, M.; Rodriguez, G.; Navarro, E.; Pulido, B.; Orozco, L. C.

1996-01-01

We describe an outbreak of skin lesions due to Mycobacterium chelonae subsp. abscessus associated with injections of lidocaine (lignocaine) given by a 'bioenergetic' (a practitioner of alternative medicine) in Colombia. The lidocaine carpules and the lesions of the patients yielded mycobacteria with identical biochemical characteristics. Using the methodology of Sartwell and a case control design we examined the incubation period and assessed risk factors. Of 667 potentially exposed individuals, a total of 298 patients were interviewed, of whom 232 had skin lesions. The median incubation period was 30.5 days (range 15-59 days). Male sex (OR 2.85, 95% CI 1.26-6.51), increasing age (OR 1.25, 95% CI 1.03-1.53), subcutaneous injection route (OR 3.72, 95% CI 1.09-12.7) and number of injections (OR 1.01, 95% CI 1.00-1.03) were risk factors for disease. To our knowledge, this is the largest reported outbreak of M. chelonae infection, the first in which the organism has been isolated from the putative vehicle of infection, and the first in which the incubation period could be determined. PMID:8760958

Environmental determinants of type 1 diabetes: a role for overweight and insulin resistance.

PubMed

Islam, Sadia T; Srinivasan, Shubha; Craig, Maria E

2014-11-01

Rates of type 1 diabetes are rising globally, with a decreasing proportion of high-risk genotypes and twin concordance rates below 50%. Therefore, environmental factors such as viruses, nutrition and overweight have been examined as putative aetiological agents. The accelerator hypothesis proposes that overweight and insulin resistance are central to both type 1 and type 2 diabetes and may explain, in part, the rise in type 1 diabetes incidence. The temporal rise in body mass index at type 1 diabetes onset and the observation that pre-diabetic children are heavier and more insulin resistant than their peers suggests convergence of type 1 and type 2 diabetes phenotypes. The influence of insulin resistance may begin in utero, although the aetiological role of birthweight in type 1 diabetes remains unclear. Further research to elucidate the role of these modifiable risk factors in today's obesogenic environment may provide future potential for diabetes prevention. © 2014 The Authors. Journal of Paediatrics and Child Health © 2014 Paediatrics and Child Health Division (Royal Australasian College of Physicians).

Linking vascular disorders and Alzheimer’s disease: Potential involvement of BACE1

PubMed Central

Cole, Sarah L.; Vassar, Robert

2012-01-01

The etiology of Alzheimer’s disease (AD) remains unknown. However, specific risk factors have been identified, and aging is the strongest AD risk factor. The majority of cardiovascular events occur in older people and a close relationship between vascular disorders and AD exists. Amyloid plaques, composed of the beta amyloid peptide (Aβ), are hallmark lesions in AD and evidence indicates that Aβ plays a central role in AD pathophysiology. The BACE1 enzyme is essential for Aβ generation, and BACE1 levels are elevated in AD brain. The cause(s) of this BACE1 elevation remains undetermined. Here we review the potential contribution of vascular disease to AD pathogenesis. We examine the putative vasoactive properties of Aβ and how the cellular changes associated with vascular disease may elevate BACE1 levels. Despite increasing evidence, the exact role(s) vascular disorders play in AD remains to be determined. However, given that vascular diseases can be addressed by lifestyle and pharmacologic interventions, the potential benefits of these therapies in delaying the clinical appearance and progression of AD may warrant investigation. PMID:18289733

Premature mortality in active convulsive epilepsy in rural Kenya: causes and associated factors.

PubMed

Ngugi, Anthony K; Bottomley, Christian; Fegan, Gregory; Chengo, Eddie; Odhiambo, Rachael; Bauni, Evasius; Neville, Brian; Kleinschmidt, Immo; Sander, Josemir W; Newton, Charles R

2014-02-18

We estimated premature mortality and identified causes of death and associated factors in people with active convulsive epilepsy (ACE) in rural Kenya. In this prospective population-based study, people with ACE were identified in a cross-sectional survey and followed up regularly for 3 years, during which information on deaths and associated factors was collected. We used a validated verbal autopsy tool to establish putative causes of death. Age-specific rate ratios and standardized mortality ratios were estimated. Poisson regression was used to identify mortality risk factors. There were 61 deaths among 754 people with ACE, yielding a rate of 33.3/1,000 persons/year. Overall standardized mortality ratio was 6.5. Mortality was higher across all ACE age groups. Nonadherence to antiepileptic drugs (adjusted rate ratio [aRR] 3.37), cognitive impairment (aRR 4.55), and age (50+ years) (rate ratio 4.56) were risk factors for premature mortality. Most deaths (56%) were directly related to epilepsy, with prolonged seizures/possible status epilepticus (38%) most frequently associated with death; some of these may have been due to sudden unexpected death in epilepsy (SUDEP). Possible SUDEP was the likely cause in another 7%. Mortality in people with ACE was more than 6-fold greater than expected. This may be reduced by improving treatment adherence and prompt management of prolonged seizures and supporting those with cognitive impairment.

Role of dupA in virulence of Helicobacter pylori

PubMed Central

Talebi Bezmin Abadi, Amin; Perez-Perez, Guillermo

2016-01-01

Helicobacter pylori (H. pylori) is a gastric human pathogen associated with acute and chronic gastritis, 70% of all gastric ulcers, 85% of all duodenal ulcers, and both forms of stomach cancer, mucosal-associated lymphoid tissue (MALT) lymphoma and adenocarcinoma. Recently, attention has focused on possible relationship between presence of certain virulence factor and H. pylori-associated diseases. Some contradictory data between this bacterium and related disorders has been observed since not all the colonized individuals develop to severe disease. The reported diseases plausibility related to H. pylori specific virulence factors became an interesting story about this organism. Although a number of putative virulence factors have been identified including cytotoxin-associated gene a (cagA) and vacA, there are conflicting data about their actual participation as specific risk factor for H. pylori-related diseases. Duodenal ulcer promoting gene a (dupA) is a virulence factor of H. pylori that is highly associated with duodenal ulcer development and reduced risk of gastric cancer. The prevalence of dupA in H. pylori strains isolated from western countries is relatively higher than in H. pylori strains from Asian countries. Current confusing epidemiological reports will continue unless future sophisticated and molecular studies provide data on functional and complete dupA cluster in H. pylori infected individuals. This paper elucidates available knowledge concerning role of dupA in virulence of H. pylori after a decade of its discovery. PMID:28028359

Role of dupA in virulence of Helicobacter pylori.

PubMed

Talebi Bezmin Abadi, Amin; Perez-Perez, Guillermo

2016-12-14

Helicobacter pylori ( H. pylori ) is a gastric human pathogen associated with acute and chronic gastritis, 70% of all gastric ulcers, 85% of all duodenal ulcers, and both forms of stomach cancer, mucosal-associated lymphoid tissue (MALT) lymphoma and adenocarcinoma. Recently, attention has focused on possible relationship between presence of certain virulence factor and H. pylori -associated diseases. Some contradictory data between this bacterium and related disorders has been observed since not all the colonized individuals develop to severe disease. The reported diseases plausibility related to H. pylori specific virulence factors became an interesting story about this organism. Although a number of putative virulence factors have been identified including cytotoxin-associated gene a ( cagA ) and vacA , there are conflicting data about their actual participation as specific risk factor for H. pylori -related diseases. Duodenal ulcer promoting gene a ( dupA ) is a virulence factor of H. pylori that is highly associated with duodenal ulcer development and reduced risk of gastric cancer. The prevalence of dupA in H. pylori strains isolated from western countries is relatively higher than in H. pylori strains from Asian countries. Current confusing epidemiological reports will continue unless future sophisticated and molecular studies provide data on functional and complete dupA cluster in H. pylori infected individuals. This paper elucidates available knowledge concerning role of dupA in virulence of H. pylori after a decade of its discovery.

Risk factors for retrovirus and hepatitis virus infections in accepted blood donors.

PubMed

Custer, Brian; Kessler, Debra; Vahidnia, Farnaz; Leparc, German; Krysztof, David E; Shaz, Beth; Kamel, Hany; Glynn, Simone; Dodd, Roger Y; Stramer, Susan L

2015-05-01

Risk factor surveillance among infected blood donors provides information on the effectiveness of eligibility assessment and is critical for reducing risk of transfusion-transmitted infection. American Red Cross, Blood Systems, Inc., New York Blood Center, and OneBlood participated in a case-control study from 2010 to 2013. Donors with serologic and nucleic acid testing (NAT) or NAT-only confirmed human immunodeficiency virus (HIV), hepatitis B virus (HBV), hepatitis C virus (HCV), or serology-confirmed human T-lymphotropic virus (HTLV) infections (cases) and donors with false-positive results (controls) were interviewed for putative behavioral and demographic risks. Frequencies and adjusted odds ratios (AORs) from multivariable logistic regression analyses for each exposure in cases compared to controls are reported. In the study, 196 HIV, 292 HBV, 316 HCV, and 198 HTLV cases, and 1587 controls were interviewed. For HIV, sex with an HIV+ person (AOR, 132; 95% confidence interval [CI], 27-650) and male-male sex (AOR, 62; 95% CI, 27-140) were primary risk factors. For HBV, first-time donor status (AOR, 16; 95% CI, 10-27), sex with an injection drug user (IDU; AOR, 11; 95% CI, 5-28), and black race (AOR, 11; 95% CI, 6-19) were primary. For HCV, IDU (AOR, 42; 95% CI, 13-136), first time (AOR, 18; 95% CI, 10-30), and a family member with hepatitis (AOR, 15; 95% CI, 6-40) were primary. For HTLV, sex with an IDU (AOR, 22; 95% CI, 10-48), 55 years old or more (AOR, 21; 95% CI, 8-52], and first time (AOR, 15; 95% CI, 9-24) were primary. Despite education efforts and risk screening, individuals with deferrable risks still donate; they may fail to understand or ignore or do not believe they have risk. Recipients have potential transfusion-transmitted infection risk because of nondisclosure by donors. © 2014 AABB.

Can Genetic Analysis of Putative Blood Alzheimer’s Disease Biomarkers Lead to Identification of Susceptibility Loci?

PubMed Central

Huebinger, Ryan M.; Shewale, Shantanu J.; Koenig, Jessica L.; Mitchel, Jeffrey S.; O’Bryant, Sid E.; Waring, Stephen C.; Diaz-Arrastia, Ramon; Chasse, Scott

2015-01-01

Although 24 Alzheimer’s disease (AD) risk loci have been reliably identified, a large portion of the predicted heritability for AD remains unexplained. It is expected that additional loci of small effect will be identified with an increased sample size. However, the cost of a significant increase in Case-Control sample size is prohibitive. The current study tests whether exploring the genetic basis of endophenotypes, in this case based on putative blood biomarkers for AD, can accelerate the identification of susceptibility loci using modest sample sizes. Each endophenotype was used as the outcome variable in an independent GWAS. Endophenotypes were based on circulating concentrations of proteins that contributed significantly to a published blood-based predictive algorithm for AD. Endophenotypes included Monocyte Chemoattractant Protein 1 (MCP1), Vascular Cell Adhesion Molecule 1 (VCAM1), Pancreatic Polypeptide (PP), Beta2 Microglobulin (B2M), Factor VII (F7), Adiponectin (ADN) and Tenascin C (TN-C). Across the seven endophenotypes, 47 SNPs were associated with outcome with a p-value ≤1x10-7. Each signal was further characterized with respect to known genetic loci associated with AD. Signals for several endophenotypes were observed in the vicinity of CR1, MS4A6A/MS4A4E, PICALM, CLU, and PTK2B. The strongest signal was observed in association with Factor VII levels and was located within the F7 gene. Additional signals were observed in MAP3K13, ZNF320, ATP9B and TREM1. Conditional regression analyses suggested that the SNPs contributed to variation in protein concentration independent of AD status. The identification of two putatively novel AD loci (in the Factor VII and ATP9B genes), which have not been located in previous studies despite massive sample sizes, highlights the benefits of an endophenotypic approach for resolving the genetic basis for complex diseases. The coincidence of several of the endophenotypic signals with known AD loci may point to novel genetic interactions and should be further investigated. PMID:26625115

Can Genetic Analysis of Putative Blood Alzheimer's Disease Biomarkers Lead to Identification of Susceptibility Loci?

PubMed

Barber, Robert C; Phillips, Nicole R; Tilson, Jeffrey L; Huebinger, Ryan M; Shewale, Shantanu J; Koenig, Jessica L; Mitchel, Jeffrey S; O'Bryant, Sid E; Waring, Stephen C; Diaz-Arrastia, Ramon; Chasse, Scott; Wilhelmsen, Kirk C

2015-01-01

Although 24 Alzheimer's disease (AD) risk loci have been reliably identified, a large portion of the predicted heritability for AD remains unexplained. It is expected that additional loci of small effect will be identified with an increased sample size. However, the cost of a significant increase in Case-Control sample size is prohibitive. The current study tests whether exploring the genetic basis of endophenotypes, in this case based on putative blood biomarkers for AD, can accelerate the identification of susceptibility loci using modest sample sizes. Each endophenotype was used as the outcome variable in an independent GWAS. Endophenotypes were based on circulating concentrations of proteins that contributed significantly to a published blood-based predictive algorithm for AD. Endophenotypes included Monocyte Chemoattractant Protein 1 (MCP1), Vascular Cell Adhesion Molecule 1 (VCAM1), Pancreatic Polypeptide (PP), Beta2 Microglobulin (B2M), Factor VII (F7), Adiponectin (ADN) and Tenascin C (TN-C). Across the seven endophenotypes, 47 SNPs were associated with outcome with a p-value ≤1x10(-7). Each signal was further characterized with respect to known genetic loci associated with AD. Signals for several endophenotypes were observed in the vicinity of CR1, MS4A6A/MS4A4E, PICALM, CLU, and PTK2B. The strongest signal was observed in association with Factor VII levels and was located within the F7 gene. Additional signals were observed in MAP3K13, ZNF320, ATP9B and TREM1. Conditional regression analyses suggested that the SNPs contributed to variation in protein concentration independent of AD status. The identification of two putatively novel AD loci (in the Factor VII and ATP9B genes), which have not been located in previous studies despite massive sample sizes, highlights the benefits of an endophenotypic approach for resolving the genetic basis for complex diseases. The coincidence of several of the endophenotypic signals with known AD loci may point to novel genetic interactions and should be further investigated.

Attribution of human infections with Shiga toxin-producing Escherichia coli (STEC) to livestock sources and identification of source-specific risk factors, The Netherlands (2010-2014).

PubMed

Mughini-Gras, L; van Pelt, W; van der Voort, M; Heck, M; Friesema, I; Franz, E

2018-02-01

Shiga toxin-producing Escherichia coli (STEC) is a zoonotic pathogen of public health concern whose sources and transmission routes are difficult to trace. Using a combined source attribution and case-control analysis, we determined the relative contributions of four putative livestock sources (cattle, small ruminants, pigs, poultry) to human STEC infections and their associated dietary, animal contact, temporal and socio-econo-demographic risk factors in the Netherlands in 2010/2011-2014. Dutch source data were supplemented with those from other European countries with similar STEC epidemiology. Human STEC infections were attributed to sources using both the modified Dutch model (mDM) and the modified Hald model (mHM) supplied with the same O-serotyping data. Cattle accounted for 48.6% (mDM) and 53.1% (mHM) of the 1,183 human cases attributed, followed by small ruminants (mDM: 23.5%; mHM: 25.4%), pigs (mDM: 12.5%; mHM: 5.7%) and poultry (mDM: 2.7%; mHM: 3.1%), whereas the sources of the remaining 12.8% of cases could not be attributed. Of the top five O-serotypes infecting humans, O157, O26, O91 and O103 were mainly attributed to cattle (61%-75%) and O146 to small ruminants (71%-77%). Significant risk factors for human STEC infection as a whole were the consumption of beef, raw/undercooked meat or cured meat/cold cuts. For cattle-attributed STEC infections, specific risk factors were consuming raw meat spreads and beef. Consuming raw/undercooked or minced meat were risk factors for STEC infections attributed to small ruminants. For STEC infections attributed to pigs, only consuming raw/undercooked meat was significant. Consuming minced meat, raw/undercooked meat or cured meat/cold cuts were associated with poultry-attributed STEC infections. Consuming raw vegetables was protective for all STEC infections. We concluded that domestic ruminants account for approximately three-quarters of reported human STEC infections, whereas pigs and poultry play a minor role and that risk factors for human STEC infection vary according to the attributed source. © 2017 Blackwell Verlag GmbH.

Risk factors for hospital-associated venous thromboembolism in critically ill children following cardiothoracic surgery or therapeutic cardiac catheterisation.

PubMed

Atchison, Christie M; Amankwah, Ernest; Wilhelm, Jean; Arlikar, Shilpa; Branchford, Brian R; Stock, Arabela; Streiff, Michael; Takemoto, Clifford; Ayala, Irmel; Everett, Allen; Stapleton, Gary; Jacobs, Marshall L; Jacobs, Jeffrey P; Goldenberg, Neil A

2018-02-01

Paediatric hospital-associated venous thromboembolism is a leading quality and safety concern at children's hospitals. The aim of this study was to determine risk factors for hospital-associated venous thromboembolism in critically ill children following cardiothoracic surgery or therapeutic cardiac catheterisation. We conducted a retrospective, case-control study of children admitted to the cardiovascular intensive care unit at Johns Hopkins All Children's Hospital (St. Petersburg, Florida, United States of America) from 2006 to 2013. Hospital-associated venous thromboembolism cases were identified based on ICD-9 discharge codes and validated using radiological record review. We randomly selected two contemporaneous cardiovascular intensive care unit controls without hospital-associated venous thromboembolism for each hospital-associated venous thromboembolism case, and limited the study population to patients who had undergone cardiothoracic surgery or therapeutic cardiac catheterisation. Odds ratios and 95% confidence intervals for associations between putative risk factors and hospital-associated venous thromboembolism were determined using univariate and multivariate logistic regression. Among 2718 admissions to the cardiovascular intensive care unit during the study period, 65 met the criteria for hospital-associated venous thromboembolism (occurrence rate, 2%). Restriction to cases and controls having undergone the procedures of interest yielded a final study population of 57 hospital-associated venous thromboembolism cases and 76 controls. In a multiple logistic regression model, major infection (odds ratio=5.77, 95% confidence interval=1.06-31.4), age ⩽1 year (odds ratio=6.75, 95% confidence interval=1.13-160), and central venous catheterisation (odds ratio=7.36, 95% confidence interval=1.13-47.8) were found to be statistically significant independent risk factors for hospital-associated venous thromboembolism in these children. Patients with all three factors had a markedly increased post-test probability of having hospital-associated venous thromboembolism. Major infection, infancy, and central venous catheterisation are independent risk factors for hospital-associated venous thromboembolism in critically ill children following cardiothoracic surgery or cardiac catheter-based intervention, which, in combination, define a high-risk group for hospital-associated venous thromboembolism.

Chromosome 17 alterations identify good-risk and poor-risk tumors independently of clinical factors in medulloblastoma

PubMed Central

McCabe, Martin G.; Bäcklund, L. Magnus; Leong, Hui Sun; Ichimura, Koichi; Collins, V. Peter

2011-01-01

Current risk stratification schemas for medulloblastoma, based on combinations of clinical variables and histotype, fail to accurately identify particularly good- and poor-risk tumors. Attempts have been made to improve discriminatory power by combining clinical variables with cytogenetic data. We report here a pooled analysis of all previous reports of chromosomal copy number related to survival data in medulloblastoma. We collated data from previous reports that explicitly quoted survival data and chromosomal copy number in medulloblastoma. We analyzed the relative prognostic significance of currently used clinical risk stratifiers and the chromosomal aberrations previously reported to correlate with survival. In the pooled dataset metastatic disease, incomplete tumor resection and severe anaplasia were associated with poor outcome, while young age at presentation was not prognostically significant. Of the chromosomal variables studied, isolated 17p loss and gain of 1q correlated with poor survival. Gain of 17q without associated loss of 17p showed a trend to improved outcome. The most commonly reported alteration, isodicentric chromosome 17, was not prognostically significant. Sequential multivariate models identified isolated 17p loss, isolated 17q gain, and 1q gain as independent prognostic factors. In a historical dataset, we have identified isolated 17p loss as a marker of poor outcome and 17q gain as a novel putative marker of good prognosis. Biological markers of poor-risk and good-risk tumors will be critical in stratifying treatment in future trials. Our findings should be prospectively validated independently in future clinical studies. PMID:21292688

Expression of putative pathogenicity-related genes in Xylella fastidiosa grown at low and high cell density conditions in vitro.

PubMed

Scarpari, Leandra M; Lambais, Marcio R; Silva, Denise S; Carraro, Dirce M; Carrer, Helaine

2003-05-16

Xylella fastidiosa is the causal agent of economically important plant diseases, including citrus variegated chlorosis and Pierce's disease. Hitherto, there has been no information on the molecular mechanisms controlling X. fastidiosa-plant interactions. To determine whether predicted open reading frames (ORFs) encoding putative pathogenicity-related factors were expressed by X. fastidiosa 9a5c cells grown at low (LCD) and high cell density (HCD) conditions in liquid modified PW medium, reverse Northern blot hybridization and reverse transcription-polymerase chain reaction (RT-PCR) experiments were performed. Our results indicated that ORFs XF2344, XF2369, XF1851 and XF0125, encoding putative Fur, GumC, a serine-protease and RsmA, respectively, were significantly suppressed at HCD conditions. In contrast, ORF XF1115, encoding putative RpfF, was significantly induced at HCD conditions. Expressions of ORFs XF2367, XF2362 and XF0290, encoding putative GumD, GumJ and RpfA, respectively, were detected only at HCD conditions, whereas expression of ORF XF0287, encoding putative RpfB was detected only at LCD conditions. Bioassays with an Agrobacterium traG::lacZ reporter system indicated that X. fastidiosa does not synthesize N-acyl-homoserine lactones, whereas bioassays with a diffusible signal factor (DSF)-responsive Xanthomonas campestris pv. campestris mutant indicate that X. fastidiosa synthesizes a molecule similar to DSF in modified PW medium. Our data also suggest that the synthesis of the DSF-like molecule and fastidian gum by X. fastidiosa is affected by cell density in vitro.

What causes psychosis? An umbrella review of risk and protective factors

PubMed Central

Radua, Joaquim; Ramella‐Cravaro, Valentina; Ioannidis, John P.A.; Reichenberg, Abraham; Phiphopthatsanee, Nacharin; Amir, Taha; Yenn Thoo, Hyi; Oliver, Dominic; Davies, Cathy; Morgan, Craig; McGuire, Philip; Murray, Robin M.; Fusar‐Poli, Paolo

2018-01-01

Psychosis is a heterogeneous psychiatric condition for which a multitude of risk and protective factors have been suggested. This umbrella review aimed to classify the strength of evidence for the associations between each factor and psychotic disorders whilst controlling for several biases. The Web of Knowledge database was searched to identify systematic reviews and meta‐analyses of observational studies which examined associations between socio‐demographic, parental, perinatal, later factors or antecedents and psychotic disorders, and which included a comparison group of healthy controls, published from 1965 to January 31, 2017. The literature search and data extraction followed PRISMA and MOOSE guidelines. The association between each factor and ICD or DSM diagnoses of non‐organic psychotic disorders was graded into convincing, highly suggestive, suggestive, weak, or non‐significant according to a standardized classification based on: number of psychotic cases, random‐effects p value, largest study 95% confidence interval, heterogeneity between studies, 95% prediction interval, small study effect, and excess significance bias. In order to assess evidence for temporality of association, we also conducted sensitivity analyses restricted to data from prospective studies. Fifty‐five meta‐analyses or systematic reviews were included in the umbrella review, corresponding to 683 individual studies and 170 putative risk or protective factors for psychotic disorders. Only the ultra‐high‐risk state for psychosis (odds ratio, OR=9.32, 95% CI: 4.91‐17.72) and Black‐Caribbean ethnicity in England (OR=4.87, 95% CI: 3.96‐6.00) showed convincing evidence of association. Six factors were highly suggestive (ethnic minority in low ethnic density area, second generation immigrants, trait anhedonia, premorbid IQ, minor physical anomalies, and olfactory identification ability), and nine were suggestive (urbanicity, ethnic minority in high ethnic density area, first generation immigrants, North‐African immigrants in Europe, winter/spring season of birth in Northern hemisphere, childhood social withdrawal, childhood trauma, Toxoplasma gondii IgG, and non‐right handedness). When only prospective studies were considered, the evidence was convincing for ultra‐high‐risk state and suggestive for urbanicity only. In summary, this umbrella review found several factors to be associated with psychotic disorders with different levels of evidence. These risk or protective factors represent a starting point for further etiopathological research and for the improvement of the prediction of psychosis. PMID:29352556

Paternal age effect: Replication in schizophrenia with intriguing dissociation between bipolar with and without psychosis.

PubMed

Lehrer, Douglas S; Pato, Michele T; Nahhas, Ramzi W; Miller, Brian R; Malaspina, Dolores; Buckley, Peter F; Sobell, Janet L; Walsh-Messinger, Julie; Genomic Psychiatry Cohort Consortium; Pato, Carlos N

2016-06-01

Advanced paternal age (APA) is a risk factor for schizophrenia (Sz) and bipolar disorder (BP). Putative mechanisms include heritable genetic factors, de novo mutations, and epigenetic mechanisms. Few studies have explored phenotypic features associated with APA. The Genomic Psychiatry Cohort established a clinically characterized repository of genomic samples from subjects with a Sz-BP diagnosis or unaffected controls, 12,975 with parental age information. We estimated relative risk ratios for Sz, schizoaffective depressed and bipolar types (SA-D, SA-B), and BP with and without history of psychotic features (PF) relative to the control group, comparing each paternal age group to the reference group 20-24 years. All tests were two-sided with adjustment for multiple comparisons. Subjects with fathers age 45+ had significantly higher risk for all diagnoses except for BP w/o PF. APA also bore no significant relation to family psychiatric history. In conclusion, we replicated APA as a risk factor for Sz. To our knowledge, this is the first published report of APA in a BP sample stratified by psychosis history, extending this association only in BP w/PF. This suggests that phenotypic expression of the APA effect in Sz-BP spectrum is psychosis, per se, rather than other aspects of these complex disorders. The lack of a significant relationship between paternal age and familial disease patterns suggests that underlying mechanisms of the paternal age effect may involve a complex interaction of heritable and non-heritable factors. The authors discuss implications and testable hypotheses, starting with a focus on genetic mechanisms and endophenotypic expressions of dopaminergic function. © 2015 Wiley Periodicals, Inc. © 2015 Wiley Periodicals, Inc.

Biomarkers of Aging: From Function to Molecular Biology

PubMed Central

Wagner, Karl-Heinz; Cameron-Smith, David; Wessner, Barbara; Franzke, Bernhard

2016-01-01

Aging is a major risk factor for most chronic diseases and functional impairments. Within a homogeneous age sample there is a considerable variation in the extent of disease and functional impairment risk, revealing a need for valid biomarkers to aid in characterizing the complex aging processes. The identification of biomarkers is further complicated by the diversity of biological living situations, lifestyle activities and medical treatments. Thus, there has been no identification of a single biomarker or gold standard tool that can monitor successful or healthy aging. Within this short review the current knowledge of putative biomarkers is presented, focusing on their application to the major physiological mechanisms affected by the aging process including physical capability, nutritional status, body composition, endocrine and immune function. This review emphasizes molecular and DNA-based biomarkers, as well as recent advances in other biomarkers such as microRNAs, bilirubin or advanced glycation end products. PMID:27271660

The Association between KIF6 Single Nucleotide Polymorphism rs20455 and Serum Lipids in Filipino-American Women

PubMed Central

Ancheta, Irma B.; Battie, Cynthia A.; Ancheta, Christine V.; Volgman, Annabelle S.; Conley, Yvette

2014-01-01

The Trp719Arg allele of KIF6 rs20455, a putative risk factor for CHD especially in those with elevated low-density lipoprotein cholesterol (LDL-C), was investigated in Filipino-American women (FAW, n = 235) participating in health screenings in four cities. The rs20455 genotype of each subject was determined by a multiplex assay using a Luminex-OLA procedure. The risk allele Trp719Arg was present in 77% of the subjects. The genotype distribution was 23% Trp/Trp, 51% Arg/Trp, and 26% Arg/Arg. Genotype did not predict the presence of CHD risk factors. Moreover, LDL-C, HDL-C, and triglycerides mean values did not vary as a function of genotype. However, those with the Arg/Arg genotype on statin medication exhibited a significantly higher mean triglycerides level (P < 0.01). Approximately 60% of participants regardless of genotype exhibited LDL-C levels ≥100 mg/dL but were not taking medication. Approximately 43% of those with the Trp719Arg risk allele on statins exhibited elevated LDL-C levels. Our study suggests that the Trp719Arg allele of KIF 6 rs20455 is common among Filipino-American women; thus, even with borderline LDL-C levels would benefit from statin treatment. Secondly, many participants did not exhibit guideline recommended LDL-C levels including many who were on statin drugs. PMID:24587901

VISLISI trial, a prospective clinical study allowing identification of a new metalloprotease and putative virulence factor from Staphylococcus lugdunensis.

PubMed

Argemi, X; Prévost, G; Riegel, P; Keller, D; Meyer, N; Baldeyrou, M; Douiri, N; Lefebvre, N; Meghit, K; Ronde Oustau, C; Christmann, D; Cianférani, S; Strub, J M; Hansmann, Y

2017-05-01

Staphylococcus lugdunensis is a coagulase-negative staphylococcus that displays an unusually high virulence rate close to that of Staphylococcus aureus. It also shares phenotypic properties with S. aureus and several studies found putative virulence factors. The objective of the study was to describe the clinical manifestations of S. lugdunensis infections and investigate putative virulence factors. We conducted a prospective study from November 2013 to March 2016 at the University Hospital of Strasbourg. Putative virulence factors were investigated by clumping factor detection, screening for proteolytic activity, and sequence analysis using tandem nano-liquid chromatography-mass spectrometry. In total, 347 positive samples for S. lugdunensis were collected, of which 129 (37.2%) were from confirmed cases of S. lugdunensis infection. Eighty-one of these 129 patients were included in the study. Bone and prosthetic joints (PJI) were the most frequent sites of infection (n=28; 34.6%) followed by skin and soft tissues (n=23; 28.4%). We identified and purified a novel protease secreted by 50 samples (61.7%), most frequently associated with samples from deep infections and PJI (pr 0.97 and pr 0.91, respectively). Protease peptide sequencing by nano-liquid chromatography-mass spectrometry revealed a novel protease bearing 62.42% identity with ShpI, a metalloprotease secreted by Staphylococcus hyicus. This study confirms the pathogenicity of S. lugdunensis, particularly in bone and PJI. We also identified a novel metalloprotease called lugdulysin that may contribute to virulence. Copyright © 2016 European Society of Clinical Microbiology and Infectious Diseases. Published by Elsevier Ltd. All rights reserved.

Network analysis of S. aureus response to ramoplanin reveals modules for virulence factors and resistance mechanisms and characteristic novel genes.

PubMed

Subramanian, Devika; Natarajan, Jeyakumar

2015-12-10

Staphylococcus aureus is a major human pathogen and ramoplanin is an antimicrobial attributed for effective treatment. The goal of this study was to examine the transcriptomic profiles of ramoplanin sensitive and resistant S. aureus to identify putative modules responsible for virulence and resistance-mechanisms and its characteristic novel genes. The dysregulated genes were used to reconstruct protein functional association networks for virulence-factors and resistance-mechanisms individually. Strong link between metabolic-pathways and development of virulence/resistance is suggested. We identified 15 putative modules of virulence factors. Six hypothetical genes were annotated with novel virulence activity among which SACOL0281 was discovered to be an essential virulence factor EsaD. The roles of MazEF toxin-antitoxin system, SACOL0202/SACOL0201 two-component system and that of amino-sugar and nucleotide-sugar metabolism in virulence are also suggested. In addition, 14 putative modules of resistance mechanisms including modules of ribosomal protein-coding genes and metabolic pathways such as biotin-synthesis, TCA-cycle, riboflavin-biosynthesis, peptidoglycan-biosynthesis etc. are also indicated. Copyright © 2015 Elsevier B.V. All rights reserved.

Genes involved in stress response and alcohol use among high-risk African American youth.

PubMed

Goyal, Neeru; Aliev, Fazil; Latendresse, Shawn J; Kertes, Darlene A; Bolland, John M; Byck, Gayle R; Mustanski, Brian; Salvatore, Jessica E; Dick, Danielle M

2016-01-01

Genetic and environmental factors influence substance use behaviors in youth. One of the known environmental risk factors is exposure to life stressors. The aim of this project is to study the interaction between NR3C1 and CRHBP, genes thought to be involved in stress pathways, exposure to stressful life events, and adolescent alcohol use/misuse. The sample included 541 African American individuals (ages 13-18) from the Genes, Environment, and Neighborhood Initiative, a subset of the Mobile Youth Survey sample from whom DNA and more extensive phenotypic data were collected. Participants were selected from high-poverty neighborhoods in Mobile, Alabama, with potential exposure to a variety of extreme life stressors. A measure of stressful life events was significantly predictive of alcohol use/misuse. In addition, this association was significantly dependent upon the number of putative risk variants at rs1715749, a single-nucleotide polymorphism (SNP) in CRHBP (P ≤ .006). There was no significant interaction between NR3C1 and stressful life events with respect to alcohol use/misuse, after taking into account multiple testing. These findings suggest that CRHBP variants are potentially relevant for adolescent alcohol use/misuse among African American youth populations being reared within the context of stressful life events and warrant replication.

Airborne geographical dispersal of Q fever from livestock holdings to human communities: a systematic review and critical appraisal of evidence.

PubMed

Clark, Nicholas J; Soares Magalhães, Ricardo J

2018-05-15

Q fever is a zoonotic disease caused by Coxiella burnetii. This bacterium survives harsh conditions and attaches to dust, suggesting environmental dispersal is a risk factor for outbreaks. Spatial epidemiology studies collating evidence on Q fever geographical contamination gradients are needed, as human cases without occupational exposure are increasing worldwide. We used a systematic literature search to assess the role of distance from ruminant holdings as a risk factor for human Q fever outbreaks. We also collated evidence for other putative drivers of C. burnetii geographical dispersal. In all documented outbreaks, infective sheep or goats, not cattle, was the likely source. Evidence suggests a prominent role of airborne dispersal; Coxiella burnetii travels up to 18 km on gale force winds. In rural areas, highest infection risk occurs within 5 km of sources. Urban outbreaks generally occur over smaller distances, though evidence on attack rate gradients is limited. Wind speed / direction, spreading of animal products, and stocking density may all contribute to C. burnetii environmental gradients. Q fever environmental gradients depend on urbanization level, ruminant species, stocking density and wind speed. While more research is needed, evidence suggests that residential exclusion zones around holdings may be inadequate to contain this zoonotic disease, and should be species-specific.

Behavioral and Psychological Phenotyping of Physical Activity and Sedentary Behavior: Implications for Weight Management.

PubMed

Bryan, Angela D; Jakicic, John M; Hunter, Christine M; Evans, Mary E; Yanovski, Susan Z; Epstein, Leonard H

2017-10-01

Risk for obesity is determined by a complex mix of genetics and lifetime exposures at multiple levels, from the metabolic milieu to psychosocial and environmental influences. These phenotypic differences underlie the variability in risk for obesity and response to weight management interventions, including differences in physical activity and sedentary behavior. As part of a broader effort focused on behavioral and psychological phenotyping in obesity research, the National Institutes of Health convened a multidisciplinary workshop to explore the state of the science in behavioral and psychological phenotyping in humans to explain individual differences in physical activity, both as a risk factor for obesity development and in response to activity-enhancing interventions. Understanding the behavioral and psychological phenotypes that contribute to differences in physical activity and sedentary behavior could allow for improved treatment matching and inform new targets for tailored, innovative, and effective weight management interventions. This summary provides the rationale for identifying psychological and behavioral phenotypes relevant to physical activity and identifies opportunities for future research to better understand, define, measure, and validate putative phenotypic factors and characterize emerging phenotypes that are empirically associated with initiation of physical activity, response to intervention, and sustained changes in physical activity. © 2017 The Obesity Society.

SOX2 as a New Regulator of HPV16 Transcription.

PubMed

Martínez-Ramírez, Imelda; Del-Castillo-Falconi, Víctor; Mitre-Aguilar, Irma B; Amador-Molina, Alfredo; Carrillo-García, Adela; Langley, Elizabeth; Zentella-Dehesa, Alejandro; Soto-Reyes, Ernesto; García-Carrancá, Alejandro; Herrera, Luis A; Lizano, Marcela

2017-07-05

Persistent infections with high-risk human papillomavirus (HPV) constitute the main risk factor for cervical cancer development. HPV16 is the most frequent type associated to squamous cell carcinomas (SCC), followed by HPV18. The long control region (LCR) in the HPV genome contains the replication origin and sequences recognized by cellular transcription factors (TFs) controlling viral transcription. Altered expression of E6 and E7 viral oncogenes, modulated by the LCR, causes modifications in cellular pathways such as proliferation, leading to malignant transformation. The aim of this study was to identify specific TFs that could contribute to the modulation of high-risk HPV transcriptional activity, related to the cellular histological origin. We identified sex determining region Y (SRY)-box 2 (SOX2) response elements present in HPV16-LCR. SOX2 binding to the LCR was demonstrated by in vivo and in vitro assays. The overexpression of this TF repressed HPV16-LCR transcriptional activity, as shown through reporter plasmid assays and by the down-regulation of endogenous HPV oncogenes. Site-directed mutagenesis revealed that three putative SOX2 binding sites are involved in the repression of the LCR activity. We propose that SOX2 acts as a transcriptional repressor of HPV16-LCR, decreasing the expression of E6 and E7 oncogenes in a SCC context.

Predictive factors of gestational diabetes in pregnancies following assisted reproductive technology: a nested case-control study.

PubMed

Kouhkan, Azam; Khamseh, Mohammad E; Moini, Ashraf; Pirjani, Reihaneh; Valojerdi, Ameneh Ebrahim; Arabipoor, Arezoo; Hosseini, Roya; Baradaran, Hamid Reza

2018-05-05

To evaluate predictive factors for gestational diabetes mellitus (GDM) in singleton pregnancy following assisted reproductive technology (ART). This nested case-control study was performed during October 2016-June 2017. Pregnant women who conceived following ART procedures referred to infertility clinic were selected and categorized into GDM and non-GDM based on ADA/IAPDSG criteria. The study variables including age, educational status, first-degree family history of chronic diseases, systolic and diastolic blood pressure, previous obstetric and perinatal outcomes, infertility history, and ART cycle characteristics were collected from medical records. Prediction model to develop GDM was employed by binary logistic regression analysis after adjustment for age and body mass index, family history of diabetes, and gravidity. In total, 270 women with singleton pregnancies (consisted of 135 GDM and 135 non-GDM women) conceived were studied. According to the final model, significant predictors of GDM were history of polycystic ovarian syndrome (PCOS), previous ovarian hyper-stimulation syndrome (OHSS) risk and progesterone injections. Administration of injectable progesterone during the first 10-12 weeks of pregnancy was associated with an approximately twofold increased risk of developing GDM [odds ratio (OR) 2.28, 95% confidence interval (CI) 1.27-4.09)] compared to vaginal progesterone. In addition, the regression analysis revealed that previous OHSS risk (OR 2.40, 95% CI 1.34-4.31) and history of PCOS (OR 2.76, 95% CI 1.26-6.06) were other most important predictors of GDM. The route of progesterone administration, previous OHSS risk and history of PCOS seem to be putative risk factors for GDM in women conceived by ART.

Ten Putative Contributors to the Obesity Epidemic

PubMed Central

McAllister, Emily J.; Dhurandhar, Nikhil V.; Keith, Scott W.; Aronne, Louis J.; Barger, Jamie; Baskin, Monica; Benca, Ruth M.; Biggio, Joseph; Boggiano, Mary M.; Eisenmann, Joe C.; Elobeid, Mai; Fontaine, Kevin R.; Gluckman, Peter; Hanlon, Erin C.; Katzmarzyk, Peter; Pietrobelli, Angelo; Redden, David T.; Ruden, Douglas M.; Wang, Chenxi; Waterland, Robert A.; Wright, Suzanne M.; Allison, David B.

2010-01-01

The obesity epidemic is a global issue and shows no signs of abating, while the cause of this epidemic remains unclear. Marketing practices of energy-dense foods and institutionally-driven declines in physical activity are the alleged perpetrators for the epidemic, despite a lack of solid evidence to demonstrate their causal role. While both may contribute to obesity, we call attention to their unquestioned dominance in program funding and public efforts to reduce obesity, and propose several alternative putative contributors that would benefit from equal consideration and attention. Evidence for microorganisms, epigenetics, increasing maternal age, greater fecundity among people with higher adiposity, assortative mating, sleep debt, endocrine disruptors, pharmaceutical iatrogenesis, reduction in variability of ambient temperatures, and intrauterine and intergenerational effects, as contributing factors to the obesity epidemic are reviewed herein. While the evidence is strong for some contributors such as pharmaceutical-induced weight gain, it is still emerging for other reviewed factors. Considering the role of such putative etiological factors of obesity may lead to comprehensive, cause specific, and effective strategies for prevention and treatment of this global epidemic. PMID:19960394

Genetically determined height and coronary artery disease.

PubMed

Nelson, Christopher P; Hamby, Stephen E; Saleheen, Danish; Hopewell, Jenna C; Zeng, Lingyao; Assimes, Themistocles L; Kanoni, Stavroula; Willenborg, Christina; Burgess, Stephen; Amouyel, Phillipe; Anand, Sonia; Blankenberg, Stefan; Boehm, Bernhard O; Clarke, Robert J; Collins, Rory; Dedoussis, George; Farrall, Martin; Franks, Paul W; Groop, Leif; Hall, Alistair S; Hamsten, Anders; Hengstenberg, Christian; Hovingh, G Kees; Ingelsson, Erik; Kathiresan, Sekar; Kee, Frank; König, Inke R; Kooner, Jaspal; Lehtimäki, Terho; März, Winifred; McPherson, Ruth; Metspalu, Andres; Nieminen, Markku S; O'Donnell, Christopher J; Palmer, Colin N A; Peters, Annette; Perola, Markus; Reilly, Muredach P; Ripatti, Samuli; Roberts, Robert; Salomaa, Veikko; Shah, Svati H; Schreiber, Stefan; Siegbahn, Agneta; Thorsteinsdottir, Unnur; Veronesi, Giovani; Wareham, Nicholas; Willer, Cristen J; Zalloua, Pierre A; Erdmann, Jeanette; Deloukas, Panos; Watkins, Hugh; Schunkert, Heribert; Danesh, John; Thompson, John R; Samani, Nilesh J

2015-04-23

The nature and underlying mechanisms of an inverse association between adult height and the risk of coronary artery disease (CAD) are unclear. We used a genetic approach to investigate the association between height and CAD, using 180 height-associated genetic variants. We tested the association between a change in genetically determined height of 1 SD (6.5 cm) with the risk of CAD in 65,066 cases and 128,383 controls. Using individual-level genotype data from 18,249 persons, we also examined the risk of CAD associated with the presence of various numbers of height-associated alleles. To identify putative mechanisms, we analyzed whether genetically determined height was associated with known cardiovascular risk factors and performed a pathway analysis of the height-associated genes. We observed a relative increase of 13.5% (95% confidence interval [CI], 5.4 to 22.1; P<0.001) in the risk of CAD per 1-SD decrease in genetically determined height. There was a graded relationship between the presence of an increased number of height-raising variants and a reduced risk of CAD (odds ratio for height quartile 4 versus quartile 1, 0.74; 95% CI, 0.68 to 0.84; P<0.001). Of the 12 risk factors that we studied, we observed significant associations only with levels of low-density lipoprotein cholesterol and triglycerides (accounting for approximately 30% of the association). We identified several overlapping pathways involving genes associated with both development and atherosclerosis. There is a primary association between a genetically determined shorter height and an increased risk of CAD, a link that is partly explained by the association between shorter height and an adverse lipid profile. Shared biologic processes that determine achieved height and the development of atherosclerosis may explain some of the association. (Funded by the British Heart Foundation and others.).

Associations between prior management of cattle and risk of bovine respiratory disease in feedlot cattle.

PubMed

Hay, K E; Morton, J M; Schibrowski, M L; Clements, A C A; Mahony, T J; Barnes, T S

2016-05-01

Bovine respiratory disease (BRD) is the major cause of clinical disease and death in feedlot populations worldwide. A longitudinal study was conducted to assess associations between risk factors related to on-farm management prior to transport to the feedlot and risk of BRD in a population of feedlot beef cattle sourced from throughout the cattle producing regions of Australia. Exposure variables were derived from questionnaire data provided by farmers supplying cattle (N=10,721) that were a subset of the population included in a nationwide prospective study investigating numerous putative risk factors for BRD. Causal diagrams were used to inform model building to allow estimation of effects of interest. Multilevel mixed effects logistic regression models were fitted within the Bayesian framework. Animals that were yard weaned were at reduced risk (OR: 0.7, 95% credible interval: 0.5-1.0) of BRD at the feedlot compared to animals immediately returned to pasture after weaning. Animals that had previously been fed grain (OR: 0.6, 95% credible interval: 0.3-1.1) were probably at reduced risk of BRD at the feedlot compared to animals not previously fed grain. Animals that received prior vaccinations against Bovine viral diarrhoea virus 1 (OR: 0.8, 95% credible interval: 0.5-1.1) or Mannheimia haemolytica (OR: 0.8, 95% credible interval: 0.6-1.0) were also probably at reduced risk compared to non-vaccinated animals. The results of this study confirm that on-farm management before feedlot entry can alter risk of BRD after beef cattle enter feedlots. Copyright © 2016 Elsevier B.V. All rights reserved.

Does the Concept of “Sensitization” Provide a Plausible Mechanism for the Putative Link Between the Environment and Schizophrenia?

PubMed Central

Collip, Dina; Myin-Germeys, Inez; Van Os, Jim

2008-01-01

Previous evidence reviewed in Schizophrenia Bulletin suggests the importance of a range of different environmental factors in the development of psychotic illness. It is unlikely, however, that the diversity of environmental influences associated with schizophrenia can be linked to as many different underlying mechanisms. There is evidence that environmental exposures may induce, in interaction with (epi)genetic factors, psychological or physiological alterations that can be traced to a final common pathway of cognitive biases and/or altered dopamine neurotransmission, broadly referred to as “sensitization,” facilitating the onset and persistence of psychotic symptoms. At the population level, the behavioral phenotype for sensitization may be examined by quantifying, in populations exposed to environmental risk factors associated with stress or dopamine-agonist drugs, (1) the increased rate of persistence (indicating lasting sensitization) of normally transient developmental expressions of subclinical psychotic experiences and (2) the subsequent increased rate of transition to clinical psychotic disorder. PMID:18203757

Chronic intermittent hypoxia activates nuclear factor-{kappa}B in cardiovascular tissues in vivo

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

Greenberg, Harly; Ye Xiaobing; Wilson, David

2006-05-05

Obstructive sleep apnea (OSA) is an important risk factor for cardiovascular morbidity and mortality. The mechanisms through which OSA promotes the development of cardiovascular disease are poorly understood. In this study, we tested the hypotheses that chronic exposure to intermittent hypoxia and reoxygenation (CIH) is a major pathologic factor causing cardiovascular inflammation, and that CIH-induces cardiovascular inflammation and pathology by activating the NF-{kappa}B pathway. We demonstrated that exposure of mice to CIH activated NF-{kappa}B in cardiovascular tissues, and that OSA patients had markedly elevated monocyte NF-{kappa}B activity, which was significantly decreased when obstructive apneas and their resultant CIH were eliminatedmore » by nocturnal CPAP therapy. The elevated NF-{kappa}B activity induced by CIH is accompanied by and temporally correlated to the increased expression of iNOS protein, a putative and important NF-{kappa}B-dependent gene product. Thus, CIH-mediated NF-{kappa}B activation may be a molecular mechanism linking OSA and cardiovascular pathologies seen in OSA patients.« less

Characteristics of functional enrichment and gene expression level of human putative transcriptional target genes.

PubMed

Osato, Naoki

2018-01-19

Transcriptional target genes show functional enrichment of genes. However, how many and how significantly transcriptional target genes include functional enrichments are still unclear. To address these issues, I predicted human transcriptional target genes using open chromatin regions, ChIP-seq data and DNA binding sequences of transcription factors in databases, and examined functional enrichment and gene expression level of putative transcriptional target genes. Gene Ontology annotations showed four times larger numbers of functional enrichments in putative transcriptional target genes than gene expression information alone, independent of transcriptional target genes. To compare the number of functional enrichments of putative transcriptional target genes between cells or search conditions, I normalized the number of functional enrichment by calculating its ratios in the total number of transcriptional target genes. With this analysis, native putative transcriptional target genes showed the largest normalized number of functional enrichments, compared with target genes including 5-60% of randomly selected genes. The normalized number of functional enrichments was changed according to the criteria of enhancer-promoter interactions such as distance from transcriptional start sites and orientation of CTCF-binding sites. Forward-reverse orientation of CTCF-binding sites showed significantly higher normalized number of functional enrichments than the other orientations. Journal papers showed that the top five frequent functional enrichments were related to the cellular functions in the three cell types. The median expression level of transcriptional target genes changed according to the criteria of enhancer-promoter assignments (i.e. interactions) and was correlated with the changes of the normalized number of functional enrichments of transcriptional target genes. Human putative transcriptional target genes showed significant functional enrichments. Functional enrichments were related to the cellular functions. The normalized number of functional enrichments of human putative transcriptional target genes changed according to the criteria of enhancer-promoter assignments and correlated with the median expression level of the target genes. These analyses and characters of human putative transcriptional target genes would be useful to examine the criteria of enhancer-promoter assignments and to predict the novel mechanisms and factors such as DNA binding proteins and DNA sequences of enhancer-promoter interactions.

Initial evidence that polymorphisms in neurotransmitter-regulating genes contribute to being born small for gestational age

PubMed Central

Morgan, Angharad R.; Thompson, John M.D.; Waldie, Karen E.; Cornforth, Christine M.; Turic, Darko; Sonuga-Barke, Edmund J.S.; Lam, Wen-Jiun; Ferguson, Lynnette R.; Mitchell, Edwin A.

2012-01-01

Being born small for gestational age (SGA) is a putative risk factor for the development of later cognitive and psychiatric health problems. While the inter-uterine environment has been shown to play an important role in predicting birth weight, little is known about the genetic factors that might be important. Here we test the hypothesis that neurotransmitter-regulating genes implicated in psychiatric disorders previously shown to be associated with SGA (such as attention-deficit hyperactivity disorder) are themselves predictive of SGA. DNA was collected from 227 SGA and 319 appropriate for gestational age children taking part in the Auckland Birthweight Collaborative Study. Candidate single nucleotide polymorphisms in genes regulating activity within dopamine, serotonin, glutamate and gamma-aminobutyric acid pathways were genotyped. Multiple regression analysis, controlling for potentially confounding factors, supported nominally significant associations between SGA and single nucleotide polymorphisms in COMT, HTR2A, SLC1A1 and SLC6A1. This is the first evidence that genes implicated in psychiatric disorders previously linked to SGA status themselves predict SGA. This highlights the possibility that the link between SGA and psychiatric disorders such as attention-deficit hyperactivity disorder may in part be genetically determined – that SGA marks pre-existing genetic risk for later problems. PMID:27625810

Differences in somatic mutation landscape of hepatocellular carcinoma in Asian American and European American populations

PubMed Central

Hu, Qiang; Yan, Li; Liu, Biao; Ambrosone, Christine B.; Wang, Jianmin; Liu, Song

2016-01-01

The incidence rate of hepatocellular carcinoma (HCC) is higher in populations of Asian ancestry than European ancestry (EA). We sought to investigate HCC mutational differences between the two populations, which may reflect differences in the prevalence of etiological factors. We compared HCC somatic mutations in patients of self-reported Asian American and EA from The Cancer Genome Atlas (TCGA), and assessed associations of tumor mutations with established HCC risk factors. Although the average mutation burden was similar, TP53 and RB1 were mutated at a much higher frequency in Asian Americans than in EAs (TP53: 43% vs. 21%; RB1: 19% vs. 2%). Three putative oncogenic genes, including TRPM3, SAGE1, and ADAMTS7, were mutated exclusively in Asians. In addition, VEGF binding pathway, a druggable target by tyrosine kinase inhibitors such as sorafenib, was mutated at a higher frequency among Asians (13% vs. 2%); while the negative regulation of IL17 production, involved in inflammation and autoimmunity, was mutated only in EAs (12% vs. 0). Accounting for HCC risk factors had little impact on any of the mutational differences. In conclusion, we demonstrated here mutational differences in important cancer genes and pathways between Asian and European ancestries. These differences may have implications for the prevention and treatment of HCC. PMID:27246981

Differences in somatic mutation landscape of hepatocellular carcinoma in Asian American and European American populations.

PubMed

Yao, Song; Johnson, Christopher; Hu, Qiang; Yan, Li; Liu, Biao; Ambrosone, Christine B; Wang, Jianmin; Liu, Song

2016-06-28

The incidence rate of hepatocellular carcinoma (HCC) is higher in populations of Asian ancestry than European ancestry (EA). We sought to investigate HCC mutational differences between the two populations, which may reflect differences in the prevalence of etiological factors. We compared HCC somatic mutations in patients of self-reported Asian American and EA from The Cancer Genome Atlas (TCGA), and assessed associations of tumor mutations with established HCC risk factors. Although the average mutation burden was similar, TP53 and RB1 were mutated at a much higher frequency in Asian Americans than in EAs (TP53: 43% vs. 21%; RB1: 19% vs. 2%). Three putative oncogenic genes, including TRPM3, SAGE1, and ADAMTS7, were mutated exclusively in Asians. In addition, VEGF binding pathway, a druggable target by tyrosine kinase inhibitors such as sorafenib, was mutated at a higher frequency among Asians (13% vs. 2%); while the negative regulation of IL17 production, involved in inflammation and autoimmunity, was mutated only in EAs (12% vs. 0). Accounting for HCC risk factors had little impact on any of the mutational differences. In conclusion, we demonstrated here mutational differences in important cancer genes and pathways between Asian and European ancestries. These differences may have implications for the prevention and treatment of HCC.

Neuregulin 1 transcripts are differentially expressed in schizophrenia and regulated by 5′ SNPs associated with the disease

PubMed Central

Law, Amanda J.; Lipska, Barbara K.; Weickert, Cynthia Shannon; Hyde, Thomas M.; Straub, Richard E.; Hashimoto, Ryota; Harrison, Paul J.; Kleinman, Joel E.; Weinberger, Daniel R.

2006-01-01

Genetic variation in neuregulin 1 (NRG1) is associated with schizophrenia. The disease-associated SNPs are noncoding, and their functional implications remain unknown. We hypothesized that differential expression of the NRG1 gene explains its association to the disease. We examined four of the disease-associated SNPs that make up the original risk haplotype in the 5′ upstream region of the gene for their effects on mRNA abundance of NRG1 types I–IV in human postmortem hippocampus. Diagnostic comparisons revealed a 34% increase in type I mRNA in schizophrenia and an interaction of diagnosis and genotype (SNP8NRG221132) on this transcript. Of potentially greater interest, a single SNP within the risk haplotype (SNP8NRG243177) and a 22-kb block of this core haplotype are associated with mRNA expression for the novel type IV isoform in patients and controls. Bioinformatic promoter analyses indicate that both SNPs lead to a gain/loss of putative binding sites for three transcription factors, serum response factor, myelin transcription factor-1, and High Mobility Group Box Protein-1. These data implicate variation in isoform expression as a molecular mechanism for the genetic association of NRG1 with schizophrenia. PMID:16618933

Premature mortality in active convulsive epilepsy in rural Kenya

PubMed Central

Bottomley, Christian; Fegan, Gregory; Chengo, Eddie; Odhiambo, Rachael; Bauni, Evasius; Neville, Brian; Kleinschmidt, Immo; Sander, Josemir W.; Newton, Charles R.

2014-01-01

Objective: We estimated premature mortality and identified causes of death and associated factors in people with active convulsive epilepsy (ACE) in rural Kenya. Methods: In this prospective population-based study, people with ACE were identified in a cross-sectional survey and followed up regularly for 3 years, during which information on deaths and associated factors was collected. We used a validated verbal autopsy tool to establish putative causes of death. Age-specific rate ratios and standardized mortality ratios were estimated. Poisson regression was used to identify mortality risk factors. Results: There were 61 deaths among 754 people with ACE, yielding a rate of 33.3/1,000 persons/year. Overall standardized mortality ratio was 6.5. Mortality was higher across all ACE age groups. Nonadherence to antiepileptic drugs (adjusted rate ratio [aRR] 3.37), cognitive impairment (aRR 4.55), and age (50+ years) (rate ratio 4.56) were risk factors for premature mortality. Most deaths (56%) were directly related to epilepsy, with prolonged seizures/possible status epilepticus (38%) most frequently associated with death; some of these may have been due to sudden unexpected death in epilepsy (SUDEP). Possible SUDEP was the likely cause in another 7%. Conclusion: Mortality in people with ACE was more than 6-fold greater than expected. This may be reduced by improving treatment adherence and prompt management of prolonged seizures and supporting those with cognitive impairment. PMID:24443454

Landmarks in the history of cancer epidemiology.

PubMed

Greenwald, Peter; Dunn, Barbara K

2009-03-15

The application of epidemiology to cancer prevention is relatively new, although observations of the potential causes of cancer have been reported for more than 2,000 years. Cancer was generally considered incurable until the late 19th century. Only with a refined understanding of the nature of cancer and strategies for cancer treatment could a systematic approach to cancer prevention emerge. The 20th century saw the elucidation of clues to cancer causation from observed associations with population exposures to tobacco, diet, environmental chemicals, and other exogenous factors. With repeated confirmation of such associations, researchers entertained for the first time the possibility that cancer, like many of the infectious diseases of the time, might be prevented. By the mid-20th century, with antibiotics successfully addressing the majority of infectious diseases and high blood pressure treatment beginning to affect the prevalence of heart disease in a favorable direction, the focus of much of epidemiology shifted to cancer. The early emphasis was on exploring, in greater depth, the environmental, dietary, hormonal, and other exogenous exposures for their potential associations with increased cancer risk. The first major breakthrough in identifying a modifiable cancer risk factor was the documentation of an association between tobacco smoking and lung cancer. During the past four decades, epidemiologic studies have generated population data identifying risk factors for cancers at almost every body site, with many cancers having multiple risk factors. The development of technologies to identify biological molecules has facilitated the incorporation of these molecular manifestations of biological variation into epidemiologic studies, as markers of exposure as well as putative surrogate markers of cancer outcome. This technological trend has, during the past two decades, culminated in emphasis on the identification of genetic variants and their products as correlates of cancer risk, in turn, creating opportunities to incorporate the discipline of molecular/genetic epidemiology into the study of cancer prevention. Epidemiology will undoubtedly continue contributing to cancer prevention by using traditional epidemiologic study designs to address broad candidate areas of interest, with molecular/genetic epidemiology investigations honing in on promising areas to identify specific factors that can be modified with the goal of reducing risk.

Significance, definition, classification and risk factors of chronic kidney disease in South Africa.

PubMed

Meyers, A M

2015-03-01

Renal dysfunction or chronic kidney disease (CKD) is found in 10% of the global population and is classified into five stages according to the estimated glomerular filtration rate (eGFR). No matter where a patient lives, estimation of the GFR is mandatory for decision-making and obtained by the simple measurement of a serum creatinine level. The objective of diagnosing CKD lies in its future prevention, early detection and proper treatment, which will prevent or delay functional deterioration. Primary hypertension (PH) occurs in 25% of South Africa (SA)s black population and is the putative cause of stage 5 CKD in 40 - 60% of these patients. Moreover, in this group, stage 5 CKD occurs at a relatively young age (35 - 45 years) compared with other population groups in whom stage 5 CKD resulting from PH usually occurs between 60 and 70 years of age. In the cohort study, PH has been found in 12 - 16% of black school learners (mean age 17 years) compared with 1.8 - 2% of other ethnic groups (mixed race, Asian, white). End-stage renal failure (ESRF) is the fifth most common cause of death in SA, excluding post-traumatic cases. In addition, undiagnosed or poorly controlled PH is a potent risk factor for other cardiovascular disease (CVD), e.g. congestive cardiac failure, myocardial infarction, stroke. Significant protein is also associated with CVD and protein >1 g/d is a significant risk factor for ESRF.

The sigma factor SigD of Mycobacterium tuberculosis putatively enhances gene expression of the septum site determining protein under stressful environments.

PubMed

Ares, Miguel A; Rios-Sarabia, Nora; De la Cruz, Miguel A; Rivera-Gutiérrez, Sandra; García-Morales, Lázaro; León-Solís, Lizbel; Espitia, Clara; Pacheco, Sabino; Cerna-Cortés, Jorge F; Helguera-Repetto, Cecilia A; García, María Jesús; González-Y-Merchand, Jorge A

2017-07-01

This work examined the expression of the septum site determining gene (ssd) of Mycobacterium tuberculosis CDC1551 and its ∆sigD mutant under different growing conditions. The results showed an up-regulation of ssd during stationary phase and starvation conditions, but not during in vitro dormancy, suggesting a putative role for SigD in the control of ssd expression mainly under lack-of-nutrients environments. Furthermore, we elucidated a putative link between ssd expression and cell elongation of bacilli at stationary phase. In addition, a -35 sigD consensus sequence was found for the ssd promoter region, reinforcing the putative regulation of ssd by SigD, and in turn, supporting this protein role during the adaptation of M. tuberculosis to some stressful environments.

Assessing the evidence for shared genetic risks across psychiatric disorders and traits.

PubMed

Martin, Joanna; Taylor, Mark J; Lichtenstein, Paul

2017-12-04

Genetic influences play a significant role in risk for psychiatric disorders, prompting numerous endeavors to further understand their underlying genetic architecture. In this paper, we summarize and review evidence from traditional twin studies and more recent genome-wide molecular genetic analyses regarding two important issues that have proven particularly informative for psychiatric genetic research. First, emerging results are beginning to suggest that genetic risk factors for some (but not all) clinically diagnosed psychiatric disorders or extreme manifestations of psychiatric traits in the population share genetic risks with quantitative variation in milder traits of the same disorder throughout the general population. Second, there is now evidence for substantial sharing of genetic risks across different psychiatric disorders. This extends to the level of characteristic traits throughout the population, with which some clinical disorders also share genetic risks. In this review, we summarize and evaluate the evidence for these two issues, for a range of psychiatric disorders. We then critically appraise putative interpretations regarding the potential meaning of genetic correlation across psychiatric phenotypes. We highlight several new methods and studies which are already using these insights into the genetic architecture of psychiatric disorders to gain additional understanding regarding the underlying biology of these disorders. We conclude by outlining opportunities for future research in this area.

Exploring Factors Associated with Recent HIV Testing among Heterosexuals at High Risk for HIV Infection Recruited with Venue-based Sampling.

PubMed

Gwadz, Marya; Cleland, Charles M; Jenness, Samuel M; Silverman, Elizabeth; Hagan, Holly; Ritchie, Amanda S; Leonard, Noelle R; McCright-Gill, Talaya; Martinez, Belkis; Swain, Quentin; Kutnick, Alexandra; Sherpa, Dawa

2016-02-01

Annual HIV testing is recommended for high-risk populations in the United States, to identify HIV infections early and provide timely linkage to treatment. However, heterosexuals at high risk for HIV, due to their residence in urban areas of high poverty and elevated HIV prevalence, test for HIV less frequently than other risk groups, and late diagnosis of HIV is common. Yet the factors impeding HIV testing in this group, which is predominantly African American/Black and Latino/Hispanic, are poorly understood. The present study addresses this gap. Using a systematic community-based sampling method, venue-based sampling (VBS), we estimate rates of lifetime and recent (past year) HIV testing among high-risk heterosexuals (HRH), and explore a set of putative multi-level barriers to and facilitators of recent testing, by gender. Participants were 338 HRH African American/Black and Latino/Hispanic adults recruited using VBS, who completed a computerized structured assessment battery guided by the Theory of Triadic Influence, comprised of reliable/valid measures on socio-demographic characteristics, HIV testing history, and multi-level barriers to HIV testing. Logistic regression analysis was used to identify factors associated with HIV testing within the past year. Most HRH had tested at least once (94%), and more than half had tested within the past year (58%), but only 37% tested annually. In both men and women, the odds of recent testing were similar and associated with structural factors (better access to testing) and sexually transmitted infection (STI) testing and diagnosis. Thus VBS identified serious gaps in rates of annual HIV testing among HRH. Improvements in access to high-quality HIV testing and leveraging of STI testing are needed to increase the proportion of HRH testing annually for HIV. Such improvements could increase early detection of HIV, improve the long-term health of individuals, and reduce HIV transmission by increasing rates of viral suppression.

Interplay between cardiac transcription factors and non-coding RNAs in predisposing to atrial fibrillation.

PubMed

Mikhailov, Alexander T; Torrado, Mario

2018-05-12

There is growing evidence that putative gene regulatory networks including cardio-enriched transcription factors, such as PITX2, TBX5, ZFHX3, and SHOX2, and their effector/target genes along with downstream non-coding RNAs can play a potentially important role in the process of adaptive and maladaptive atrial rhythm remodeling. In turn, expression of atrial fibrillation-associated transcription factors is under the control of upstream regulatory non-coding RNAs. This review broadly explores gene regulatory mechanisms associated with susceptibility to atrial fibrillation-with key examples from both animal models and patients-within the context of both cardiac transcription factors and non-coding RNAs. These two systems appear to have multiple levels of cross-regulation and act coordinately to achieve effective control of atrial rhythm effector gene expression. Perturbations of a dynamic expression balance between transcription factors and corresponding non-coding RNAs can provoke the development or promote the progression of atrial fibrillation. We also outline deficiencies in current models and discuss ongoing studies to clarify remaining mechanistic questions. An understanding of the function of transcription factors and non-coding RNAs in gene regulatory networks associated with atrial fibrillation risk will enable the development of innovative therapeutic strategies.

Structural equation modeling in environmental risk assessment.

PubMed

Buncher, C R; Succop, P A; Dietrich, K N

1991-01-01

Environmental epidemiology requires effective models that take individual observations of environmental factors and connect them into meaningful patterns. Single-factor relationships have given way to multivariable analyses; simple additive models have been augmented by multiplicative (logistic) models. Each of these steps has produced greater enlightenment and understanding. Models that allow for factors causing outputs that can affect later outputs with putative causation working at several different time points (e.g., linkage) are not commonly used in the environmental literature. Structural equation models are a class of covariance structure models that have been used extensively in economics/business and social science but are still little used in the realm of biostatistics. Path analysis in genetic studies is one simplified form of this class of models. We have been using these models in a study of the health and development of infants who have been exposed to lead in utero and in the postnatal home environment. These models require as input the directionality of the relationship and then produce fitted models for multiple inputs causing each factor and the opportunity to have outputs serve as input variables into the next phase of the simultaneously fitted model. Some examples of these models from our research are presented to increase familiarity with this class of models. Use of these models can provide insight into the effect of changing an environmental factor when assessing risk. The usual cautions concerning believing a model, believing causation has been proven, and the assumptions that are required for each model are operative.

A putative placebo analysis of the effects of LCZ696 on clinical outcomes in heart failure

PubMed Central

McMurray, John; Packer, Milton; Desai, Akshay; Gong, Jianjian; Greenlaw, Nicola; Lefkowitz, Martin; Rizkala, Adel; Shi, Victor; Rouleau, Jean; Solomon, Scott; Swedberg, Karl; Zile, Michael R.; Andersen, Karl; Arango, Juan Luis; Arnold, Malcolm; Be˘lohlávek, Jan; Böhm, Michael; Boytsov, Sergey; Burgess, Lesley; Cabrera, Walter; Chen, Chen-Huan; Erglis, Andrejs; Fu, Michael; Gomez, Efrain; Gonzalez, Angel; Hagege, Albert-Alain; Katova, Tzvetana; Kiatchoosakun, Songsak; Kim, Kee-Sik; Bayram, Edmundo; Martinez, Felipe; Merkely, Bela; Mendoza, Iván; Mosterd, Arend; Negrusz-Kawecka, Marta; Peuhkurinen, Keijo; Ramires, Felix; Refsgaard, Jens; Senni, Michele; Sibulo, Antonio S.; Silva-Cardoso, José; Squire, Iain; Starling, Randall C.; Vinereanu, Dragos; Teerlink, John R.; Wong, Raymond

2015-01-01

Aims Although active-controlled trials with renin–angiotensin inhibitors are ethically mandated in heart failure with reduced ejection fraction, clinicians and regulators often want to know how the experimental therapy would perform compared with placebo. The angiotensin receptor-neprilysin inhibitor LCZ696 was compared with enalapril in PARADIGM-HF. We made indirect comparisons of the effects of LCZ696 with putative placebos. Methods and results We used the treatment-arm of the Studies Of Left Ventricular Dysfunction (SOLVD-T) as the reference trial for comparison of an ACE inhibitor to placebo and the Candesartan in Heart failure: Assessment of Reduction in Mortality and morbidity-Alternative trial (CHARM-Alternative) as the reference trial for comparison of an ARB to placebo. The hazard ratio of LCZ696 vs. a putative placebo was estimated through the product of the hazard ratio of LCZ696 vs. enalapril (active-control) and that of the historical active-control (enalapril or candesartan) vs. placebo. For the primary composite outcome of cardiovascular death or heart failure hospitalization in PARADIGM-HF, the relative risk reduction with LCZ696 vs. a putative placebo from SOLVD-T was 43% (95%CI 34–50%; P < 0.0001) with similarly large effects on cardiovascular death (34%, 21–44%; P < 0.0001) and heart failure hospitalization (49%, 39–58%; P < 0.0001). For all-cause mortality, the reduction compared with a putative placebo was 28% (95%CI 15–39%; P < 0.0001). Putative placebo analyses based on CHARM-Alternative gave relative risk reductions of 39% (95%CI 27–48%; P < 0.0001) for the composite outcome of cardiovascular death or heart failure hospitalization, 32% (95%CI 16–45%; P < 0.0001) for cardiovascular death, 46% (33–56%; P < 0.0001) for heart failure hospitalization, and 26% (95%CI 11–39%; P < 0.0001) for all-cause mortality. Conclusion These indirect comparisons of LCZ696 with a putative placebo show that the strategy of combined angiotensin receptor blockade and neprilysin inhibition led to striking reductions in cardiovascular and all-cause mortality, as well as heart failure hospitalization. These benefits were obtained even though LCZ696 was added to comprehensive background beta-blocker and mineralocorticoid receptor antagonist therapy. PMID:25416329

The age and other factors in the evaluation of compliance with nasal continuous positive airway pressure for obstructive sleep apnea syndrome. A Cox's proportional hazard analysis.

PubMed

Pelletier-Fleury, N; Rakotonanahary, D; Fleury, B

2001-05-01

Objective: To elucidate the predictive role of age and other pre-treatment, putative confounding factors on compliance with nasal continuous positive airway pressure (nCPAP) therapy.Patients and methods: This study was designed as a prospective cohort study in the setting of a sleep laboratory in a teaching hospital at Saint Antoine, Paris. One hundred and sixty-three patients referred to the sleep laboratory with complaints of snoring and excessive daytime sleepiness for whom nCPAP had been prescribed for obstructive sleep apnea syndrome (OSAS; defined as an apnea-hypopnea index (AHI) of >15/h of sleep during a polysomnographic recording) were followed for a median period of 887 days. The main outcome measure was the risk ratio for elderly patients associated with nCPAP compliance.Results: Four patients, who remained under treatment, died before the end of the study, and 50 patients stopped their nCPAP therapy for reasons other than death (insomnia, equipment too noisy, etc.). When compliance curves were compared by univariate analysis (log-rank test), the oldest group (57/163 patients, >60 years old) was significantly less compliant with nCPAP than the youngest (P=0.01). However, in the Cox's proportional hazards model, age did not exert any independent effect on compliance with nCPAP after controlling for confounding factors (adjusted relative risk, 1.09, 0.5-2; P=0.70). On the other hand, female sex (adjusted relative risk, 2.8, 1.4-5.4; P=0.002), a body mass index (BMI) of /=12 cmH(2)O (adjusted relative risk, 2.3, 1.2-4.4; P=0.011) were predictive factors for non-compliance.Conclusion: This study suggests that there is no independent effect of age on compliance with nCPAP therapy.

Comparative genome analysis of 24 bovine-associated Staphylococcus isolates with special focus on the putative virulence genes

PubMed Central

Åvall-Jääskeläinen, Silja; Paulin, Lars; Blom, Jochen

2018-01-01

Non-aureus staphylococci (NAS) are most commonly isolated from subclinical mastitis. Different NAS species may, however, have diverse effects on the inflammatory response in the udder. We determined the genome sequences of 20 staphylococcal isolates from clinical or subclinical bovine mastitis, belonging to the NAS species Staphylococcus agnetis, S. chromogenes, and S. simulans, and focused on the putative virulence factor genes present in the genomes. For comparison we used our previously published genome sequences of four S. aureus isolates from bovine mastitis. The pan-genome and core genomes of the non-aureus isolates were characterized. After that, putative virulence factor orthologues were searched in silico. We compared the presence of putative virulence factors in the NAS species and S. aureus and evaluated the potential association between bacterial genotype and type of mastitis (clinical vs. subclinical). The NAS isolates had much less virulence gene orthologues than the S. aureus isolates. One third of the virulence genes were detected only in S. aureus. About 100 virulence genes were present in all S. aureus isolates, compared to about 40 to 50 in each NAS isolate. S. simulans differed the most. Several of the virulence genes detected among NAS were harbored only by S. simulans, but it also lacked a number of genes present both in S. agnetis and S. chromogenes. The type of mastitis was not associated with any specific virulence gene profile. It seems that the virulence gene profiles or cumulative number of different virulence genes are not directly associated with the type of mastitis (clinical or subclinical), indicating that host derived factors such as the immune status play a pivotal role in the manifestation of mastitis. PMID:29610707

The environment and susceptibility to schizophrenia

PubMed Central

Brown, Alan S.

2012-01-01

In the present article the putative role of environmental factors in schizophrenia is reviewed and synthesized. Accumulating evidence from recent studies suggests that environmental exposures may play a more significant role in the etiopathogenesis of this disorder than previously thought. This expanding knowledge base is largely a consequence of refinements in the methodology of epidemiologic studies, including birth cohort investigations, and in preclinical research that has been inspired by the evolving literature on animal models of environmental exposures. This paper is divided into four sections. In the first, the descriptive epidemiology of schizophrenia is reviewed. This includes general studies on incidence, prevalence, and differences in these measures by urban–rural, neighborhood, migrant, and season of birth status, as well as time trends. In the second section, we discuss the contribution of environmental risk factors acting during fetal and perinatal life; these include infections [e.g. rubella, influenza, Toxoplasma gondii (T. gondii), herpes simplex virus type 2 (HSV-2)], nutritional deficiencies (e.g., famine, folic acid, iron, vitamin D), paternal age, fetal/neonatal hypoxic and other obstetric insults and complications, maternal stress and other exposures [e.g. lead, rhesus (Rh) incompatibility, maternal stress]. Other putative neurodevelopmental determinants, including cannabis, socioeconomic status, trauma, and infections during childhood and adolescence are also covered. In the third section, these findings are synthesized and their implications for prevention and uncovering biological mechanisms, including oxidative stress, apoptosis, and inflammation, are discussed. Animal models, including maternal immune activation, have yielded evidence suggesting that these exposures cause brain and behavioral phenotypes that are analogous to findings observed in patients with schizophrenia. In the final section, future studies including new, larger, and more rigorous epidemiologic investigations, and research on translational and clinical neuroscience, gene–environment interactions, epigenetics, developmental trajectories and windows of vulnerability, are elaborated upon. These studies are aimed at confirming observed risk factors, identifying new environmental exposures, elucidating developmental mechanisms, and shedding further light on genes and exposures that may not be identified in the absence of these integrated approaches. The study of environmental factors in schizophrenia may have important implications for the identification of causes and prevention of this disorder, and offers the potential to complement, and refine, existing efforts on explanatory neurodevelopmental models. PMID:20955757

Brains in the City: Neurobiological effects of urbanization

PubMed Central

Lambert, Kelly G.; Nelson, Randy J.; Jovanovic, Tanja; Cerdá, Magdalena

2016-01-01

With a majority of humans now living in cities, strategic research is necessary to elucidate the impact of this evolutionarily unfamiliar habitat on neural functions and well-being. In this review, both rodent and human models are considered in the evaluation of the changing physical and social landscapes associated with urban dwellings. Animal models assessing increased exposure to artificial physical elements characteristic of urban settings, as well as exposure to unnatural sources of light for extended durations, are reviewed. In both cases, increased biomarkers of mental illnesses such as major depression have been observed. Additionally, applied human research emphasizing the emotional impact of environmental threats associated with urban habitats is considered. Subjects evaluated in an inner-city hospital reveal the impact of combined specific genetic vulnerabilities and heightened stress responses in the expression of posttraumatic stress disorder. Finally, algorithm-based models of cities have been developed utilizing population-level analyses to identify risk factors for psychiatric illness. Although complex, the use of multiple research approaches, as described herein, results in an enhanced understanding of urbanization and its far-reaching effects--confirming the importance of continued research directed toward the identification of putative risk factors associated with psychiatric illness in urban settings. PMID:25936504

Peripartum events and molar-incisor hypomineralisation (MIH) amongst young patients in southwest France.

PubMed

Garot, E; Manton, D; Rouas, P

2016-08-01

This was to investigate the association of peripartum events with the occurrence of MIH. This study, carried out between 2010 and 2011, was based on objective information noted in child health booklets on putative risk factors for MIH during the Peripartum period, aged between 6 to 28 years. The target population consisted of patients with MIH and a control group. Among the 849 patients examined by two calibrated paediatric dentists, 75 patients with MIH were recorded. These patients attended for consultation either at the teaching dental hospital of Bordeaux (France) or at a private dental practice (Bordeaux, France). Pearson's Chi-squared test was used and Odds ratios (OR) with 95 % test-based confidence intervals (CI) were calculated. Correlations were observed between hypoxia during delivery and occurrence of MIH (OR = 6.1; CI = 1.7-21.85), and also between birth by caesarean section and MIH (OR = 2.9; CI = 1.2-6.9). There was no association between prematurity and MIH. Peripartum events such as hypoxia during birth or delivery by caesarean section are suggested to be risk factors for the occurrence of MIH in this population.

Metal Dyshomeostasis and Inflammation in Alzheimer's and Parkinson's Diseases: Possible Impact of Environmental Exposures

PubMed Central

Myhre, Oddvar; Utkilen, Hans; Duale, Nur; Brunborg, Gunnar; Hofer, Tim

2013-01-01

A dysregulated metal homeostasis is associated with both Alzheimer's (AD) and Parkinson's (PD) diseases; AD patients have decreased cortex and elevated serum copper levels along with extracellular amyloid-beta plaques containing copper, iron, and zinc. For AD, a putative hepcidin-mediated lowering of cortex copper mechanism is suggested. An age-related mild chronic inflammation and/or elevated intracellular iron can trigger hepcidin production followed by its binding to ferroportin which is the only neuronal iron exporter, thereby subjecting it to lysosomal degradation. Subsequently raised neuronal iron levels can induce translation of the ferroportin assisting and copper binding amyloid precursor protein (APP); constitutive APP transmembrane passage lowers the copper pool which is important for many enzymes. Using in silico gene expression analyses, we here show significantly decreased expression of copper-dependent enzymes in AD brain and metallothioneins were upregulated in both diseases. Although few AD exposure risk factors are known, AD-related tauopathies can result from cyanobacterial microcystin and β-methylamino-L-alanine (BMAA) intake. Several environmental exposures may represent risk factors for PD; for this disease neurodegeneration is likely to involve mitochondrial dysfunction, microglial activation, and neuroinflammation. Administration of metal chelators and anti-inflammatory agents could affect disease outcomes. PMID:23710288

Identification of regulatory targets for the bacterial Nus factor complex.

PubMed

Baniulyte, Gabriele; Singh, Navjot; Benoit, Courtney; Johnson, Richard; Ferguson, Robert; Paramo, Mauricio; Stringer, Anne M; Scott, Ashley; Lapierre, Pascal; Wade, Joseph T

2017-12-11

Nus factors are broadly conserved across bacterial species, and are often essential for viability. A complex of five Nus factors (NusB, NusE, NusA, NusG and SuhB) is considered to be a dedicated regulator of ribosomal RNA folding, and has been shown to prevent Rho-dependent transcription termination. Here, we identify an additional cellular function for the Nus factor complex in Escherichia coli: repression of the Nus factor-encoding gene, suhB. This repression occurs primarily by translation inhibition, followed by Rho-dependent transcription termination. Thus, the Nus factor complex can prevent or promote Rho activity depending on the gene context. Conservation of putative NusB/E binding sites upstream of Nus factor genes suggests that Nus factor autoregulation occurs in many bacterial species. Additionally, many putative NusB/E binding sites are also found upstream of other genes in diverse species, and we demonstrate Nus factor regulation of one such gene in Citrobacter koseri. We conclude that Nus factors have an evolutionarily widespread regulatory function beyond ribosomal RNA, and that they are often autoregulatory.

Prevalence of latent tuberculosis infection and associated risk factors among 1557 nursing students in a context of low endemicity.

PubMed

Lamberti, Monica; Uccello, Rossella; Monaco, Maria Grazia Lourdes; Muoio, Mariarosaria; Sannolo, Nicola; Arena, Paola; Mazzarella, Gennaro; Arnese, Antonio; La Cerra, Giuseppe

2015-01-01

The risk of tuberculosis (TBC) in nurses is related to its incidence in the general population. Nursing students involved in clinical training could be exposed to occupational risks similar to those of healthcare workers (HCWs). To better understand the epidemiology of nosocomial TBC among nurses in a context of low endemicity, we recruited a cohort of young nursing trainees at the Second University of Naples. A screening programme for LTBI in nursing students was conducted between January 2012 and December 2013, at the Second University of Naples, with clinical evaluations, tuberculin skin test (TST) and, in positive TST student, the interferon-g release assays (IGRA). Putative risk factors for LTBI were assessed by a standardized questionnaire. 1577 nursing students attending the Second University of Naples have been submitted to screening programme for TBC. 1575 have performed TST as first level test and 2 Quantiferon test (QFT). 19 students were TST positive and continued the diagnostic workup practicing QFT, that was positive in 1 student. Of the 2 subjects that have practiced QFT as first level test only 1 was positive. In 2 students positive to QFT test we formulated the diagnosis of LTBI by clinical and radiographic results. The prevalence of LTBI among nursing students in our study resulted very low. In countries with a low incidence of TBC, the screening programs of healthcare students can be useful for the early identification and treatment of the sporadic cases of LTBI.

Arterial stiffness is increased in asymptomatic nondiabetic postmenopausal women with a polycystic ovary syndrome phenotype.

PubMed

Armeni, Eleni; Stamatelopoulos, Kimon; Rizos, Demetrios; Georgiopoulos, George; Kazani, Maria; Kazani, Aikaterini; Kolyviras, Athanasios; Stellos, Konstantinos; Panoulis, Konstantinos; Alexandrou, Andreas; Creatsa, Maria; Papamichael, Christos; Lambrinoudaki, Irene

2013-10-01

The metabolic dysfunction accompanying the polycystic ovary syndrome (PCOS) may increase the risk of hypertension and cardiovascular disease (CVD). Although menopause per se may be an additional risk factor of CVD, the association between PCOS in postmenopausal women and cardiovascular risk has not been adequately investigated. We aimed to evaluate the effect of PCOS on markers of subclinical atherosclerosis in nondiabetic postmenopausal women. This cross-sectional study included 286 postmenopausal women with intact ovaries. PCOS phenotype was defined if three of the following were present: insulin resistance, current hyperandrogenism or history of clinical androgen excess, history of infertility, central obesity and history of irregular menses. Traditional CVD risk factors, as well as indices of arterial structure (intima-media thickness, atheromatous plaques presence) and function [flow-mediated dilation, pulse wave velocity (PWV), augmentation index] were compared between women with a PCOS phenotype and the rest of the sample, who served as controls. Women with the PCOS phenotype (N=43) had higher SBP and triglycerides and lower high-density lipoprotein (HDL)-cholesterol than controls. Mean values of PWV differed significantly between PCOS cases and controls (9.46±1.74 vs. 8.60±1.51 m/s, P=0.001, univariate). Multivariate regression analysis showed that the PCOS phenotype, age and SBP were the only independent predictors of PWV. Arterial stiffness is increased in asymptomatic, nondiabetic women with a putative PCOS phenotype, independently of age, BMI or blood pressure. This might present one mechanism through which PCOS increases the risk of CVD and hypertension later in life.

Community carriage of ESBL-producing Escherichia coli is associated with strains of low pathogenicity: a Swedish nationwide study.

PubMed

Ny, Sofia; Löfmark, Sonja; Börjesson, Stefan; Englund, Stina; Ringman, Maj; Bergström, Jakob; Nauclér, Pontus; Giske, Christian G; Byfors, Sara

2017-02-01

Community carriage of ESBL-producing Escherichia coli (EPE) is common worldwide and there is a need to understand the connection between carriage and infection. We compared the molecular characteristics of EPE among Swedish community carriers with those of EPE causing invasive infections. We collected 2134 faecal samples from randomly selected Swedish inhabitants and examined them for the presence of EPE. All participating volunteers answered a questionnaire about putative risk factors for EPE carriage. Suspected EPE isolates (n = 418) from patients with bloodstream infection (BSI) were collected from Swedish laboratories. Isolates were genotypically and phenotypically characterized. Our results show that the EPE population found in carriers generally had lower pathogenicity compared with the isolates from BSIs, since carriers had a lower proportion of E. coli belonging to phylogroup B2, ST131 and ST131 subclone H30-Rx. Isolates from carriers also had lower levels of multiresistance. The Swedish carriage rate of EPE was 4.7% (101/2134) among healthy volunteers. Risk factors associated with carriage were travel to countries in Asia (OR = 3.6, 95% CI = 1.4-9.2) and Africa (OR = 3.6, 95% CI = 1.7-7.7) and a diet without pork (OR = 0.5, 95% CI = 0.3-0.8 for pork eaters). E. coli host factors previously associated with higher pathogenicity were all more common in BSIs compared with carriers. This indicates that the risk of invasive infection with EPE may be relatively modest in many community carriers and that EPE carriage of high-risk strains should be the focus of attention for prevention. © The Author 2016. Published by Oxford University Press on behalf of the British Society for Antimicrobial Chemotherapy.

Leishmania infantum, Dirofilaria spp. and other endoparasite infections in kennel dogs in central Italy

PubMed Central

Sauda, Federica; Malandrucco, Livia; Macrì, Gladia; Scarpulla, Manuela; De Liberato, Claudio; Terracciano, Giuliana; Fichi, Gianluca; Berrilli, Federica; Perrucci, Stefania

2018-01-01

Prevalence and risk factors of Leishmania infantum, Dirofilaria spp. and other potentially zoonotic or canine-specific endoparasite infections were assessed in 639 kennel dogs from central Italy. To this end, individual blood and fecal samples were examined using parasitological, immunological and molecular techniques. The presence of compatible clinical pictures, as well as age and gender were considered as putative risks factors. To evaluate risk factors, multivariable analysis with logistic regression and univariable analysis with a Chi square test and a Fischer’s exact test were performed. Overall, 52.6% of dogs (95% CI 48.6-56.5) were found positive, while 39.6% of dogs (95% CI 35.8-43.5) were infected by potentially zoonotic species. Leishmania infantum and Dirofilaria repens showed prevalences of 2.5% (95% CI 1.5-4.1) and 2.8% (95% CI 1.7-4.5), respectively. The prevalence of cardiorespiratory parasites was 7.8% (95% CI 5.9-10.3) and included the species Angiostrongylus vasorum, Eucoleus aerophilus, Eucoleus boehmi and D. immitis; the latter showed a prevalence of 0.2% (95% CI 0.001-1). Intestinal parasites were significantly prevalent (38.8%, 95% CI 35-42.7) and they consisted mainly of species of major zoonotic concern, including ancylostomatids, Toxocara canis, Giardia duodenalis, Dipylidium caninum, Taeniidae, Strongyloides stercoralis and Cryptosporidium parvum. Endoparasites were significantly prevalent in clinically suspected dogs. Leishmania infantum and cardiorespiratory nematodes were prevalent in older dogs, while intestinal parasites were prevalent in younger dogs. Results show high dog and public health risks in kennels in central Italy, and suggest the need for more effective control measures. PMID:29388550

CT fluoroscopy-guided core needle biopsy of anterior mediastinal masses.

PubMed

Iguchi, T; Hiraki, T; Matsui, Y; Fujiwara, H; Sakurai, J; Masaoka, Y; Uka, M; Tanaka, T; Gobara, H; Kanazawa, S

2018-02-01

To retrospectively evaluate the safety, diagnostic yield, and risk factors of diagnostic failure of computed tomography (CT) fluoroscopy-guided biopsies of anterior mediastinal masses. Biopsy procedures and results of anterior mediastinal masses in 71 patients (32 women/39 men; mean [±standard deviation] age, 53.8±20.0years; range, 14-88years) were analyzed. Final diagnoses were based on surgical outcomes, imaging findings, or clinical follow-up findings. The biopsy results were compared with the final diagnosis, and the biopsy procedures grouped by pathologic findings into diagnostic success and failure groups. Multiple putative risk factors for diagnostic failure were then assessed. Seventy-one biopsies (71 masses; mean size, 67.5±27.3mm; range 8.6-128.2mm) were analyzed. We identified 17 grade 1 and one grade 2 adverse events (25.4% overall) according to the National Cancer Institute Common Terminology Criteria for Adverse Events version 4.0. Sixty-nine biopsies (97.2%) provided samples fit for pathologic analysis. Diagnostic failure was found for eight (11.3%) masses; the 63 masses diagnosed successfully included thymic carcinoma (n=17), lung cancer (n=14), thymoma (n=12), malignant lymphoma (n=11), germ cell tumor (n=3), and others (n=6). Using a thinner needle (i.e., a 20-gauge needle) was the sole significant risk factor for diagnostic failure (P=0.039). CT fluoroscopy-guided biopsy of anterior mediastinal masses was safe and had a high diagnostic yield; however, using a thinner biopsy needle significantly increased the risk of a failed diagnosis. Copyright © 2017 Éditions françaises de radiologie. Published by Elsevier Masson SAS. All rights reserved.

Genome-wide association study with the risk of schizophrenia in a Korean population.

PubMed

Kim, Lyoung Hyo; Park, Byung Lae; Cheong, Hyun Sub; Namgoong, Suhg; Kim, Ji On; Kim, Jeong-Hyun; Shin, Joong-Gon; Park, Chul Soo; Kim, Bong-Jo; Kim, Jae Won; Choi, Ihn-Geun; Hwang, Jaeuk; Shin, Hyoung Doo; Woo, Sung-Il

2016-03-01

Schizophrenia is regarded as a multifactorial and polygenic brain disorder that is attributed to different combinations of genetic and environmental risk factors. Recently, several genome-wide association studies (GWASs) of schizophrenia have identified numerous risk factors, but the replication results remain controversial and ambiguous. To identify schizophrenia susceptibility loci in the Korean population, we performed a GWAS using the Illumina HumanOmni1-Quad V1.0 Microarray. We genotyped 1,140,419 single nucleotide polymorphisms (SNPs) in 350 Korea schizophrenia patients and 700 control subjects, and approximately 620,001 autosomal SNPs were passed our quality control. In the case-control analysis, the rs9607195 A>G on intergenic area 250 kb away from the ISX gene and the rs12738007 A>G on the intron of the MECR gene were the most strongly associated SNPs with the risk of schizophrenia (P = 6.2 × 10(-8) , OR = 0.50 and P = 3.7 × 10(-7) , OR = 2.39, respectively). In subsequent fine-mapping analysis, 6 SNPs of MECR were genotyped with 310 schizophrenia patients and 604 control subjects. The association of the MECR rs12738007, a top ranked-SNP in GWAS, was replicated (P = 1.5 × 10(-2) , OR = 1.53 in fine mapping analysis, P = 1.5 × 10(-6) , OR = 1.90 in combined analysis). The identification of putative schizophrenia susceptibility loci could provide new insights into genetic factors related with schizophrenia and clues for the development of diagnosis strategies. © 2015 Wiley Periodicals, Inc.

Phylogenetic factorization of compositional data yields lineage-level associations in microbiome datasets.

PubMed

Washburne, Alex D; Silverman, Justin D; Leff, Jonathan W; Bennett, Dominic J; Darcy, John L; Mukherjee, Sayan; Fierer, Noah; David, Lawrence A

2017-01-01

Marker gene sequencing of microbial communities has generated big datasets of microbial relative abundances varying across environmental conditions, sample sites and treatments. These data often come with putative phylogenies, providing unique opportunities to investigate how shared evolutionary history affects microbial abundance patterns. Here, we present a method to identify the phylogenetic factors driving patterns in microbial community composition. We use the method, "phylofactorization," to re-analyze datasets from the human body and soil microbial communities, demonstrating how phylofactorization is a dimensionality-reducing tool, an ordination-visualization tool, and an inferential tool for identifying edges in the phylogeny along which putative functional ecological traits may have arisen.

Dyslipidemia: Obese or Not Obese-That Is Not the Question.

PubMed

Ipsen, David H; Tveden-Nyborg, Pernille; Lykkesfeldt, Jens

2016-12-01

Purpose of review: It is becoming increasingly clear that some obese individuals do not develop dyslipidemia and instead remain healthy, while some normal weight individuals become dyslipidemic and unhealthy. The present review examines the similarities and differences between healthy and unhealthy individuals with and without obesity and discusses putative underlying mechanisms of dyslipidemia. The presence of dyslipidemia and compromised metabolic health in both lean and obese individuals suggests that the obese phenotype per se does not represent a main independent risk factor for the development of dyslipidemia and that dyslipidemia, rather than obesity, may be the driver of metabolic diseases. Notably, adipose tissue dysfunction and ectopic lipid deposition, in particular in the liver, seems a common trait of unhealthy individuals.

Sleep disorders in kidney disease.

PubMed

De Santo, R M; Perna, A; Di Iorio, B R; Cirillo, M

2010-03-01

Sleep disorders are common in patients with end stage renal disease receiving hemodialysis or peritoneal dialysis. However also a well functioning renal graft does not cure the poor sleep pattern which now emerges as a problem even in early chronic kidney disease (CKD). When patients are made aware for the first time of a disease such as CKD, which may brink to dialysis or at the best to a renal transplant patients begin to experience a disordered sleep. Sleeping disorders include insomnia (I), sleep apnoea (SAS), restless legs syndrome (RLS), periodic limb movement disorder (PLMD), excessive daily sleeping (EDS), sleepwalking, nightmares, and narcolepsy. Disordered sleep did not meet the clinical and scientific interest it deserves, in addition and we do not have a well defined solution for sleeping complaints. However, awareness that a poor sleep is associated with poor quality of life and carries an increase in mortality risk has recently stimulated interest in the field. There are many putative causes for a disordered sleep in chronic kidney disease and in end-stage renal disease. For a unifying hypothesis demographic factors, lifestyles, disease related factors, psychological factors, treatment related factors, and social factor must be taken into consideration.

Multi-country study on the prevalence and clinical features of peripheral arterial disease in Asian type 2 diabetes patients at high risk of atherosclerosis.

PubMed

Rhee, Sang Youl; Guan, Heng; Liu, Zhi Min; Cheng, Stephen Wing-Keung; Waspadji, Sarwono; Palmes, Patricio; Tai, Tong Yuan; Suwanwalaikorn, Sompongse; Kim, Young Seol

2007-04-01

PAD-SEARCH was the first international study to investigate the prevalence of peripheral arterial disease (PAD) in Asian type 2 diabetic patients and to demonstrate the relationships between putative risk factors and PAD. In total 6625 type 2 diabetic patients aged 50 and older were enrolled and determined ankle-brachial index (ABI) and brachial-ankle pulse wave velocity (baPWV) in Korea, China, Taiwan, Hong Kong, Indonesia, Thailand and the Philippines. Mean patient age was 63.7+/-8.2 years and mean duration of diabetes was 10.3+/-8.0 years. One thousand one hundred and seventy-two (17.7%) subjects were diagnosed as PAD by ABI (< or =0.9). PAD subjects had a significantly longer duration of diabetes, hypertension, higher HbA1c, and a significantly lower mean BMI than non-PAD subjects. In terms of lipid profiles, triglyceride was the only significant variable. Notably, mean ABI and baPWV in females were significantly poorer than age matched males in subjects with a normal ABI. However, mean ABI and baPWV in males were significantly poorer than in age matched females in subjects with PAD. These findings suggest that PAD is a common complication in Asian type 2 diabetic patients. Therefore, PAD screening and treatment should be emphasized for Asian diabetic patients with high risk factors.

The role of FKBP5 genotype in moderating long-term effectiveness of exposure-based psychotherapy for posttraumatic stress disorder.

PubMed

Wilker, S; Pfeiffer, A; Kolassa, S; Elbert, T; Lingenfelder, B; Ovuga, E; Papassotiropoulos, A; de Quervain, D; Kolassa, I-T

2014-06-24

Exposure-based therapies are considered the state-of-the-art treatment for Posttraumatic Stress Disorder (PTSD). Yet, a substantial number of PTSD patients do not recover after therapy. In the light of the well-known gene × environment interactions on the risk for PTSD, research on individual genetic factors that influence treatment success is warranted. The gene encoding FK506-binding protein 51 (FKBP5), a co-chaperone of the glucocorticoid receptor (GR), has been associated with stress reactivity and PTSD risk. As FKBP5 single-nucleotide polymorphism rs1360780 has a putative functional role in the regulation of FKBP5 expression and GR sensitivity, we hypothesized that this polymorphism influences PTSD treatment success. We investigated the effects of FKBP5 rs1360780 genotype on Narrative Exposure Therapy (NET) outcome, an exposure-based short-term therapy, in a sample of 43 survivors of the rebel war in Northern Uganda. PTSD symptom severity was assessed before and 4 and 10 months after treatment completion. At the 4-month follow-up, there were no genotype-dependent differences in therapy outcome. However, the FKBP5 genotype significantly moderated the long-term effectiveness of exposure-based psychotherapy. At the 10-month follow-up, carriers of the rs1360780 risk (T) allele were at increased risk of symptom relapse, whereas non-carriers showed continuous symptom reduction. This effect was reflected in a weaker treatment effect size (Cohen's D=1.23) in risk allele carriers compared with non-carriers (Cohen's D=3.72). Genetic factors involved in stress response regulation seem to not only influence PTSD risk but also responsiveness to psychotherapy and could hence represent valuable targets for accompanying medication.

The role of FKBP5 genotype in moderating long-term effectiveness of exposure-based psychotherapy for posttraumatic stress disorder

PubMed Central

Wilker, S; Pfeiffer, A; Kolassa, S; Elbert, T; Lingenfelder, B; Ovuga, E; Papassotiropoulos, A; de Quervain, D; Kolassa, I-T

2014-01-01

Exposure-based therapies are considered the state-of-the-art treatment for Posttraumatic Stress Disorder (PTSD). Yet, a substantial number of PTSD patients do not recover after therapy. In the light of the well-known gene × environment interactions on the risk for PTSD, research on individual genetic factors that influence treatment success is warranted. The gene encoding FK506-binding protein 51 (FKBP5), a co-chaperone of the glucocorticoid receptor (GR), has been associated with stress reactivity and PTSD risk. As FKBP5 single-nucleotide polymorphism rs1360780 has a putative functional role in the regulation of FKBP5 expression and GR sensitivity, we hypothesized that this polymorphism influences PTSD treatment success. We investigated the effects of FKBP5 rs1360780 genotype on Narrative Exposure Therapy (NET) outcome, an exposure-based short-term therapy, in a sample of 43 survivors of the rebel war in Northern Uganda. PTSD symptom severity was assessed before and 4 and 10 months after treatment completion. At the 4-month follow-up, there were no genotype-dependent differences in therapy outcome. However, the FKBP5 genotype significantly moderated the long-term effectiveness of exposure-based psychotherapy. At the 10-month follow-up, carriers of the rs1360780 risk (T) allele were at increased risk of symptom relapse, whereas non-carriers showed continuous symptom reduction. This effect was reflected in a weaker treatment effect size (Cohen's D=1.23) in risk allele carriers compared with non-carriers (Cohen's D=3.72). Genetic factors involved in stress response regulation seem to not only influence PTSD risk but also responsiveness to psychotherapy and could hence represent valuable targets for accompanying medication. PMID:24959896

HIGHER SERUM TOTAL CHOLESTEROL LEVELS IN LATE MIDDLE AGE ARE ASSOCIATED WITH GLUCOSE HYPOMETABOLISM IN BRAIN REGIONS AFFECTED BY ALZHEIMER’S DISEASE AND NORMAL AGING

PubMed Central

Reiman, Eric M.; Chen, Kewei; Langbaum, Jessica B.S.; Lee, Wendy; Reschke, Cole; Bandy, Daniel; Alexander, Gene E.; Caselli, Richard J.

2010-01-01

Epidemiological studies suggest that higher midlife serum total cholesterol levels are associated with an increased risk of Alzheimer’s disease (AD). Using fluorodeoxyglucose positron emission tomography (PET) in the study of cognitively normal late-middle-aged people, we demonstrated an association between apolipoprotein E (APOE) ε4 gene dose, the major genetic risk factor for late-onset AD, and lower measurements of the cerebral metabolic rate for glucose (CMRgl) in AD-affected brain regions, we proposed using PET as a presymptomatic endophenotype to evaluate other putative AD risk modifiers, and we then used it to support an aggregate cholesterol-related genetic risk score in the risk of AD. In the present study, we used PET to investigate the association between serum total cholesterol levels and cerebral metabolic rate for glucose metabolism (CMRgl) in 117 cognitively normal late middle-aged APOE ε4 homozygotes, heterozygotes and noncarriers. Higher serum total cholesterol levels were associated with lower CMRgl bilaterally in precuneus, parietotemporal and prefrontal regions previously found to be preferentially affected by AD, and in additional frontal regions previously found to be preferentially affected by normal aging. The associations were greater in APOE ε4 carriers than non-carriers in some of the AD-affected brain regions. We postulate the higher midlife serum total cholesterol levels accelerate brain processes associated with normal aging and conspire with other risk factors in the predisposition to AD. We propose using PET in proof-of-concept randomized controlled trials to rapidly evaluate the effects of midlife cholesterol-lowering treatments on the brain changes associated with normal aging and AD. PMID:19631758

Predicting Low Accrual in the National Cancer Institute’s Cooperative Group Clinical Trials

PubMed Central

Bennette, Caroline S.; Ramsey, Scott D.; McDermott, Cara L.; Carlson, Josh J.; Basu, Anirban; Veenstra, David L.

2016-01-01

Background: The extent to which trial-level factors differentially influence accrual to trials has not been comprehensively studied. Our objective was to evaluate the empirical relationship and predictive properties of putative risk factors for low accrual in the National Cancer Institute’s (NCI’s) Cooperative Group Program, now the National Clinical Trials Network (NCTN). Methods: Data from 787 phase II/III adult NCTN-sponsored trials launched between 2000 and 2011 were used to develop a logistic regression model to predict low accrual, defined as trials that closed with or were accruing at less than 50% of target; 46 trials opened between 2012 and 2013 were used for prospective validation. Candidate predictors were identified from a literature review and expert interviews; final predictors were selected using stepwise regression. Model performance was evaluated by calibration and discrimination via the area under the curve (AUC). All statistical tests were two-sided. Results: Eighteen percent (n = 145) of NCTN-sponsored trials closed with low accrual or were accruing at less than 50% of target three years or more after initiation. A multivariable model of twelve trial-level risk factors had good calibration and discrimination for predicting trials with low accrual (AUC in trials launched 2000–2011 = 0.739, 95% confidence interval [CI] = 0.696 to 0.783]; 2012–2013: AUC = 0.732, 95% CI = 0.547 to 0.917). Results were robust to different definitions of low accrual and predictor selection strategies. Conclusions: We identified multiple characteristics of NCTN-sponsored trials associated with low accrual, several of which have not been previously empirically described, and developed a prediction model that can provide a useful estimate of accrual risk based on these factors. Future work should assess the role of such prediction tools in trial design and prioritization decisions. PMID:26714555

Doublesex and mab-3 related transcription factor 1 (DMRT1) is a sex-specific genetic determinant of childhood-onset asthma and is expressed in testis and macrophages.

PubMed

Schieck, Maximilian; Schouten, Jan P; Michel, Sven; Suttner, Kathrin; Toncheva, Antoaneta A; Gaertner, Vincent D; Illig, Thomas; Lipinski, Simone; Franke, Andre; Klintschar, Michael; Kalayci, Omer; Sahiner, Umit M; Birben, Esra; Melén, Erik; Pershagen, Göran; Freidin, Maxim B; Ogorodova, Ludmila M; Granell, Raquel; Henderson, John; Brunekreef, Bert; Smit, Henriëtte A; Vogelberg, Christian; von Berg, Andrea; Bufe, Albrecht; Heinzmann, Andrea; Laub, Otto; Rietschel, Ernst; Simma, Burkhard; Genuneit, Jon; Jonigk, Danny; Postma, Dirkje S; Koppelman, Gerard H; Vonk, Judith M; Timens, Wim; Boezen, H Marike; Kabesch, Michael

2016-08-01

Asthma is a disease affecting more boys than girls in childhood and more women than men in adulthood. The mechanisms behind these sex-specific differences are not yet understood. We analyzed whether and how genetic factors contribute to sex-specific predisposition to childhood-onset asthma. Interactions between sex and polymorphisms on childhood asthma risk were evaluated in the Multicentre Asthma Genetics in Childhood Study (MAGICS)/Phase II International Study of Asthma and Allergies in Childhood (ISAAC II) population on a genome-wide level, and findings were validated in independent populations. Genetic fine mapping of sex-specific asthma association signals was performed, and putatively causal polymorphisms were characterized in vitro by using electrophoretic mobility shift and luciferase activity assays. Gene and protein expression of the identified gene doublesex and mab-3 related transcription factor 1 (DMRT1) were measured in different human tissues by using quantitative real-time PCR and immunohistochemistry. Polymorphisms in the testis-associated gene DMRT1 displayed interactions with sex on asthma status in a population of primarily clinically defined asthmatic children and nonasthmatic control subjects (lowest P = 5.21 × 10(-6)). Replication of this interaction was successful in 2 childhood populations clinically assessed for asthma but showed heterogeneous results in other population-based samples. Polymorphism rs3812523 located in the putative DMRT1 promoter was associated with allele-specific changes in transcription factor binding and promoter activity in vitro. DMRT1 expression was observed not only in the testis but also in lung macrophages. DMRT1 might influence sex-specific patterns of childhood asthma, and its expression in testis tissue and lung macrophages suggests a potential involvement in hormone or immune cell regulation. Copyright © 2016 American Academy of Allergy, Asthma & Immunology. All rights reserved.

Evidence for the Influence of the Iron Regulatory MHC Class I Molecule HFE on Tumor Progression in Experimental Models and Clinical Populations

PubMed Central

Weston, Cody; Connor, James

2014-01-01

Proteins involved in iron regulation are modifiers of cancer risk and progression. Of these, the HFE protein (high iron gene and its protein product) is of particular interest because of its interaction with both iron handling and immune function and the high rate of genetic polymorphisms resulting in a mutant protein. Clinical studies suggest that HFE polymorphisms increase the risk of certain cancers, but the inconsistent outcomes suggest a more nuanced effect, possibly interacting with other genetic or environmental factors. Some basic science research has been conducted to begin to understand the implications of variant HFE genotype on cancer, but the story is far from complete. In particular, putative mechanisms exist for HFE to affect tumor progression through its role in iron handling and its major histocompatibility complex class I structural features. In this review, the current understanding of the role of HFE in cancer is described and models for future directions are identified. PMID:25520556

X: a case study of a Swedish neo-Nzi and his reintegration into Swedish society.

PubMed

Stern, Jessica Eve

2014-01-01

This article provides a case study of a Swedish neo-Nazi and the reintegration program being provided to him. During an extensive interview that took place over two days, he told a researcher that he was interested in having a violent adventure, and that he was drawn to Nazi symbols and history more than their creed. In comparison with ordinary crime, terrorist crime is quite rare, and access to detailed case studies is rarer still, making the development of a prospective risk-assessment instrument extremely difficult. Researchers' "thick descriptions" of their encounters with terrorists can help us to develop putative risk factors which can then be tested against controls. The article concludes by arguing that just as there is no single pathway into or out of terrorism, there can be no single reintegration program. A series of thick descriptions is a first step toward understanding what leads individuals into and out of terrorism. Copyright © 2014 John Wiley & Sons, Ltd.

Modulation of glioma risk and progression by dietary nutrients and anti-inflammatory agents

PubMed Central

Kyritsis, Athanassios P.; Bondy, Melissa L.; Levin, Victor A.

2011-01-01

Gliomas are tumors of glial origin formed in the central nervous system and exhibit profound morphological and genetic heterogeneity. The etiology of this heterogeneity involves an interaction between genetic alterations and environmental risk factors. Scientific evidence suggests that certain natural dietary components, such as phytoestrogens, flavonoids, polyunsaturated fatty acids and vitamins may exert a protective effect against gliomas by changing the nature of the interaction between genetics and environment. Similarly, certain anti-inflammatory drugs and dietary modifications, such as methionine restriction and the adoption of low-calorie or ketogenic diets, may take advantage of glioma and normal glial cells’ differential requirements for glucose, methionine, and ketone bodies and may therefore be effective as part of preventive or treatment strategies for gliomas. Treatment trials of glioma patients and chemoprevention trials of individuals with a known genetic predisposition to glioma using the most promising of these agents, such as the anti-inflammatory drugs curcumin and gamma-linolenic acid, are needed to validate or refute these agents’ putative role in gliomas. PMID:21302177

Proteinaceous Pheromone Homologs Identified from the Cloacal Gland Transcriptome of a Male Axolotl, Ambystoma mexicanum.

PubMed

Hall, Kevin W; Eisthen, Heather L; Williams, Barry L

2016-01-01

Pheromones play an important role in modifying vertebrate behavior, especially during courtship and mating. Courtship behavior in urodele amphibians often includes female exposure to secretions from the cloacal gland, as well as other scent glands. The first vertebrate proteinaceous pheromone discovered, the decapeptide sodefrin, is a female attracting pheromone secreted by the cloacal gland of male Cynops pyrrhogaster. Other proteinaceous pheromones in salamanders have been shown to elicit responses from females towards conspecific males. The presence and levels of expression of proteinaceous pheromones have not been identified in the family Ambystomatidae, which includes several important research models. The objective of this research was therefore to identify putative proteinaceous pheromones from male axolotls, Ambystoma mexicanum, as well as their relative expression levels. The results indicate that axolotls possess two different forms of sodefrin precursor-like factor (alpha and beta), as well as a putative ortholog of plethodontid modulating factor. The beta form of sodefrin precursor-like factor was amongst the most highly expressed transcripts within the cloacal gland. The ortholog of plethodontid modulating factor was expressed at a level equivalent to the beta sodefrin precursor-like factor. The results are from a single male axolotl; therefore, we are unable to assess how representative our results may be. Nevertheless, the presence of these highly expressed proteinaceous pheromones suggests that male axolotls use multiple chemical cues to attract female conspecifics. Behavioral assays would indicate whether the putative protein pheromones elicit courtship activity from female axolotls.

Proteinaceous Pheromone Homologs Identified from the Cloacal Gland Transcriptome of a Male Axolotl, Ambystoma mexicanum

PubMed Central

Hall, Kevin W.; Eisthen, Heather L.; Williams, Barry L.

2016-01-01

Pheromones play an important role in modifying vertebrate behavior, especially during courtship and mating. Courtship behavior in urodele amphibians often includes female exposure to secretions from the cloacal gland, as well as other scent glands. The first vertebrate proteinaceous pheromone discovered, the decapeptide sodefrin, is a female attracting pheromone secreted by the cloacal gland of male Cynops pyrrhogaster. Other proteinaceous pheromones in salamanders have been shown to elicit responses from females towards conspecific males. The presence and levels of expression of proteinaceous pheromones have not been identified in the family Ambystomatidae, which includes several important research models. The objective of this research was therefore to identify putative proteinaceous pheromones from male axolotls, Ambystoma mexicanum, as well as their relative expression levels. The results indicate that axolotls possess two different forms of sodefrin precursor-like factor (alpha and beta), as well as a putative ortholog of plethodontid modulating factor. The beta form of sodefrin precursor-like factor was amongst the most highly expressed transcripts within the cloacal gland. The ortholog of plethodontid modulating factor was expressed at a level equivalent to the beta sodefrin precursor-like factor. The results are from a single male axolotl; therefore, we are unable to assess how representative our results may be. Nevertheless, the presence of these highly expressed proteinaceous pheromones suggests that male axolotls use multiple chemical cues to attract female conspecifics. Behavioral assays would indicate whether the putative protein pheromones elicit courtship activity from female axolotls. PMID:26885665

An efficient cDNA-AFLP-based strategy for the identification of putative pathogenicity factors from the potato cyst nematode Globodera rostochiensis.

PubMed

Qin, L; Overmars, H; Helder, J; Popeijus, H; van der Voort, J R; Groenink, W; van Koert, P; Schots, A; Bakker, J; Smant, G

2000-08-01

A new strategy has been designed to identify putative pathogenicity factors from the dorsal or subventral esophageal glands of the potato cyst nematode Globodera rostochiensis. Three independent criteria were used for selection. First, genes of interest should predominantly be expressed in infective second-stage juveniles, and not, or to a far lesser extent, in younger developmental stages. For this, gene expression profiles from five different developmental stages were generated with cDNA-AFLP (amplified fragment length polymorphism). Secondly, the mRNA corresponding to such a putative pathogenicity factor should predominantly be present in the esophageal glands of pre-parasitic juveniles. This was checked by in situ hybridization. As a third criterion, these proteinaceous factors should be preceded by a signal peptide for secretion. Expression profiles of more than 4,000 genes were generated and three up-regulated, dorsal gland-specific proteins preceded by signal peptide for secretion were identified. No dorsal gland genes have been cloned before from plant-parasitic nematodes. The partial sequence of these three factors, A4, A18, and A41, showed no significant homology to any known gene. Their presence in the dorsal glands of infective juveniles suggests that these proteins could be involved in feeding cell initiation, and not in migration in the plant root or in protection against plant defense responses. Finally, the applicability of this new strategy in other plant-microbe interactions is discussed.

Differential proteomic analysis of Aspergillus fumigatus morphotypes reveals putative drug targets.

PubMed

Kubitschek-Barreira, Paula H; Curty, Nathalia; Neves, Gabriela W P; Gil, Concha; Lopes-Bezerra, Leila M

2013-01-14

Aspergillus fumigatus is the main etiological agent of invasive aspergillosis, an important opportunistic infection for neutropenic patients. The main risk groups are patients with acute leukemia and bone marrow transplantation recipients. The lack of an early diagnostic test together with the limited spectrum of antifungal drugs remains a setback to the successful treatment of this disease. During invasive infection the inhaled fungal conidia enter the morphogenic cycle leading to angioinvasive hyphae. This work aimed to study differentially expressed proteins of A. fumigatus during morphogenesis. To achieve this goal, a 2D-DIGE approach was applied to study surface proteins extractable by reducing agents of two A. fumigatus morphotypes: germlings and hyphae. Sixty-three differentially expressed proteins were identified by MALDI-ToF/MS. We observed that proteins associated with biosynthetic pathways and proteins with multiple functions (miscellaneous) were over-expressed in the early stages of germination, while in hyphae, the most abundant proteins detected were related to metabolic processes or have unknown functions. Among the most interesting proteins regulated during morphogenesis, two putative drug targets were identified, the translational factor, eEF3 and the CipC-like protein. Neither of these proteins are present in mammalian cells. Copyright © 2012 Elsevier B.V. All rights reserved.

Skin Colonization by Malassezia spp. in hospitalized neonates and infants in a tertiary care centre in North India.

PubMed

Gupta, Prerna; Chakrabarti, Arunaloke; Singhi, Sunit; Kumar, Praveen; Honnavar, Prasanna; Rudramurthy, Shivaprakash M

2014-10-01

Malassezia, a skin colonizer, is associated with multiple skin disorders in adults, and cephalic pustulosis and folliculitis in children. It can cause fungemia in infants and neonates. The time and pattern of colonization, risk factors associated with colonization and causing fungemia in children, are not well understood. The prospective cohort study was conducted to determine the rate of Malassezia species colonization and associated factors in hospitalized neonates and infants. Consecutive 50 neonates and infants admitted in neonatal and pediatric intensive care units were studied. The skin swabs were collected on the day of admission and every fifth day, thereafter, till the patient was discharged or died. Putative risk factors for the colonization of Malassezia species were recorded. Isolates were identified by phenotypic methods and sequencing of the D1 and D2 region of rDNA. Neonates were not colonized at the time of entry in neonatal ICU or at birth. Nineteen (38 %) neonates were colonized with Malassezia species during their hospital stay. Among the infants, three (6 %) came to ICU with Malassezia colonization and 26 (52 %) acquired Malassezia during ICU stay. Mechanical ventilation, duration of hospital stay, central venous catheterization, and antifungal therapy were the significantly associated factors for colonization. Malassezia furfur was the most common species isolated from the skin of infants and neonates. Colonization by Malassezia species in infants and neonates in a hospital is not uncommon and can be a potential source of nosocomial infection.

Adipocyte-derived factors in age-related dementia and their contribution to vascular and Alzheimer pathology.

PubMed

Ishii, Makoto; Iadecola, Costantino

2016-05-01

Age-related dementia is increasingly recognized as having a mixed pathology, with contributions from both cerebrovascular factors and pathogenic factors associated with Alzheimer's disease (AD). Furthermore, there is accumulating evidence that vascular risk factors in midlife, e.g., obesity, diabetes, and hypertension, increase the risk of developing late-life dementia. Since obesity and changes in body weight/adiposity often drive diabetes and hypertension, understanding the relationship between adiposity and age-related dementia may reveal common underlying mechanisms. Here we offer a brief appraisal of how changes in body weight and adiposity are related to both AD and dementia on vascular basis, and examine the involvement of two key adipocyte-derived hormones: leptin and adiponectin. The evidence suggests that in midlife increased body weight/adiposity and subsequent changes in adipocyte-derived hormones may increase the long-term susceptibility to dementia. On the other hand, later in life, decreases in body weight/adiposity and related hormonal changes are early manifestations of disease that precede the onset of dementia and may promote AD and vascular pathology. Understanding the contribution of adiposity to age-related dementia may help identify the underlying pathological mechanisms common to both vascular dementia and AD, and provide new putative targets for early diagnosis and therapy. This article is part of a Special Issue entitled: Vascular Contributions to Cognitive Impairment and Dementia, edited by M. Paul Murphy, Roderick A. Corriveau and Donna M. Wilcock. Copyright © 2015 Elsevier B.V. All rights reserved.

PuTmiR: A database for extracting neighboring transcription factors of human microRNAs

PubMed Central

2010-01-01

Background Some of the recent investigations in systems biology have revealed the existence of a complex regulatory network between genes, microRNAs (miRNAs) and transcription factors (TFs). In this paper, we focus on TF to miRNA regulation and provide a novel interface for extracting the list of putative TFs for human miRNAs. A putative TF of an miRNA is considered here as those binding within the close genomic locality of that miRNA with respect to its starting or ending base pair on the chromosome. Recent studies suggest that these putative TFs are possible regulators of those miRNAs. Description The interface is built around two datasets that consist of the exhaustive lists of putative TFs binding respectively in the 10 kb upstream region (USR) and downstream region (DSR) of human miRNAs. A web server, named as PuTmiR, is designed. It provides an option for extracting the putative TFs for human miRNAs, as per the requirement of a user, based on genomic locality, i.e., any upstream or downstream region of interest less than 10 kb. The degree distributions of the number of putative TFs and miRNAs against each other for the 10 kb USR and DSR are analyzed from the data and they explore some interesting results. We also report about the finding of a significant regulatory activity of the YY1 protein over a set of oncomiRNAs related to the colon cancer. Conclusion The interface provided by the PuTmiR web server provides an important resource for analyzing the direct and indirect regulation of human miRNAs. While it is already an established fact that miRNAs are regulated by TFs binding to their USR, this database might possibly help to study whether an miRNA can also be regulated by the TFs binding to their DSR. PMID:20398296

Seroprevalence and Correlates of Hepatitis C Virus Infection in Secondary School Children in Enugu, Nigeria

PubMed Central

Eke, CB; Ogbodo, SO; Ukoha, OM; Muoneke, VU; Ibekwe, RC; Ikefuna, AN

2016-01-01

Background: Although children comprise a small fraction of the burden of hepatitis C virus (HCV) infections, which is a major global health challenge, a significant number of them develop chronic HCV infection and are at risk of its complications. Aim: The aim of the current study was to determine the prevalence and associated factors of HCV infection in school children in Enugu urban. Subjects and Methods: This was a cross-sectional seroepidemiological study involving children aged 10–18 years selected using multistage systematic sampling in Enugu metropolis, Southeast Nigeria. The anti-HCV was tested using a 3rd generation enzyme-linked immunosorbent assay. Data were analyzed using SPSS Version 16.0 with the level of significance set at P < 0.05. Results: Four hundred and twenty children were selected and screened comprising 210 (50.0%) males and females. The seroprevalence of anti-HCV was 4 (1.0%). Three (75%) out of the four positive cases for the anti-HCV were females while one was a male giving a male to female ratio of 0.3–1. Traditional scarifications/tattoos were the putative risk factors observed to be significantly associated with anti-HCV seropositivity. Conclusion: This study has demonstrated an anti-HCV seroprevalence of 1.0% among children aged 10–18 years in Enugu with traditional scarification as the predominant associated risk factor. Proper health education including school health education and promotion of behavioral change among the public on the practice of safe scarifications/tattoos should be encouraged in our setting. PMID:27398246

Distribution of serum total homocysteine and its association with diabetes and cardiovascular risk factors of the insulin resistance syndrome in Mexican American men: the Third National Health and Nutrition Examination Survey.

PubMed

Gillum, Richard

2003-08-05

Few data have been published on the association of variables of the insulin resistance syndrome and serum total homocysteine (tHcy), a putative risk factor for cardiovascular morbidity, in representative samples of total populations or in Hispanic Americans. To describe the distributions of serum tHcy concentration and variables associated with insulin resistance in Mexican American men and to assess their association, data from a cross-sectional survey of a large national sample, the Third National Health and Nutrition Examination Survey were analyzed. Analyses were restricted to Mexican American men aged 40-74 years with data on glycated hemoglobin (%), body mass index (BMI), body fat distribution, HDL cholesterol, fasting serum insulin, serum triglycerides and serum tHcy concentrations. Cumulative distributions of serum tHcy shifted to the right with increasing age. Log serum tHcy was not associated with prevalence of diagnosed diabetes mellitus or glycated hemoglobin percent or other risk factors other than age. Log serum tHcy concentration showed borderline significant (p = 0.049) positive association with fasting serum insulin concentration independent of age and BMI, only in men aged 60-74. No consistent association of tHcy with diabetes prevalence or variables of the insulin resistance syndrome were found in Mexican American men aged 40-74 years. Further research is needed on the associations of serum tHcy concentration with insulin resistance and other components of the insulin resistance syndrome in persons of varying ethnicity.

A Multidimensional Model of Mothers’ Perceptions of Parent Alcohol Socialization and Adolescent Alcohol Misuse

PubMed Central

Ennett, Susan T.; Jackson, Christine; Cole, Veronica T.; Haws, Susan; Foshee, Vangie A.; Reyes, Heathe Luz McNaughton; Burns, Alison Reimuller; Cox, Melissa J.; Cai, Li

2015-01-01

We assessed a multidimensional model of parent alcohol socialization in which key socialization factors were considered simultaneously to identify combinations of factors that increase or decrease risk for development of adolescent alcohol misuse. Of interest was the interplay between putative risk and protective factors, such as whether the typically detrimental effects on youth drinking of parenting practices tolerant of some adolescent alcohol use are mitigated by an effective overall approach to parenting and parental modeling of modest alcohol use. The sample included 1,530 adolescents and their mothers; adolescents’ mean age was 13.0 (SD = .99) at the initial assessment. Latent profile analysis was conducted of mothers’ reports of their attitude toward teen drinking, alcohol-specific parenting practices, parental alcohol use and problem use, and overall approach to parenting. The profiles were used to predict trajectories of adolescent alcohol misuse from early to middle adolescence. Four profiles were identified: two profiles reflected conservative alcohol-specific parenting practices and two reflected alcohol-tolerant practices, all in the context of other attributes. Alcohol misuse accelerated more rapidly from grade 6 through 10 in the two alcohol-tolerant compared with conservative profiles. Results suggest that maternal tolerance of some youth alcohol use, even in the presence of dimensions of an effective parenting style and low parental alcohol use and problem use, is not an effective strategy for reducing risky adolescent alcohol use. PMID:26415053

Car Travel-Related Thrombosis: Fact or Fiction?

PubMed

Lippi, Giuseppe; Favaloro, Emmanuel J

2018-06-01

The condition sometimes referred to as "economy class syndrome," and also known as "traveler's thrombosis," is a distinctive pathological condition characterized by occurrence of venous thromboembolism (VTE) in a patient who has recently experienced a long journey (i.e., ≥ 4 h). Typically, the identified travel is by airplane, but travel with other vehicles, such as trains, trucks, buses, or cars, could potentially qualify as contributing to VTE events. Although the enhanced risk of VTE after long haul flights is now widely acknowledged, albeit potentially overhyped, the risk of venous thrombosis after prolonged travel by other modes of transport, in particular, by cars, is less well appreciated. Current evidence, collected from some epidemiological studies, suggests that if any risk of VTE can be attributed to prolonged and uninterrupted car travels, and we give moderate credibility to such an association, the risk may be similar to that already proven for long haul flights. The risk is especially high in individuals undergoing uninterrupted car journeys lasting 4 hours or longer, in vehicles with a narrow seat-pitch, and in particularly would affect those with pre-existing acquired or inherited prothrombotic conditions. The putative biological mechanisms basically entail venous stasis and edema, which are often compounded by a certain degree of hypercoagulability. When these factors are combined with preexistent prothrombotic conditions, the risk may be substantially magnified. In this perspective, then, 'car thrombosis' may be regarded as a trigger rather than a risk factor for venous thrombosis. Although the current evidence is certainly not solid enough to endorse the use of general chemical prophylaxis for lowering the risk of car-related VTE, a set of possible precautionary measures, with no or very little side effects, may be suggested before planning prolonged car travels, especially for at risk individuals. Thieme Medical Publishers 333 Seventh Avenue, New York, NY 10001, USA.

Prevalence of and risk factors for feline hyperthyroidism among a clinic population in Southern Germany.

PubMed

Köhler, Ines; Ballhausen, Bianca Desiree; Stockhaus, Christian; Hartmann, Katrin; Wehner, Astrid

2016-06-16

Feline hyperthyroidism is a common endocrine disorder in older cats. Previous studies have identified nutritional imbalances, thyroid-disrupting compounds, increasing age and being non-purebred as risk factors but the final trigger remains unknown. The purpose of this prospective study was a) to determine the hospital prevalence of hyperthyroidism in a client-owned cat population in Southern Germany, b) to exploit how frequently hyperthyroidism was diagnosed after the initial clinical suspicion and c) to determine putative intrinsic and extrinsic risk factors from the cats' signalment and a questionnaire analysis, respectively. Total thyroxine (T4) was measured in sera of 495 cats ≥ 8 years. Prevalence was calculated with a 95% confidence interval (95% CI) Association between signalment and hyperthyroidism was analysed by Student's unpaired-t-test, chi-square test and Mann-Whitney U-test. Level of significance was set at 0.05. Multivariate logistic regression model was used to determine extrinsic risk factors. Sixty-one cats were diagnosed with hyperthyroidism leading to a prevalence of 12.3% (95% CI: 9.7-15.5). Older (p < 0.001) female cats (p = 0.019; odds ratio 1.9) were significantly more often affected. Domestic shorthair and domestic longhair cats were more likely hyperthyroid than purebred cats (p = 0.016). In 164 cats hyperthyroidism was considered a differential diagnosis and was verified in 20.1% (33/164). In 2.4% (12/495) cases the elevated T4 was an incidental finding. Hyperthyroid cats were more likely to be fed with moist cat food from aluminum tins (p < 0.013) compared to non-hyperthyroid cats. Older, female non-purebred cats are predisposed to hyperthyroidism which is frequently diagnosed after the initial clinical suspicion leading to a prevalence of 12.3% among the study population. Components of the aluminum tins or the moist food itself or both may play a role in the etiopathogenesis.

Risk Factors for Trimethoprim-Sulfamethoxazole Resistance in Patients with Acute Uncomplicated Cystitis▿

PubMed Central

Colgan, Richard; Johnson, James R.; Kuskowski, Michael; Gupta, Kalpana

2008-01-01

Emerging antimicrobial resistance among uropathogens makes the management of acute uncomplicated cystitis increasingly challenging. Few prospective data are available on the risk factors for resistance to trimethoprim-sulfamethoxazole (TMP-SMX), the drug of choice in most settings. In order to evaluate this, we prospectively enrolled women 18 to 50 years of age presenting to an urban primary care practice with symptoms of cystitis. Potentially eligible women provided a urine sample for culture and completed a questionnaire regarding putative risk factors for TMP-SMX resistance. Escherichia coli isolates were tested for clonal group A (CGA) membership by a fumC-specific PCR. Of 165 women with cystitis symptoms, 103 had a positive urine culture and were eligible for participation. E. coli was the predominant uropathogen (86%). Fifteen (14.6%) women had a TMP-SMX-resistant (TMP-SMXr) organism (all of which were E. coli). Compared with the women who had a TMP-SMX-susceptible organism, women in the TMP-SMXr group were more likely to have traveled (odds ratio [OR], 15.4; 95% confidence interval [CI], 4.4 to 54.3; P < 0.001) and to be Asian (OR, 6.1; 95% CI, 1.0 to 36.4; P = 0.048). CGA was also independently associated with TMP-SMX resistance (OR, 105; 95% CI, 6.3 to 1,777.6; P = 0.001). No association with TMP-SMX resistance was demonstrated for the use of either TMP-SMX or another antibiotic in the past 3 months or with having a child in day care. Among these women with acute uncomplicated cystitis, Asian race and recent travel were independently associated with TMP-SMX resistance. TMP-SMXr isolates were more likely to belong to CGA. Knowledge of these risk factors for TMP-SMX resistance could facilitate the accurate selection of empirical therapy. PMID:18086847

The epidemiology of regional and widespread musculoskeletal pain in rural versus urban settings in those ≥55 years

PubMed Central

Docking, Rachael E; Beasley, Marcus; Steinerowski, Artur; Jones, Elizabeth A; Farmer, Jane; Macfarlane, Gary J

2015-01-01

Objectives: To examine whether the prevalence of regional and chronic widespread pain (CWP) varies with rurality and to determine the characteristics of persons in rural locations in whom pain is found to be in excess. Methods: Participants, aged ≥55 years, from participating general practices in seven different geographical locations in Scotland were sent a postal questionnaire. The 1-month prevalence of 10 regional pain conditions plus CWP was identified using body manikins. Differences in the prevalence of pain with differing rurality were examined using Chi2 test for trend. Thereafter, among the rural population, the relationships between pain and putative risk factors were examined using Poisson regression. Thus, results are described as risk ratios. Results: There was some evidence to suggest that the prevalence of CWP increased with increasing rurality, although the magnitude of this was slight. No large or significant differences were observed with any regional pain conditions. Factors associated with the reporting of CWP included poor general health, feeling downhearted most of the time and selected measures of social contact. Factors independently associated with CWP included female gender (risk ratio: 1.24; 95% confidence interval (CI): 0.997–1.55), poor self-rated health (risk ratio: 3.50; 95% CI: 1.92–6.39) and low mood (risk ratio: 1.54; 95% CI: 1.07–2.20). Also, having fewer than 10 people to turn to in a crisis was associated with a decrease in the risk of CWP – risk ratio: 0.68 (95% CI: 0.50–0.93) and 0.78 (95% CI: 0.60–1.02) for those with 5–10 and <5 people, respectively. Conclusions: This study provides no evidence that the prevalence of regional musculoskeletal pain is increased in rural settings, although there is some evidence of a modest increase in CWP. Risk factors for CWP are similar to those seen in the urban setting, including markers of general health, mental health and also aspects of social contact. It may be, however, that social networks are more difficult to maintain in rural settings, and clinicians should be aware of the negative effect of perceived social isolation on pain in rural areas. PMID:26516563

The association between type 2 diabetes mellitus and women cancer: the epidemiological evidences and putative mechanisms.

PubMed

Joung, Kyong Hye; Jeong, Jae-Wook; Ku, Bon Jeong

2015-01-01

Type 2 diabetes mellitus (T2DM), a chronic disease increasing rapidly worldwide, is well established as an important risk factor for various types of cancer. Although many factors impact the development of T2DM and cancer including sex, age, ethnicity, obesity, diet, physical activity levels, and environmental exposure, many epidemiological and experimental studies are gradually contributing to knowledge regarding the interrelationship between DM and cancer. The insulin resistance, hyperinsulinemia, and chronic inflammation associated with diabetes mellitus are all associated strongly with cancer. The changes in bioavailable ovarian steroid hormone that occur in diabetes mellitus (the increasing levels of estrogen and androgen and the decreasing level of progesterone) are also considered potentially carcinogenic conditions for the breast, endometrium, and ovaries in women. In addition, the interaction among insulin, insulin-like growth factors (IGFs), and ovarian steroid hormones, such as estrogen and progesterone, could act synergistically during cancer development. Here, we review the cancer-related mechanisms in T2DM, the epidemiological evidence linking T2DM and cancers in women, and the role of antidiabetic medication in these cancers.

The Association between Type 2 Diabetes Mellitus and Women Cancer: The Epidemiological Evidences and Putative Mechanisms

PubMed Central

2015-01-01

Type 2 diabetes mellitus (T2DM), a chronic disease increasing rapidly worldwide, is well established as an important risk factor for various types of cancer. Although many factors impact the development of T2DM and cancer including sex, age, ethnicity, obesity, diet, physical activity levels, and environmental exposure, many epidemiological and experimental studies are gradually contributing to knowledge regarding the interrelationship between DM and cancer. The insulin resistance, hyperinsulinemia, and chronic inflammation associated with diabetes mellitus are all associated strongly with cancer. The changes in bioavailable ovarian steroid hormone that occur in diabetes mellitus (the increasing levels of estrogen and androgen and the decreasing level of progesterone) are also considered potentially carcinogenic conditions for the breast, endometrium, and ovaries in women. In addition, the interaction among insulin, insulin-like growth factors (IGFs), and ovarian steroid hormones, such as estrogen and progesterone, could act synergistically during cancer development. Here, we review the cancer-related mechanisms in T2DM, the epidemiological evidence linking T2DM and cancers in women, and the role of antidiabetic medication in these cancers. PMID:25866823

The nature of schizotypy among multigenerational multiplex schizophrenia families

PubMed Central

Tarbox, Sarah I.; Almasy, Laura; Gur, Raquel E.; Nimgaonkar, Vishwajit L.; Pogue-Geile, Michael F.

2012-01-01

Identification of endophenotypes (Gottesman & Gould, 2003; Gottesman & Shields, 1972) that genetically correlate with schizophrenia and are genetically homogeneous is an important strategy for detecting genes that affect schizophrenia risk. Symptoms of schizotypy may familially correlate with schizophrenia; however, there are critical limitations of the current literature concerning this association. The present study examined the genetic architecture and genetic associations between schizotypy and schizophrenia among multigenerational, multiplex schizophrenia families. Genetic schizotypy factor scales were developed that genetically correlated with schizophrenia, although some relations were unexpected in direction suggesting minimization of “psychotic-like” symptoms. These genetic schizotypy factor scales did not genetically correlate with major depressive disorder or substance dependence indicating specificity to schizophrenia. The results highlight the possibility of significant response bias in schizophrenia families, particularly among close relatives, and suggest an important consideration when acquiring self-report information. This is a topic that deserves future study as the origins of this putative bias in relatives are unclear. In addition, the results support the identification of genetic schizotypy factors as a promising technique for maximizing genetic correlation of endophenotypes with schizophrenia. PMID:22288909

Putative lung adenocarcinoma with epidermal growth factor receptor mutation presenting as carcinoma of unknown primary site

PubMed Central

Yamasaki, Masahiro; Funaishi, Kunihiko; Saito, Naomi; Sakano, Ayaka; Fujihara, Megumu; Daido, Wakako; Ishiyama, Sayaka; Deguchi, Naoko; Taniwaki, Masaya; Ohashi, Nobuyuki; Hattori, Noboru

2018-01-01

Abstract Rationale: Only a few cases of putative lung adenocarcinoma presenting as carcinoma of unknown primary site (CUP) with epidermal growth factor receptor (EGFR) mutation have been reported, and the efficacy of EGFR-tyrosine kinase inhibitors (TKIs) for these cases is unclear. Patient concerns and diagnoses: A 67-year-old man complained of paresis of the right lower extremity, dysarthria, and memory disturbance. Computed tomography and magnetic resonance imaging showed multiple brain tumors with brain edema and swelling of the left supraclavicular, mediastinal, and upper abdominal lymph nodes. Moreover, a metastatic duodenal tumor was detected via upper gastrointestinal endoscopy examination. The biopsy specimen of the lesion was examined and was diagnosed as adenocarcinoma with CK7 and TTF-1 positivity. Finally, the case was diagnosed as EGFR mutation-positive putative lung adenocarcinoma presenting as CUP. Interventions and outcomes: Oral erlotinib, an EGFR-TKI, was administered at 150 mg daily. Five weeks later, the brain lesions and several swollen lymph nodes showed marked improvement, and the symptoms of the patient also improved. Three months later, the duodenal lesion was undetected on upper gastrointestinal endoscopy. After an 8-month follow-up, the patient was well with no disease progression. Lessons: Putative lung adenocarcinoma presenting as CUP may have EGFR mutation, and EGFR-TKI therapy may be effective for such malignancy. PMID:29443782

Epidemiology and risk factors of peri-implantitis: A systematic review.

PubMed

Dreyer, H; Grischke, J; Tiede, C; Eberhard, J; Schweitzer, A; Toikkanen, S E; Glöckner, S; Krause, G; Stiesch, M

2018-06-07

The purpose of this systematic review and meta-analysis was to assess the prevalence, incidence and risk factors of peri-implantitis in the current literature. An electronic search was performed to identify publications from January 1980 until March 2016 on 9 databases. The prevalence and incidence of peri-implantitis were assessed in different subgroups of patients and the prevalences were adjusted for sample size (SSA) of studies. For 12 of 111 identified putative risk factors and risk indicators, forest plots were created. Heterogeneity analysis and random effect meta-analysis were performed for selected potential risk factors of peri-implantitis. The search retrieved 8357 potentially relevant studies. Fifty-seven studies were included in the systematic review. Overall, the prevalence of peri-implantitis on implant level ranged from 1.1% to 85.0% and the incidence from 0.4% within 3 years, to 43.9% within 5 years, respectively. The median prevalence of peri-implantitis was 9.0% (SSA 10.9%) for regular participants of a prophylaxis program, 18.8% (SSA 8.8%) for patients without regular preventive maintenance, 11.0% (SSA 7.4%) for non-smokers, 7.0% (SSA 7.0%) among patients representing the general population, 9.6% (SSA 9.6%) for patients provided with fixed partial dentures, 14.3% (SSA 9.8%) for subjects with a history of periodontitis, 26.0% (SSA 28.8%) for patients with implant function time ≥5 years and 21.2% (SSA 38.4%) for ≥10 years. On a medium and medium-high level of evidence, smoking (effect summary OR 1.7, 95% CI 1.25-2.3), diabetes mellitus (effect summary OR 2.5; 95% CI 1.4-4.5), lack of prophylaxis and history or presence of periodontitis were identified as risk factors of peri-implantitis. There is medium-high evidence that patient's age (effect summary OR 1.0, 95% CI 0.87-1.16), gender and maxillary implants are not related to peri-implantitis. Currently, there is no convincing or low evidence available that identifies osteoporosis, absence of keratinized mucosa, implant surface characteristics or edentulism as risk factors for peri-implantitis. Based on the data analyzed in this systematic review, insufficient high-quality evidence is available to the research question. Future studies of prospective, randomized and controlled type including sufficient sample sizes are needed. The application of consistent diagnostic criteria (eg, according to the latest definition by the European Workshop on Periodontology) is particularly important. Very few studies evaluated the incidence of peri-implantitis; however, this study design may contribute to examine further the potential risk factors. © 2018 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

Association of levels of antibodies against citrullinated cyclic peptides and citrullinated α-enolase in chronic and aggressive periodontitis as a risk factor of Rheumatoid arthritis: a case control study.

PubMed

Reichert, Stefan; Schlumberger, Wolfgang; Dähnrich, Cornelia; Hornig, Nora; Altermann, Wolfgang; Schaller, Hans-Günter; Schulz, Susanne

2015-08-29

Periodontal disease could be a risk factor for rheumatoid arthritis (RA). It is assumed that the bacterial strain Porphyromonas gingivalis mediates citrullination of host peptides and thereby the generation of RA-associated autoantibodies in genetically predisposed individuals. For that reason non-RA individuals who suffered from generalized aggressive (GAgP, N = 51) and generalized chronic periodontitis (GChP, N = 50) were investigated regarding the occurrence of antibodies against citrullinated cyclic peptides (anti-CCP) and citrullinated α-enolase peptide-1 (anti-CEP-1) in comparison to non-RA non-periodontitis controls (N = 89). Furthermore, putative associations between infections with five periodontopathic bacteria or expression of certain human leucocyte antigens (HLA) to these autoantibodies were investigated. The presence of anti-CCP and anti-CEP-1 in plasma samples was conducted with enzyme linked immunosorbent assay. Subgingival plaque specimens were taken from the deepest pocket of each quadrant and pooled. For detection of DNA of five periodontopathic bacteria PCR with sequence specific oligonucleotides was carried out. Low resolution HLA typing was carried out with PCR with sequence specific primers. Differences between patients and controls were assessed using Chi square test with Yates correction or Fisher`s exact test if the expected number n in one group was <5. Two patients with GAgP (3.9%), no patient with GChP and two controls (2.2%, pFisher = 0.662) were positive for anti-CEP-1 whereas no study participant was anti-CCP positive. Individuals with P. gingivalis were slightly more often anti-CEP-1 positive in comparison to individuals without P. gingivalis (3.2 vs. 1.1%, pFisher = 0.366). Carrier of HLA-DQB1*06 or the HLA combination DRB1*13; DRB3*; DQB1*06 were slightly more anti-CEP-1 positive (6.1 and 4.3%) than no carriers (0.7 and 0%, pFisher 0.053). GAgP and GChP and the presence of periodontopathic bacteria are not associated with an increased risk for occurrence of anti-CCP and anti-CEP-1 autoantibodies. The putative relationship between periodontitis and RA should be investigated in further studies.

Pathogenesis of Germline and Somatic NF1 Rearrangements

DTIC Science & Technology

1998-10-01

skin and skeletal features consistent with a connective tissue disorder and neoplasms at a young age (7, 8, 9, 10) To test this hypothesis, patients need... myeloproliferative phenotype, these data suggest a putative role of modifying gene(s) on chromosome 17 that may contribute to the development of acute...risk for certain types of neoplasms , NF1 subjects also have an increased risk of developing a second malignancy. The risk for NF l patients is 8-20

Comparative analyses of putative toxin gene homologs from an Old World viper, Daboia russelii

PubMed Central

Krishnan, Neeraja M.

2017-01-01

Availability of snake genome sequences has opened up exciting areas of research on comparative genomics and gene diversity. One of the challenges in studying snake genomes is the acquisition of biological material from live animals, especially from the venomous ones, making the process cumbersome and time-consuming. Here, we report comparative sequence analyses of putative toxin gene homologs from Russell’s viper (Daboia russelii) using whole-genome sequencing data obtained from shed skin. When compared with the major venom proteins in Russell’s viper studied previously, we found 45–100% sequence similarity between the venom proteins and their putative homologs in the skin. Additionally, comparative analyses of 20 putative toxin gene family homologs provided evidence of unique sequence motifs in nerve growth factor (NGF), platelet derived growth factor (PDGF), Kunitz/Bovine pancreatic trypsin inhibitor (Kunitz BPTI), cysteine-rich secretory proteins, antigen 5, andpathogenesis-related1 proteins (CAP) and cysteine-rich secretory protein (CRISP). In those derived proteins, we identified V11 and T35 in the NGF domain; F23 and A29 in the PDGF domain; N69, K2 and A5 in the CAP domain; and Q17 in the CRISP domain to be responsible for differences in the largest pockets across the protein domain structures in crotalines, viperines and elapids from the in silico structure-based analysis. Similarly, residues F10, Y11 and E20 appear to play an important role in the protein structures across the kunitz protein domain of viperids and elapids. Our study highlights the usefulness of shed skin in obtaining good quality high-molecular weight DNA for comparative genomic studies, and provides evidence towards the unique features and evolution of putative venom gene homologs in vipers. PMID:29230357

EGRINs (Environmental Gene Regulatory Influence Networks) in Rice That Function in the Response to Water Deficit, High Temperature, and Agricultural Environments[OPEN

PubMed Central

Hafemeister, Christoph; Nicotra, Adrienne B.; Jagadish, S.V. Krishna; Bonneau, Richard; Purugganan, Michael

2016-01-01

Environmental gene regulatory influence networks (EGRINs) coordinate the timing and rate of gene expression in response to environmental signals. EGRINs encompass many layers of regulation, which culminate in changes in accumulated transcript levels. Here, we inferred EGRINs for the response of five tropical Asian rice (Oryza sativa) cultivars to high temperatures, water deficit, and agricultural field conditions by systematically integrating time-series transcriptome data, patterns of nucleosome-free chromatin, and the occurrence of known cis-regulatory elements. First, we identified 5447 putative target genes for 445 transcription factors (TFs) by connecting TFs with genes harboring known cis-regulatory motifs in nucleosome-free regions proximal to their transcriptional start sites. We then used network component analysis to estimate the regulatory activity for each TF based on the expression of its putative target genes. Finally, we inferred an EGRIN using the estimated transcription factor activity (TFA) as the regulator. The EGRINs include regulatory interactions between 4052 target genes regulated by 113 TFs. We resolved distinct regulatory roles for members of the heat shock factor family, including a putative regulatory connection between abiotic stress and the circadian clock. TFA estimation using network component analysis is an effective way of incorporating multiple genome-scale measurements into network inference. PMID:27655842

Evaluation of stool microbiota signatures in two cohorts of Asian (Singapore and Indonesia) newborns at risk of atopy

PubMed Central

2011-01-01

Background Studies have suggested that demographic and lifestyle factors could shape the composition of fecal microbiota in early life. This study evaluated infant stool microbiota signatures in two Asian populations, Singapore (n = 42) and Indonesia (n = 32) with contrasting socioeconomic development, and examined the putative influences of demographic factors on these human fecal associated bacterial signatures. Results Longitudinal analysis showed associations of geographical origin with Clostridium leptum, Atopobium and Bifidobacterium groups. Mode of delivery had the largest effect on stool microbiota signatures influencing the abundance of four bacterial groups. Significantly higher abundance of bacterial members belonging to the Bacteroides-Prevotella, Bifidobacterium and Atopobium groups, but lower abundance of Lactobacilli-Enterococci group members, were observed in vaginal delivered compared to caesarean delivered infants. Demographic factors influencing the structure of infants stool microbiota during the first year of life included breastfeeding, age of weaning, sibship size and exposure to antibiotics. Conclusions Differences in stool microbiota signatures were observed in relation to various demographic factors. These features may confound studies relating to the association of the structure of fecal microbiota and the predisposition to human modern disease. PMID:21875444

Putative Brain Networks Underlying Repetitive Negative Thinking and Comorbid Internalizing Problems in Autism

PubMed Central

Burrows, Catherine A.; Timpano, Kiara R.; Uddin, Lucina Q.

2016-01-01

Many high-functioning individuals with autism spectrum disorder (ASD) also experience depression and anxiety, yet little is known about mechanisms underlying this comorbidity. Repetitive negative thinking (RNT) about self-referential information is a transdiagnostic cognitive vulnerability factor that may account for the relationship between these two classes of symptoms. We propose a model where self-referential processing and cognitive inflexibility interact to increase risk for RNT, leading to internalizing problems in ASD. Examination of interactions within and between two well-characterized large-scale brain networks, the default mode network and the salience network, may provide insights into neurobiological mechanisms underlying RNT in ASD. We summarize previous literature supporting this model, emphasizing moving towards understanding RNT as a factor accounting for the high rates of internalizing problems in ASD. Future research avenues include understanding heterogeneity in clinical presentation, and promise for identifying and treating cognitive flexibility and RNT to reduce comorbid internalizing problems in ASD. PMID:28603665

Let's think in alkaline phosphatase at heart function.

PubMed

Martins, Maria João; Azevedo, Isabel

2010-10-08

In their recent paper, Cheung et al [B.M. Cheung, K.L. Ong, L.Y. Wong, Elevated serum alkaline phosphatase and peripheral arterial disease in the United States National Health and Nutrition Examination Survey 1999-2004. Int J Cardiol 2008 (Electronic publication ahead of print)] described a significant association between serum alkaline phosphatase levels and low ankle-brachial blood pressure index, a risk factor for cardiovascular pathology. We had verified that alkaline phosphatase is present at the rat heart, showing a distribution compatible with cardiomyocyte sarcoplasmic reticulum. Moreover, several drugs with cardiac effect were shown to interfere with heart alkaline phosphatase activity. We therefore propose that alkaline phosphatase may be a local regulator at heart function and a putative target for therapeutic interventions. Copyright © 2009 Elsevier Ireland Ltd. All rights reserved.

Xerostomia and medications among 32-year-olds

PubMed Central

THOMSON, WILLIAM MURRAY; POULTON, RICHIE; BROADBENT, JONATHAN MARK; AL-KUBAISY, SHAIMA

2008-01-01

Objective To describe the prevalence and associations of xerostomia among adults in their early thirties, with particular attention to medication exposure as a putative risk factor. Material and Methods The prevalence and associations of xerostomia were investigated among 32-year-old participants in a long-standing prospective cohort study. Some 950 individuals were assessed at ages 26 and 32 years, with medications being recorded on both occasions. Results The prevalence of xerostomia was 10.0% (with no apparent gender difference), and was significantly higher among those taking antidepressants (odds ratio =4.7), iron supplements (OR =4.1) or narcotic analgesics (OR =2.4). Those taking antidepressants at both ages 26 and 32 years had 22 times the odds of reporting xerostomia. Conclusion Xerostomia may be a problem for a sizeable minority of young adults. PMID:16829502

Prevalence of Latent Tuberculosis Infection and Associated Risk Factors Among 1557 Nursing Students in a Context of Low Endemicity

PubMed Central

Lamberti, Monica; Uccello, Rossella; Monaco, Maria Grazia Lourdes; Muoio, Mariarosaria; Sannolo, Nicola; Arena, Paola; Mazzarella, Gennaro; Arnese, Antonio; La Cerra, Giuseppe

2015-01-01

Introduction: The risk of tuberculosis (TBC) in nurses is related to its incidence in the general population. Nursing students involved in clinical training could be exposed to occupational risks similar to those of healthcare workers (HCWs). To better understand the epidemiology of nosocomial TBC among nurses in a context of low endemicity, we recruited a cohort of young nursing trainees at the Second University of Naples. Methods: A screening programme for LTBI in nursing students was conducted between January 2012 and December 2013, at the Second University of Naples, with clinical evaluations, tuberculin skin test (TST) and, in positive TST student, the interferon-g release assays (IGRA). Putative risk factors for LTBI were assessed by a standardized questionnaire. Results: 1577 nursing students attending the Second University of Naples have been submitted to screening programme for TBC. 1575 have performed TST as first level test and 2 Quantiferon test (QFT). 19 students were TST positive and continued the diagnostic workup practicing QFT, that was positive in 1 student. Of the 2 subjects that have practiced QFT as first level test only 1 was positive. In 2 students positive to QFT test we formulated the diagnosis of LTBI by clinical and radiographic results. Conclusion: The prevalence of LTBI among nursing students in our study resulted very low. In countries with a low incidence of TBC, the screening programs of healthcare students can be useful for the early identification and treatment of the sporadic cases of LTBI. PMID:25852786

Environmental Conditions Outweigh Geographical Contiguity in Determining the Similarity of nifH-Harboring Microbial Communities in Sediments of Two Disconnected Marginal Seas

PubMed Central

Zhou, Haixia; Dang, Hongyue; Klotz, Martin G.

2016-01-01

Ecological evidence suggests that heterotrophic diazotrophs fueled by organic carbon respiration in sediments play an important role in marine nitrogen fixation. However, fundamental knowledge about the identities, abundance, diversity, biogeography, and controlling environmental factors of nitrogen-fixing communities in open ocean sediments is still elusive. Surprisingly, little is known also about nitrogen-fixing communities in sediments of the more research-accessible marginal seas. Here we report on an investigation of the environmental geochemistry and putative diazotrophic microbiota in the sediments of Bohai Sea, an eutrophic marginal sea of the western Pacific Ocean. Diverse and abundant nifH gene sequences were identified and sulfate-reducing bacteria (SRB) were found to be the dominant putative nitrogen-fixing microbes. Community statistical analyses suggested bottom water temperature, bottom water chlorophyll a content (or the covarying turbidity) and sediment porewater Eh (or the covarying pH) as the most significant environmental factors controlling the structure and spatial distribution of the putative diazotrophic communities, while sediment Hg content, sulfide content, and porewater SiO32−-Si content were identified as the key environmental factors correlated positively with the nifH gene abundance in Bohai Sea sediments. Comparative analyses between the Bohai Sea and the northern South China Sea (nSCS) identified a significant composition difference of the putative diazotrophic communities in sediments between the shallow-water (estuarine and nearshore) and deep-water (offshore and deep-sea) environments, and sediment porewater dissolved oxygen content, water depth and in situ temperature as the key environmental factors tentatively controlling the species composition, community structure, and spatial distribution of the marginal sea sediment nifH-harboring microbiota. This confirms the ecophysiological specialization and niche differentiation between the shallow-water and deep-water sediment diazotrophic communities and suggests that the in situ physical and geochemical conditions play a more important role than geographical contiguity in determining the community similarity of the diazotrophic microbiota in marginal sea sediments. PMID:27489551

Vitamin D in the Spectrum of Prediabetes and Cardiovascular Autonomic Dysfunction.

PubMed

Dimova, Rumyana; Tankova, Tsvetalina; Chakarova, Nevena

2017-09-01

Vitamin D is a fat-soluble secosteroid hormone with pleiotropic effects. 1,25-Dihydroxyvitamin D coordinates the biosynthesis of neurotransmitters in the central nervous system, which regulate cardiovascular autonomic function and may explain its putative role in the development of cardiovascular autonomic neuropathy (CAN). CAN is an independent risk factor for mortality in patients with diabetes and prediabetes and is associated with an increased risk of developing type 2 diabetes and cardiovascular disease. Accumulating data indicate the presence of peripheral nerve injury at these early stages of dysglycemia and its multifactorial pathogenesis. Prediabetes is associated with vitamin D insufficiency. Vitamin D is proposed to prevent the progression of glucose intolerance. The putative underlying mechanisms include maintenance of the intracellular calcium concentration, direct stimulation of insulin receptor expression, and enhancement of the insulin response to glucose transporters. Vitamin D exerts a protective effect on peripheral nerve fibers by decreasing the demyelination process and inducing axonal regeneration. The effects of vitamin D supplementation on glucose tolerance and related autonomic nerve dysfunction have been a recent focus of scientific interest. Although well-designed observational studies are available, the causative relation between vitamin D deficiency, glucose intolerance, and CAN is still debatable. One reason might be that interventional studies are unpersuasive with regard to the beneficial clinical effects of vitamin D supplementation. Because of its favorable side effect profile, vitamin D supplementation might represent an attractive therapeutic option for treating the pandemic prevalence of prediabetes and vitamin D deficiency. Vitamin D supplementation can improve glucose tolerance and cardiovascular autonomic function and can thus reduce cardiovascular mortality among subjects with different stages of glucose intolerance and autonomic dysfunction. However, more patient-centered trials on the use of vitamin D supplementation in different conditions are needed. © 2017 American Society for Nutrition.

The Role of the EGF Receptor First Intron in Its Regulation in Breast Canceer.

DTIC Science & Technology

1997-08-01

of EGFR, to malignantly transform mammary glands in transgenic mice (46). Future work could determine if these putative oncogene factor binding sites...general transcription factors, and the use or overuse of one promoter could monopolize the abundance of these transcription factors within a cell. The ideal

Candidate genetic modifiers for breast and ovarian cancer risk in BRCA1 and BRCA2 mutation carriers

PubMed Central

Peterlongo, Paolo; Chang-Claude, Jenny; Moysich, Kirsten B.; Rudolph, Anja; Schmutzler, Rita K.; Simard, Jacques; Soucy, Penny; Eeles, Rosalind A.; Easton, Douglas F.; Hamann, Ute; Wilkening, Stefan; Chen, Bowang; Rookus, Matti A.; Schmidt, Marjanka K; van der Baan, Frederieke H.; Spurdle, Amanda B.; Walker, Logan C.; Lose, Felicity; Maia, Ana-Teresa; Montagna, Marco; Matricardi, Laura; Lubinski, Jan; Jakubowska, Anna; Gómez Garcia, Encarna B.; Olopade, Olufunmilayo I.; Nussbaum, Robert L.; Nathanson, Katherine L.; Domchek, Susan M.; Rebbeck, Timothy R.; Arun, Banu K.; Karlan, Beth Y.; Orsulic, Sandra; Lester, Jenny; Chung, Wendy K.; Miron, Alex; Southey, Melissa C.; Goldgar, David E.; Buys, Saundra S.; Janavicius, Ramunas; Dorfling, Cecilia M.; van Rensburg, Elizabeth J.; Ding, Yuan Chun; Neuhausen, Susan L.; Hansen, Thomas V. O.; Gerdes, Anne-Marie; Ejlertsen, Bent; Jønson, Lars; Osorio, Ana; Martínez-Bouzas, Cristina; Benitez, Javier; Conway, Edye E.; Blazer, Kathleen R.; Weitzel, Jeffrey N.; Manoukian, Siranoush; Peissel, Bernard; Zaffaroni, Daniela; Scuvera, Giulietta; Barile, Monica; Ficarazzi, Filomena; Mariette, Frederique; Fortuzzi, Stefano; Viel, Alessandra; Giannini, Giuseppe; Papi, Laura; Martayan, Aline; Tibiletti, Maria Grazia; Radice, Paolo; Vratimos, Athanassios; Fostira, Florentia; Garber, Judy E.; Donaldson, Alan; Brewer, Carole; Foo, Claire; Evans, D. Gareth R.; Frost, Debra; Eccles, Diana; Brady, Angela; Cook, Jackie; Tischkowitz, Marc; Adlard, Julian; Barwell, Julian; Walker, Lisa; Izatt, Louise; Side, Lucy E.; Kennedy, M. John; Rogers, Mark T.; Porteous, Mary E.; Morrison, Patrick J.; Platte, Radka; Davidson, Rosemarie; Hodgson, Shirley V.; Ellis, Steve; Cole, Trevor; Godwin, Andrew K.; Claes, Kathleen; Van Maerken, Tom; Meindl, Alfons; Gehrig, Andrea; Sutter, Christian; Engel, Christoph; Niederacher, Dieter; Steinemann, Doris; Plendl, Hansjoerg; Kast, Karin; Rhiem, Kerstin; Ditsch, Nina; Arnold, Norbert; Varon-Mateeva, Raymonda; Wappenschmidt, Barbara; Wang-Gohrke, Shan; Bressac-de Paillerets, Brigitte; Buecher, Bruno; Delnatte, Capucine; Houdayer, Claude; Stoppa-Lyonnet, Dominique; Damiola, Francesca; Coupier, Isabelle; Barjhoux, Laure; Venat-Bouvet, Laurence; Golmard, Lisa; Boutry-Kryza, Nadia; Sinilnikova, Olga M.; Caron, Olivier; Pujol, Pascal; Mazoyer, Sylvie; Belotti, Muriel; Piedmonte, Marion; Friedlander, Michael L.; Rodriguez, Gustavo C.; Copeland, Larry J; de la Hoya, Miguel; Segura, Pedro Perez; Nevanlinna, Heli; Aittomäki, Kristiina; van Os, Theo A.M.; Meijers-Heijboer, Hanne E.J.; van der Hout, Annemarie H.; Vreeswijk, Maaike P.G.; Hoogerbrugge, Nicoline; Ausems, Margreet G.E.M.; van Doorn, Helena C.; Collée, J. Margriet; Olah, Edith; Diez, Orland; Blanco, Ignacio; Lazaro, Conxi; Brunet, Joan; Feliubadalo, Lidia; Cybulski, Cezary; Gronwald, Jacek; Durda, Katarzyna; Jaworska-Bieniek, Katarzyna; Sukiennicki, Grzegorz; Arason, Adalgeir; Chiquette, Jocelyne; Teixeira, Manuel R.; Olswold, Curtis; Couch, Fergus J.; Lindor, Noralane M.; Wang, Xianshu; Szabo, Csilla I.; Offit, Kenneth; Corines, Marina; Jacobs, Lauren; Robson, Mark E.; Zhang, Liying; Joseph, Vijai; Berger, Andreas; Singer, Christian F.; Rappaport, Christine; Kaulich, Daphne Geschwantler; Pfeiler, Georg; Tea, Muy-Kheng M.; Phelan, Catherine M.; Greene, Mark H.; Mai, Phuong L.; Rennert, Gad; Mulligan, Anna Marie; Glendon, Gord; Tchatchou, Sandrine; Andrulis, Irene L.; Toland, Amanda Ewart; Bojesen, Anders; Pedersen, Inge Sokilde; Thomassen, Mads; Jensen, Uffe Birk; Laitman, Yael; Rantala, Johanna; von Wachenfeldt, Anna; Ehrencrona, Hans; Askmalm, Marie Stenmark; Borg, Åke; Kuchenbaecker, Karoline B.; McGuffog, Lesley; Barrowdale, Daniel; Healey, Sue; Lee, Andrew; Pharoah, Paul D.P.; Chenevix-Trench, Georgia; Antoniou, Antonis C.; Friedman, Eitan

2014-01-01

Background BRCA1 and BRCA2 mutation carriers are at substantially increased risk for developing breast and ovarian cancer. The incomplete penetrance coupled with the variable age at diagnosis in carriers of the same mutation suggests the existence of genetic and non-genetic modifying factors. In this study we evaluated the putative role of variants in many candidate modifier genes. Methods Genotyping data from 15,252 BRCA1 and 8,211 BRCA2 mutation carriers, for known variants (n=3,248) located within or around 445 candidate genes, were available through the iCOGS custom-designed array. Breast and ovarian cancer association analysis was performed within a retrospective cohort approach. Results The observed p-values of association ranged between 0.005-1.000. None of the variants was significantly associated with breast or ovarian cancer risk in either BRCA1 or BRCA2 mutation carriers, after multiple testing adjustments. Conclusion There is little evidence that any of the evaluated candidate variants act as modifiers of breast and/or ovarian cancer risk in BRCA1 or BRCA2 mutation carriers. Impact Genome-wide association studies have been more successful at identifying genetic modifiers of BRCA1/2 penetrance than candidate gene studies. PMID:25336561

DNA methylation as a mediator of HLA-DRB1*15:01 and a protective variant in multiple sclerosis.

PubMed

Kular, Lara; Liu, Yun; Ruhrmann, Sabrina; Zheleznyakova, Galina; Marabita, Francesco; Gomez-Cabrero, David; James, Tojo; Ewing, Ewoud; Lindén, Magdalena; Górnikiewicz, Bartosz; Aeinehband, Shahin; Stridh, Pernilla; Link, Jenny; Andlauer, Till F M; Gasperi, Christiane; Wiendl, Heinz; Zipp, Frauke; Gold, Ralf; Tackenberg, Björn; Weber, Frank; Hemmer, Bernhard; Strauch, Konstantin; Heilmann-Heimbach, Stefanie; Rawal, Rajesh; Schminke, Ulf; Schmidt, Carsten O; Kacprowski, Tim; Franke, Andre; Laudes, Matthias; Dilthey, Alexander T; Celius, Elisabeth G; Søndergaard, Helle B; Tegnér, Jesper; Harbo, Hanne F; Oturai, Annette B; Olafsson, Sigurgeir; Eggertsson, Hannes P; Halldorsson, Bjarni V; Hjaltason, Haukur; Olafsson, Elias; Jonsdottir, Ingileif; Stefansson, Kari; Olsson, Tomas; Piehl, Fredrik; Ekström, Tomas J; Kockum, Ingrid; Feinberg, Andrew P; Jagodic, Maja

2018-06-19

The human leukocyte antigen (HLA) haplotype DRB1*15:01 is the major risk factor for multiple sclerosis (MS). Here, we find that DRB1*15:01 is hypomethylated and predominantly expressed in monocytes among carriers of DRB1*15:01. A differentially methylated region (DMR) encompassing HLA-DRB1 exon 2 is particularly affected and displays methylation-sensitive regulatory properties in vitro. Causal inference and Mendelian randomization provide evidence that HLA variants mediate risk for MS via changes in the HLA-DRB1 DMR that modify HLA-DRB1 expression. Meta-analysis of 14,259 cases and 171,347 controls confirms that these variants confer risk from DRB1*15:01 and also identifies a protective variant (rs9267649, p < 3.32 × 10 -8 , odds ratio = 0.86) after conditioning for all MS-associated variants in the region. rs9267649 is associated with increased DNA methylation at the HLA-DRB1 DMR and reduced expression of HLA-DRB1, suggesting a modulation of the DRB1*15:01 effect. Our integrative approach provides insights into the molecular mechanisms of MS susceptibility and suggests putative therapeutic strategies targeting a methylation-mediated regulation of the major risk gene.

Association between NFKB1 -94 insertion/deletion ATTG polymorphism and risk of intracranial aneurysm.

PubMed

Sima, Xiutian; Xu, Jianguo; Li, Jin; You, Chao

2013-08-01

Growing evidence indicates that vascular inflammation is a common phenomenon in the pathogenesis of intracranial aneurysms (IAs). Nuclear factor kappa B is a key molecule that is involved in the vascular inflammation of IA. We hypothesized that an insertion/deletion (ins/del) ATTG polymorphism located between two putative key promoter regulatory elements in the NFKB1 gene may be related to the risk of IA. We performed a case-control study, including 164 patients with IA and 525 healthy controls in a Chinese population using a polymerase chain reaction-polyacrylamide gel electrophoresis assay. A significantly decreased risk of IA was observed in the ATTG1/ATTG2 and ATTG2/ATTG2 genotypes compared with the ATTG1/ATTG1 genotype (ATTG1/ATTG2 vs. ATTG1/ATTG1: odds ratio [OR]=0.58, 95% confidence interval [95% CI]=0.39-0.87, p=0.007; ATTG2/ATTG2 vs. ATTG1/ATTG1: OR=0.12, 95% CI=0.06-0.23, p<0.001), and also the ATTG2 allele (ATTG2 vs. ATTG1: OR=0.41, 95% CI=0.32-0.54, p<0.001). These findings suggest that the NFKB1 -94ins/del ATTG polymorphism may contribute to the risk of IA.

The Relation Between Adolescent Social Competence and Young Adult Delinquency and Educational Attainment Among At-Risk Youth: The Mediating Role of Peer Delinquency

PubMed Central

Stepp, Stephanie D; Pardini, Dustin A; Loeber, Rolf; Morris, Nancy A

2015-01-01

Objective We examined trajectories of adolescent social competence as a resilience factor among at-risk youth. To examine potential mechanisms of this resilience process, we investigated the putative mediating effect of peer delinquency on the relation between adolescent social competence and young adult delinquency seriousness and educational attainment. Method Participants (n = 257) were screened to be at risk for antisocial behaviour at age 13 years. Data were derived from an ongoing longitudinal study of the development of antisocial and delinquent behaviour among inner-city boys, the Pittsburgh Youth Study. We used data collected from participants when aged 13 years until they were aged 25.5 years for our study. Results Results indicated that boys with high levels of social competence decreased their involvement with deviant peers throughout adolescence, which, in turn, predicted less serious forms of delinquency in early adulthood. Social competence had a direct effect on educational attainment in early adulthood, as boys who developed social competencies in adolescence went further in school irrespective of their involvement with delinquent peers. Conclusions Results suggest that promoting the development of social competencies and reducing involvement with delinquent peers will protect at-risk youth from engaging in serious delinquency in early adulthood while increasing their educational success. PMID:21878156

Candidate genetic modifiers for breast and ovarian cancer risk in BRCA1 and BRCA2 mutation carriers.

PubMed

Peterlongo, Paolo; Chang-Claude, Jenny; Moysich, Kirsten B; Rudolph, Anja; Schmutzler, Rita K; Simard, Jacques; Soucy, Penny; Eeles, Rosalind A; Easton, Douglas F; Hamann, Ute; Wilkening, Stefan; Chen, Bowang; Rookus, Matti A; Schmidt, Marjanka K; van der Baan, Frederieke H; Spurdle, Amanda B; Walker, Logan C; Lose, Felicity; Maia, Ana-Teresa; Montagna, Marco; Matricardi, Laura; Lubinski, Jan; Jakubowska, Anna; Gómez Garcia, Encarna B; Olopade, Olufunmilayo I; Nussbaum, Robert L; Nathanson, Katherine L; Domchek, Susan M; Rebbeck, Timothy R; Arun, Banu K; Karlan, Beth Y; Orsulic, Sandra; Lester, Jenny; Chung, Wendy K; Miron, Alex; Southey, Melissa C; Goldgar, David E; Buys, Saundra S; Janavicius, Ramunas; Dorfling, Cecilia M; van Rensburg, Elizabeth J; Ding, Yuan Chun; Neuhausen, Susan L; Hansen, Thomas V O; Gerdes, Anne-Marie; Ejlertsen, Bent; Jønson, Lars; Osorio, Ana; Martínez-Bouzas, Cristina; Benitez, Javier; Conway, Edye E; Blazer, Kathleen R; Weitzel, Jeffrey N; Manoukian, Siranoush; Peissel, Bernard; Zaffaroni, Daniela; Scuvera, Giulietta; Barile, Monica; Ficarazzi, Filomena; Mariette, Frederique; Fortuzzi, Stefano; Viel, Alessandra; Giannini, Giuseppe; Papi, Laura; Martayan, Aline; Tibiletti, Maria Grazia; Radice, Paolo; Vratimos, Athanassios; Fostira, Florentia; Garber, Judy E; Donaldson, Alan; Brewer, Carole; Foo, Claire; Evans, D Gareth R; Frost, Debra; Eccles, Diana; Brady, Angela; Cook, Jackie; Tischkowitz, Marc; Adlard, Julian; Barwell, Julian; Walker, Lisa; Izatt, Louise; Side, Lucy E; Kennedy, M John; Rogers, Mark T; Porteous, Mary E; Morrison, Patrick J; Platte, Radka; Davidson, Rosemarie; Hodgson, Shirley V; Ellis, Steve; Cole, Trevor; Godwin, Andrew K; Claes, Kathleen; Van Maerken, Tom; Meindl, Alfons; Gehrig, Andrea; Sutter, Christian; Engel, Christoph; Niederacher, Dieter; Steinemann, Doris; Plendl, Hansjoerg; Kast, Karin; Rhiem, Kerstin; Ditsch, Nina; Arnold, Norbert; Varon-Mateeva, Raymonda; Wappenschmidt, Barbara; Wang-Gohrke, Shan; Bressac-de Paillerets, Brigitte; Buecher, Bruno; Delnatte, Capucine; Houdayer, Claude; Stoppa-Lyonnet, Dominique; Damiola, Francesca; Coupier, Isabelle; Barjhoux, Laure; Venat-Bouvet, Laurence; Golmard, Lisa; Boutry-Kryza, Nadia; Sinilnikova, Olga M; Caron, Olivier; Pujol, Pascal; Mazoyer, Sylvie; Belotti, Muriel; Piedmonte, Marion; Friedlander, Michael L; Rodriguez, Gustavo C; Copeland, Larry J; de la Hoya, Miguel; Segura, Pedro Perez; Nevanlinna, Heli; Aittomäki, Kristiina; van Os, Theo A M; Meijers-Heijboer, Hanne E J; van der Hout, Annemarie H; Vreeswijk, Maaike P G; Hoogerbrugge, Nicoline; Ausems, Margreet G E M; van Doorn, Helena C; Collée, J Margriet; Olah, Edith; Diez, Orland; Blanco, Ignacio; Lazaro, Conxi; Brunet, Joan; Feliubadalo, Lidia; Cybulski, Cezary; Gronwald, Jacek; Durda, Katarzyna; Jaworska-Bieniek, Katarzyna; Sukiennicki, Grzegorz; Arason, Adalgeir; Chiquette, Jocelyne; Teixeira, Manuel R; Olswold, Curtis; Couch, Fergus J; Lindor, Noralane M; Wang, Xianshu; Szabo, Csilla I; Offit, Kenneth; Corines, Marina; Jacobs, Lauren; Robson, Mark E; Zhang, Liying; Joseph, Vijai; Berger, Andreas; Singer, Christian F; Rappaport, Christine; Kaulich, Daphne Geschwantler; Pfeiler, Georg; Tea, Muy-Kheng M; Phelan, Catherine M; Greene, Mark H; Mai, Phuong L; Rennert, Gad; Mulligan, Anna Marie; Glendon, Gord; Tchatchou, Sandrine; Andrulis, Irene L; Toland, Amanda Ewart; Bojesen, Anders; Pedersen, Inge Sokilde; Thomassen, Mads; Jensen, Uffe Birk; Laitman, Yael; Rantala, Johanna; von Wachenfeldt, Anna; Ehrencrona, Hans; Askmalm, Marie Stenmark; Borg, Åke; Kuchenbaecker, Karoline B; McGuffog, Lesley; Barrowdale, Daniel; Healey, Sue; Lee, Andrew; Pharoah, Paul D P; Chenevix-Trench, Georgia; Antoniou, Antonis C; Friedman, Eitan

2015-01-01

BRCA1 and BRCA2 mutation carriers are at substantially increased risk for developing breast and ovarian cancer. The incomplete penetrance coupled with the variable age at diagnosis in carriers of the same mutation suggests the existence of genetic and nongenetic modifying factors. In this study, we evaluated the putative role of variants in many candidate modifier genes. Genotyping data from 15,252 BRCA1 and 8,211 BRCA2 mutation carriers, for known variants (n = 3,248) located within or around 445 candidate genes, were available through the iCOGS custom-designed array. Breast and ovarian cancer association analysis was performed within a retrospective cohort approach. The observed P values of association ranged between 0.005 and 1.000. None of the variants was significantly associated with breast or ovarian cancer risk in either BRCA1 or BRCA2 mutation carriers, after multiple testing adjustments. There is little evidence that any of the evaluated candidate variants act as modifiers of breast and/or ovarian cancer risk in BRCA1 or BRCA2 mutation carriers. Genome-wide association studies have been more successful at identifying genetic modifiers of BRCA1/2 penetrance than candidate gene studies. ©2014 American Association for Cancer Research.

Breast cancer risk factors and HER2 over-expression in tumors.

PubMed

Swede, H; Moysich, K B; Freudenheim, J L; Quirk, J T; Muti, P C; Hurd, T C; Edge, S B; Winston, J S; Michalek, A M

2001-01-01

Few epidemiologic studies have investigated the potential role of HER2 in the etiology of breast cancer. We conducted a case-case study of 156 women with incident, invasive ductal carcinoma. Multivariate unconditional logistic regression was used to estimate the odds ratios for a HER2 positive tumor in relation to known and putative risk factors of breast cancer. HER2 status was detected by immunohistochemistry on archival tissue. HER2 positive breast cancers tended to be larger and were less likely to express estrogen receptors, and the incidence rate was higher in patients less than 40 years old. We observed an association between a self-reported history of benign breast disease and the occurrence of HER2 positive breast cancer (OR, 2.1;95% CI, 1.1-4.1). We did not detect associations between HER2 over-expression and family history of breast cancer, parity, late age at first birth, ever having breast fed an infant, or oral contraceptive use. Our findings merit consideration in light of recent evidence of HER2 amplification or over-expression in benign breast disease. Should the link to breast cancer be established, HER2 positive benign breast disease could potentially serve as an early marker for preventive intervention.

Bidirectional Connections between Depression and Ataxia Severity in Spinocerebellar Ataxia Type 3 Patients.

PubMed

Lin, Min-Ting; Yang, Jin-Shan; Chen, Ping-Ping; Qian, Mei-Zhen; Lin, Hui-Xia; Chen, Xiao-Ping; Shang, Xian-Jin; Wang, Dan-Ni; Chen, Yu-Chao; Jiang, Bin; Chen, Yi-Jun; Chen, Wan-Jin; Wang, Ning; Gan, Shi-Rui

2018-05-15

Spinocerebellar ataxia type 3 (SCA3), which is the most common subtype of SCA worldwide, exhibits common neuropsychological symptoms such as depression. However, the contribution of depression to the severity of SCA3 has not yet been thoroughly investigated. The present study investigated the prevalence of depression using Beck depression inventory in 104 molecularly confirmed SCA3 patients from China. The putative risk factors for depression and whether the depression could affect the severity of ataxia were established by multivariable linear regression models. The frequency of depression in the study subjects was 57.69% (60/104), which was higher than that in SCA3 patients from a subset of other populations. The gender (p = 0.03) and severity (p < 0.01) of ataxia were those risk factors that could affect depression. Conversely, depression (p < 0.01) together with the duration (p < 0.01) of SCA3 could also play a positive role in the severity of ataxia. The extremely common depression results from motor disability caused by ataxia; it also affects the disease severity of SCA3. These findings suggested that depression was a part of neurodegeneration in SCA3 and necessitated intensive focus and interventions while caring for SCA3 patients. © 2018 S. Karger AG, Basel.

Suicide amongst Irish migrants in Britain: a review of the identity and integration hypothesis.

PubMed

Aspinall, Peter J

2002-12-01

Studies have consistently reported higher rates of suicide amongst Irish migrants in Britain than in the population as a whole. Leavey offers a hypothetical model to explain such rates that incorporates lack of social cohesion and integration meshed with the inability to establish an authentic identity and other contributory factors. Systematic review methodologies are used to examine the central tenets of this explanatory framework. Some of the macro-level ecological associations in the model are critically evaluated in the context of findings from the 1991 Census and government social and household panel surveys. The evidence base suggests that statements on social isolation and reluctance to use health care services are questionable and Irish migration is shown to be much more heterogeneous than the model suggests. Only small positive, and as yet unreplicated, associations have been established between identity and health behaviour in a non-representative sample and evidence is lacking of Irish stoicism and anti-Irish racism as putative risk factors. Epidemiological studies show that adjusting suicide rates for social class explains virtually none of the excess in Irish migrants, although higher risks for unmarried persons are reported. Explanations in the literature for higher rates of migrant suicide are discussed. Studies based on individual-level analysis and record linkage are urgently needed to explain the high rates.

More than skin deep? Potential nicotinamide treatment applications in chronic kidney transplant recipients

PubMed Central

Bostom, Andrew G; Merhi, Basma; Walker, Joanna; Robinson-Bostom, Leslie

2016-01-01

Non-melanoma cutaneous carcinomas, or skin cancers, predominantly squamous cell carcinomas (SCCs), are the most common malignancies occurring in kidney transplant recipients (KTRs). Squamous cell carcinoma risk is dramatically elevated in KTRs, occurring at rates of up 45-250 times those reported in general populations. New non-melanoma skin cancers in KTRs with a prior non-melanoma skin cancer also develop at 3-times the rate reported in non-KTRs with the same clinical history. The unique aggressiveness of SCCs in KTRs increases patient morbidity, due to the high rate of new lesions requiring treatment, frequently surgical excision. Oral nicotinamide shows promise in the chemoprevention of the especially aggressive non-melanoma skin cancers which occur in KTRs. This benefit might be conferred via its inhibition of sirtuin enzymatic pathways. Nicotinamide’s concurrent hypophosphatemic effect may also partially ameliorate the disturbed calcium-phosphorus homeostasis in these patients-a putative risk factor for mortality, and graft failure. Conceivably, a phase 3 trial of nicotinamide for the prevention of non-melanoma skin cancers in KTRs, lasting at least 12-mo, could also incorporate imaging and laboratory measures which assess nicotinamide’s impact on subclinical cardiovascular and chronic kidney disease risk, and progression. PMID:28058215

Application environmental epidemiology to vehicular air pollution and health effects research

PubMed Central

Patil, Rajan R.; Chetlapally, Satish Kumar; Bagvandas, M.

2015-01-01

Vehicular pollution is one of the major contributors to the air pollution in urban areas and perhaps and accounts for the major share of anthropogenic green-house gases such as carbon dioxide, carbon monoxide, nitrogen oxides. Knowledge of human health risks related to environmental exposure to vehicular pollution is a current concern. Analyze the range health effects are attributed varied constituents of vehicular air pollution examine evidence for a causal association to specific health effect. In many instances scenario involves exposure to very low doses of putative agents for extended periods, sometimes the period could mean over a lifetime of an individual and yet may result in small increase in health risk that may be imperceptible. Secondary data analysis and literature review. In environmental exposures, traditional epidemiological approaches evaluating mortality and morbidity indicators display many limiting factors such as nonspecificity of biological effects latency time between exposure and magnitude of the effect. Long latency period between exposure and resultant disease, principally for carcinogenic effects and limitation of epidemiological studies for detecting small risk increments. The present paper discusses the methodological challenges in studying vehicular epidemiology and highlights issues that affect the validity of epidemiological studies in vehicular pollution. PMID:26023265

The putative forkhead transcription factor FOXL2 is mutated in blepharophimosis/ptosis/epicanthus inversus syndrome.

PubMed

Crisponi, L; Deiana, M; Loi, A; Chiappe, F; Uda, M; Amati, P; Bisceglia, L; Zelante, L; Nagaraja, R; Porcu, S; Ristaldi, M S; Marzella, R; Rocchi, M; Nicolino, M; Lienhardt-Roussie, A; Nivelon, A; Verloes, A; Schlessinger, D; Gasparini, P; Bonneau, D; Cao, A; Pilia, G

2001-02-01

In type I blepharophimosis/ptosis/epicanthus inversus syndrome (BPES), eyelid abnormalities are associated with ovarian failure. Type II BPES shows only the eyelid defects, but both types map to chromosome 3q23. We have positionally cloned a novel, putative winged helix/forkhead transcription factor gene, FOXL2, that is mutated to produce truncated proteins in type I families and larger proteins in type II. Consistent with an involvement in those tissues, FOXL2 is selectively expressed in the mesenchyme of developing mouse eyelids and in adult ovarian follicles; in adult humans, it appears predominantly in the ovary. FOXL2 represents a candidate gene for the polled/intersex syndrome XX sex-reversal goat.

Crystallization and preliminary X-ray analysis of PH1566, a putative ribosomal RNA-processing factor from the hyperthermophilic archaeon Pyrococcus horikoshii OT3

PubMed Central

Jia, Min Ze; Ohtsuka, Jun; Lee, Woo Cheol; Nagata, Koji; Tanokura, Masaru

2006-01-01

A putative ribosomal RNA-processing factor consisting of two KH domains from Pyrococcus horikoshii OT3 (PH1566; 25 kDa) was crystallized by the sitting-drop vapour-diffusion method using PEG 3000 as the precipitant. The crystals diffracted X-rays to beyond 2.0 Å resolution using a synchrotron-radiation source. The space group of the crystals was determined as primitive orthorhombic P212121, with unit-cell parameters a = 45.9, b = 47.4, c = 95.7 Å. The crystals contain one molecule in the asymmetric unit (V M = 2.5 Å3 Da−1) and have a solvent content of 50%. PMID:16511260

Structure, Regulation, and Putative Function of the Arginine Deiminase System of Streptococcus suis

PubMed Central

Gruening, Petra; Fulde, Marcus; Valentin-Weigand, Peter; Goethe, Ralph

2006-01-01

Streptococcus suis is an important cause of infectious diseases in young pigs. Little is known about the virulence factors or protective antigens of S. suis. Recently, we have identified two proteins of the arginine deiminase system (ADS) of S. suis, which were temperature induced and expressed on the streptococcal surface (N. Winterhoff, R. Goethe, P. Gruening, M. Rohde, H. Kalisz, H. E. Smith, and P. Valentin-Weigand, J. Bacteriol. 184:6768-6776, 2002). In the present study, we analyzed the complete ADS of S. suis. Due to their homologies to the recently published S. gordonii ADS genes, the genes for arginine deiminase, ornithine carbamoyl-transferase, and carbamate kinase, which were previously designated adiS, octS, and ckS, respectively, were renamed arcA, arcB, and arcC, respectively. Our data revealed that arcA, arcB, and arcC of the S. suis ADS are transcribed from an operon (arcABC operon). Additionally, putative ADS-associated genes were cloned and sequenced which, however, did not belong to the arcABC operon. These were the flpS gene upstream of the arcABC operon with homology to the flp transcription regulator of S. gordonii and the arcD, arcT, arcH, and argR genes downstream of the arcABC operon with high homologies to a putative arginine-ornithine antiporter, a putative dipeptidase of S. gordonii, a putative β-N-acetylhexosaminidase of S. pneumoniae, and a putative arginine repressor of S. gordonii, respectively. The transcriptional start point of the arcABC operon was determined, and promoter analysis provided evidence that multiple factors contribute to the regulation of the ADS. Thus, a putative binding site for a transcription regulator of the Crp/Fnr family, an ArgR-binding site, and two cis-acting catabolite response elements were identified in the promoter-operator region of the operon. Consistent with this, we could demonstrate that the ADS of S. suis is inducible by arginine and reduced O2 tension and subject to carbon catabolite repression. Furthermore, comparing an arcA knockout mutant in which expression of the three operon-encoded proteins was abolished with the parental wild-type strain showed that the arcABC operon of S. suis contributes to survival under acidic conditions. PMID:16385025

Structure, regulation, and putative function of the arginine deiminase system of Streptococcus suis.

PubMed

Gruening, Petra; Fulde, Marcus; Valentin-Weigand, Peter; Goethe, Ralph

2006-01-01

Streptococcus suis is an important cause of infectious diseases in young pigs. Little is known about the virulence factors or protective antigens of S. suis. Recently, we have identified two proteins of the arginine deiminase system (ADS) of S. suis, which were temperature induced and expressed on the streptococcal surface (N. Winterhoff, R. Goethe, P. Gruening, M. Rohde, H. Kalisz, H. E. Smith, and P. Valentin-Weigand, J. Bacteriol. 184:6768-6776, 2002). In the present study, we analyzed the complete ADS of S. suis. Due to their homologies to the recently published S. gordonii ADS genes, the genes for arginine deiminase, ornithine carbamoyl-transferase, and carbamate kinase, which were previously designated adiS, octS, and ckS, respectively, were renamed arcA, arcB, and arcC, respectively. Our data revealed that arcA, arcB, and arcC of the S. suis ADS are transcribed from an operon (arcABC operon). Additionally, putative ADS-associated genes were cloned and sequenced which, however, did not belong to the arcABC operon. These were the flpS gene upstream of the arcABC operon with homology to the flp transcription regulator of S. gordonii and the arcD, arcT, arcH, and argR genes downstream of the arcABC operon with high homologies to a putative arginine-ornithine antiporter, a putative dipeptidase of S. gordonii, a putative beta-N-acetylhexosaminidase of S. pneumoniae, and a putative arginine repressor of S. gordonii, respectively. The transcriptional start point of the arcABC operon was determined, and promoter analysis provided evidence that multiple factors contribute to the regulation of the ADS. Thus, a putative binding site for a transcription regulator of the Crp/Fnr family, an ArgR-binding site, and two cis-acting catabolite response elements were identified in the promoter-operator region of the operon. Consistent with this, we could demonstrate that the ADS of S. suis is inducible by arginine and reduced O2 tension and subject to carbon catabolite repression. Furthermore, comparing an arcA knockout mutant in which expression of the three operon-encoded proteins was abolished with the parental wild-type strain showed that the arcABC operon of S. suis contributes to survival under acidic conditions.

Food intake and the risk of endometrial endometrioid adenocarcinoma in Japanese women.

PubMed

Takayama, Shin; Monma, Yasutake; Tsubota-Utsugi, Megumi; Nagase, Satoru; Tsubono, Yoshitaka; Numata, Takehiro; Toyoshima, Masafumi; Utsunomiya, Hiroki; Sugawara, Junichi; Yaegashi, Nobuo

2013-01-01

The present study examined the association between food intake and endometrial cancer restricted to endometrial endometrioid adenocarcinoma (EEA) using a case-control study in Japanese women. One hundred sixty-one cases and 380 controls who completed a questionnaire regarding demographic, lifestyle, and food frequency questionnaire were analyzed. Odds ratio (OR) between selected food intakes and EEA were calculated by logistic regression analysis. After adjustment putative confounding factors, the higher intakes of vegetables [odds ratio (OR) = 0.47, 95% confidence interval (CI) = 0.26-0.83], peanuts (OR = 0.48, CI = 0.27-0.86), fish (OR = 0.52, CI = 0.29-0.93), boiled egg (OR = 0.24, CI = 0.33-0.92), instant noodles (OR = 1.94, CI = 1.12-3.34), instant food items (OR = 2.21, CI = 1.31-3.74), and deep-fried foods (OR = 2.87, CI = 1.58-5.21) were associated with a risk for EEA. The inverse association with a risk of EEA was also seen in higher intakes (g/1000 kcal) for vegetables (0.45, CI = 0.25-0.81) and fish (0.53, CI = 0.30-0.94) as compare to lower intake. Higher intake of vegetables, peanuts, fish, and boiled egg was associated with a reduced risk for EEA, whereas instant noodles, instant food items, and deep-fried foods was associated with an increased risk for EAA as compared to lower levels of intake.

A Multi-Disciplinary Review of the Potential Association between Closed-Suction Drains and Surgical Site Infection

PubMed Central

Reiffel, Alyssa J.; Barie, Philip S.

2013-01-01

Abstract Background Despite the putative advantages conferred by closed-suction drains (CSDs), the widespread utilization of post-operative drains has been questioned due to concerns regarding both efficacy and safety, particularly with respect to the risk of surgical site infection (SSI). Although discipline-specific reports exist delineating risk factors associated with SSI as they relate to the presence of CSDs, there are no broad summary studies to examine this issue in depth. Methods The pertinent medical literature exploring the relationship between CSDs and SSI across multiple surgical disciplines was reviewed. Results Across most surgical disciplines, studies to evaluate the risk of SSI associated with routine post-operative CSD have yielded conflicting results. A few studies do suggest an increased risk of SSI associated with drain placement, but are usually associated with open drainage and not the use of CSDs. No studies whatsoever attribute a decrease in the incidence of SSI (including organ/space SSI) to drain placement. Conclusions Until additional, rigorous randomized trials are available to address the issue definitively, we recommend judicious use and prompt, timely removal of CSDs. Given that the evidence is scant and weak to suggest that CSD use is associated with increased risk of SSI, there is no justification for the prolongation of antibiotic prophylaxis to “cover” an indwelling drain. PMID:23718273

Nocturnal polyuria and decreased serum testosterone: is there an association in men with lower urinary tract symptoms?

PubMed

Kim, Jin Wook; Oh, Mi Mi; Yoon, Cheol Yong; Bae, Jae Hyun; Kim, Je Jong; Moon, Du Geon

2014-05-01

To investigate the putative association between nocturia and decreased serum testosterone in men with lower urinary tract symptoms. Frequency volume charts and serum testosterone levels of patients visiting the outpatient clinic for lower urinary tract symptoms were collected and analyzed. Age, prostate volume, body mass index and the presence of comorbidities were accounted for. Frequency volume charts were analyzed for pathophysiological components of nocturnal polyuria, global polyuria, decreased nocturnal bladder capacity and increased frequency to identify associated risks. Frequency volume charts were also used to chart 8-h changes of volume, frequency and capacity to identify time diurnal interactions with risk factors based on serum testosterone levels. A total of 2180 patients were enrolled in the study. Multivariate analysis showed testosterone decreased 0.142 ng/mL for every increase in nocturia, independent of other factors. Logistic regression analysis showed a significant difference between pathophysiological components. Decreased testosterone was shown to carry a significant independent risk for overall nocturia (odds ratio 1.60, 95% confidence interval 1.013-2.527, P = 0.044), and particularly nocturnal polyuria (odds ratio 1.934, 95% confidence interval 1.001-3.737, P = 0.027). Repeated measurement models showed patients with serum testosterone below 2.50 ng/mL to have a paradoxical increase in nocturnal urine volume at night. Nocturia, especially nocturnal polyuria, is associated with decreased serum testosterone. Patients with low serum testosterone show increased nocturnal urine output. © 2013 The Japanese Urological Association.

Parasympathetic nervous system activity predicts mood repair use and its effectiveness among adolescents with and without histories of major depression

PubMed Central

Yaroslavsky, Ilya; Rottenberg, Jonathan; Bylsma, Lauren M.; Jennings, J. Richard; George, Charles; Baji, Ildikó; Benák, István; Dochnal, Roberta; Halas, Kitti; Kapornai, Krisztina; Kiss, Enikő; Makai, Attila; Varga, Hedvig; Vetró, Ágnes; Kovacs, Maria

2016-01-01

Depressive disorders that onset in the juvenile years have been linked to far reaching adverse consequences, making it imperative to elucidate key mechanisms and contributory factors. Excessive use of regulatory responses that exacerbate sadness (maladaptive mood repair) or insufficient use of regulatory responses that reduce it (adaptive mood repair) may reflect behavioral mechanisms of depression risk. Cardiac vagal control, indexed by patterns of respiratory sinus arrhythmia (RSA), has received attention as a putative physiological risk factor for depression. Although mood repair and RSA are related, the nature of this relationship is not well characterized in the context of depression risk. Therefore, we tested alternative models of the relationships between RSA patterns (at rest and in response to a sad film), trait mood repair, and the effectiveness of a mood repair response in the laboratory (state mood repair) among adolescents with depression histories (n=210) and emotionally healthy peers (n=161). In our data, a mediation model best explained the association between the key constructs: Adolescents with normative RSA patterns exhibited lower levels of depression and trait maladaptive mood repair, and benefited more from instructed (state) mood repair in the laboratory. By contrast, adolescents with atypical RSA patterns exhibited higher levels of depression and dispositional maladaptive mood repair, which, in turn, mediated the relations of RSA patterns and depression symptoms. Atypical RSA patterns also predicted reduced benefits from laboratory mood repair. PMID:26950752

Fine-scale mapping of the FGFR2 breast cancer risk locus: putative functional variants differentially bind FOXA1 and E2F1.

PubMed

Meyer, Kerstin B; O'Reilly, Martin; Michailidou, Kyriaki; Carlebur, Saskia; Edwards, Stacey L; French, Juliet D; Prathalingham, Radhika; Dennis, Joe; Bolla, Manjeet K; Wang, Qin; de Santiago, Ines; Hopper, John L; Tsimiklis, Helen; Apicella, Carmel; Southey, Melissa C; Schmidt, Marjanka K; Broeks, Annegien; Van 't Veer, Laura J; Hogervorst, Frans B; Muir, Kenneth; Lophatananon, Artitaya; Stewart-Brown, Sarah; Siriwanarangsan, Pornthep; Fasching, Peter A; Lux, Michael P; Ekici, Arif B; Beckmann, Matthias W; Peto, Julian; Dos Santos Silva, Isabel; Fletcher, Olivia; Johnson, Nichola; Sawyer, Elinor J; Tomlinson, Ian; Kerin, Michael J; Miller, Nicola; Marme, Federick; Schneeweiss, Andreas; Sohn, Christof; Burwinkel, Barbara; Guénel, Pascal; Truong, Thérèse; Laurent-Puig, Pierre; Menegaux, Florence; Bojesen, Stig E; Nordestgaard, Børge G; Nielsen, Sune F; Flyger, Henrik; Milne, Roger L; Zamora, M Pilar; Arias, Jose I; Benitez, Javier; Neuhausen, Susan; Anton-Culver, Hoda; Ziogas, Argyrios; Dur, Christina C; Brenner, Hermann; Müller, Heiko; Arndt, Volker; Stegmaier, Christa; Meindl, Alfons; Schmutzler, Rita K; Engel, Christoph; Ditsch, Nina; Brauch, Hiltrud; Brüning, Thomas; Ko, Yon-Dschun; Nevanlinna, Heli; Muranen, Taru A; Aittomäki, Kristiina; Blomqvist, Carl; Matsuo, Keitaro; Ito, Hidemi; Iwata, Hiroji; Yatabe, Yasushi; Dörk, Thilo; Helbig, Sonja; Bogdanova, Natalia V; Lindblom, Annika; Margolin, Sara; Mannermaa, Arto; Kataja, Vesa; Kosma, Veli-Matti; Hartikainen, Jaana M; Chenevix-Trench, Georgia; Wu, Anna H; Tseng, Chiu-Chen; Van Den Berg, David; Stram, Daniel O; Lambrechts, Diether; Thienpont, Bernard; Christiaens, Marie-Rose; Smeets, Ann; Chang-Claude, Jenny; Rudolph, Anja; Seibold, Petra; Flesch-Janys, Dieter; Radice, Paolo; Peterlongo, Paolo; Bonanni, Bernardo; Bernard, Loris; Couch, Fergus J; Olson, Janet E; Wang, Xianshu; Purrington, Kristen; Giles, Graham G; Severi, Gianluca; Baglietto, Laura; McLean, Catriona; Haiman, Christopher A; Henderson, Brian E; Schumacher, Fredrick; Le Marchand, Loic; Simard, Jacques; Goldberg, Mark S; Labrèche, France; Dumont, Martine; Teo, Soo-Hwang; Yip, Cheng-Har; Phuah, Sze-Yee; Kristensen, Vessela; Grenaker Alnæs, Grethe; Børresen-Dale, Anne-Lise; Zheng, Wei; Deming-Halverson, Sandra; Shrubsole, Martha; Long, Jirong; Winqvist, Robert; Pylkäs, Katri; Jukkola-Vuorinen, Arja; Kauppila, Saila; Andrulis, Irene L; Knight, Julia A; Glendon, Gord; Tchatchou, Sandrine; Devilee, Peter; Tollenaar, Robert A E M; Seynaeve, Caroline M; García-Closas, Montserrat; Figueroa, Jonine; Chanock, Stephen J; Lissowska, Jolanta; Czene, Kamila; Darabi, Hartef; Eriksson, Kimael; Hooning, Maartje J; Martens, John W M; van den Ouweland, Ans M W; van Deurzen, Carolien H M; Hall, Per; Li, Jingmei; Liu, Jianjun; Humphreys, Keith; Shu, Xiao-Ou; Lu, Wei; Gao, Yu-Tang; Cai, Hui; Cox, Angela; Reed, Malcolm W R; Blot, William; Signorello, Lisa B; Cai, Qiuyin; Pharoah, Paul D P; Ghoussaini, Maya; Harrington, Patricia; Tyrer, Jonathan; Kang, Daehee; Choi, Ji-Yeob; Park, Sue K; Noh, Dong-Young; Hartman, Mikael; Hui, Miao; Lim, Wei-Yen; Buhari, Shaik A; Hamann, Ute; Försti, Asta; Rüdiger, Thomas; Ulmer, Hans-Ulrich; Jakubowska, Anna; Lubinski, Jan; Jaworska, Katarzyna; Durda, Katarzyna; Sangrajrang, Suleeporn; Gaborieau, Valerie; Brennan, Paul; McKay, James; Vachon, Celine; Slager, Susan; Fostira, Florentia; Pilarski, Robert; Shen, Chen-Yang; Hsiung, Chia-Ni; Wu, Pei-Ei; Hou, Ming-Feng; Swerdlow, Anthony; Ashworth, Alan; Orr, Nick; Schoemaker, Minouk J; Ponder, Bruce A J; Dunning, Alison M; Easton, Douglas F

2013-12-05

The 10q26 locus in the second intron of FGFR2 is the locus most strongly associated with estrogen-receptor-positive breast cancer in genome-wide association studies. We conducted fine-scale mapping in case-control studies genotyped with a custom chip (iCOGS), comprising 41 studies (n = 89,050) of European ancestry, 9 Asian ancestry studies (n = 13,983), and 2 African ancestry studies (n = 2,028) from the Breast Cancer Association Consortium. We identified three statistically independent risk signals within the locus. Within risk signals 1 and 3, genetic analysis identified five and two variants, respectively, highly correlated with the most strongly associated SNPs. By using a combination of genetic fine mapping, data on DNase hypersensitivity, and electrophoretic mobility shift assays to study protein-DNA binding, we identified rs35054928, rs2981578, and rs45631563 as putative functional SNPs. Chromatin immunoprecipitation showed that FOXA1 preferentially bound to the risk-associated allele (C) of rs2981578 and was able to recruit ERα to this site in an allele-specific manner, whereas E2F1 preferentially bound the risk variant of rs35054928. The risk alleles were preferentially found in open chromatin and bound by Ser5 phosphorylated RNA polymerase II, suggesting that the risk alleles are associated with changes in transcription. Chromatin conformation capture demonstrated that the risk region was able to interact with the promoter of FGFR2, the likely target gene of this risk region. A role for FOXA1 in mediating breast cancer susceptibility at this locus is consistent with the finding that the FGFR2 risk locus primarily predisposes to estrogen-receptor-positive disease. Copyright © 2013 The American Society of Human Genetics. Published by Elsevier Inc. All rights reserved.

Fine-Scale Mapping of the FGFR2 Breast Cancer Risk Locus: Putative Functional Variants Differentially Bind FOXA1 and E2F1

PubMed Central

Meyer, Kerstin B.; O’Reilly, Martin; Michailidou, Kyriaki; Carlebur, Saskia; Edwards, Stacey L.; French, Juliet D.; Prathalingham, Radhika; Dennis, Joe; Bolla, Manjeet K.; Wang, Qin; de Santiago, Ines; Hopper, John L.; Tsimiklis, Helen; Apicella, Carmel; Southey, Melissa C.; Schmidt, Marjanka K.; Broeks, Annegien; Van ’t Veer, Laura J.; Hogervorst, Frans B.; Muir, Kenneth; Lophatananon, Artitaya; Stewart-Brown, Sarah; Siriwanarangsan, Pornthep; Fasching, Peter A.; Lux, Michael P.; Ekici, Arif B.; Beckmann, Matthias W.; Peto, Julian; dos Santos Silva, Isabel; Fletcher, Olivia; Johnson, Nichola; Sawyer, Elinor J.; Tomlinson, Ian; Kerin, Michael J.; Miller, Nicola; Marme, Federick; Schneeweiss, Andreas; Sohn, Christof; Burwinkel, Barbara; Guénel, Pascal; Truong, Thérèse; Laurent-Puig, Pierre; Menegaux, Florence; Bojesen, Stig E.; Nordestgaard, Børge G.; Nielsen, Sune F.; Flyger, Henrik; Milne, Roger L.; Zamora, M. Pilar; Arias, Jose I.; Benitez, Javier; Neuhausen, Susan; Anton-Culver, Hoda; Ziogas, Argyrios; Dur, Christina C.; Brenner, Hermann; Müller, Heiko; Arndt, Volker; Stegmaier, Christa; Meindl, Alfons; Schmutzler, Rita K.; Engel, Christoph; Ditsch, Nina; Brauch, Hiltrud; Brüning, Thomas; Ko, Yon-Dschun; Nevanlinna, Heli; Muranen, Taru A.; Aittomäki, Kristiina; Blomqvist, Carl; Matsuo, Keitaro; Ito, Hidemi; Iwata, Hiroji; Yatabe, Yasushi; Dörk, Thilo; Helbig, Sonja; Bogdanova, Natalia V.; Lindblom, Annika; Margolin, Sara; Mannermaa, Arto; Kataja, Vesa; Kosma, Veli-Matti; Hartikainen, Jaana M.; Chenevix-Trench, Georgia; Wu, Anna H.; Tseng, Chiu-chen; Van Den Berg, David; Stram, Daniel O.; Lambrechts, Diether; Thienpont, Bernard; Christiaens, Marie-Rose; Smeets, Ann; Chang-Claude, Jenny; Rudolph, Anja; Seibold, Petra; Flesch-Janys, Dieter; Radice, Paolo; Peterlongo, Paolo; Bonanni, Bernardo; Bernard, Loris; Couch, Fergus J.; Olson, Janet E.; Wang, Xianshu; Purrington, Kristen; Giles, Graham G.; Severi, Gianluca; Baglietto, Laura; McLean, Catriona; Haiman, Christopher A.; Henderson, Brian E.; Schumacher, Fredrick; Le Marchand, Loic; Simard, Jacques; Goldberg, Mark S.; Labrèche, France; Dumont, Martine; Teo, Soo-Hwang; Yip, Cheng-Har; Phuah, Sze-Yee; Kristensen, Vessela; Grenaker Alnæs, Grethe; Børresen-Dale, Anne-Lise; Zheng, Wei; Deming-Halverson, Sandra; Shrubsole, Martha; Long, Jirong; Winqvist, Robert; Pylkäs, Katri; Jukkola-Vuorinen, Arja; Kauppila, Saila; Andrulis, Irene L.; Knight, Julia A.; Glendon, Gord; Tchatchou, Sandrine; Devilee, Peter; Tollenaar, Robert A.E.M.; Seynaeve, Caroline M.; García-Closas, Montserrat; Figueroa, Jonine; Chanock, Stephen J.; Lissowska, Jolanta; Czene, Kamila; Darabi, Hartef; Eriksson, Kimael; Hooning, Maartje J.; Martens, John W.M.; van den Ouweland, Ans M.W.; van Deurzen, Carolien H.M.; Hall, Per; Li, Jingmei; Liu, Jianjun; Humphreys, Keith; Shu, Xiao-Ou; Lu, Wei; Gao, Yu-Tang; Cai, Hui; Cox, Angela; Reed, Malcolm W.R.; Blot, William; Signorello, Lisa B.; Cai, Qiuyin; Pharoah, Paul D.P.; Ghoussaini, Maya; Harrington, Patricia; Tyrer, Jonathan; Kang, Daehee; Choi, Ji-Yeob; Park, Sue K.; Noh, Dong-Young; Hartman, Mikael; Hui, Miao; Lim, Wei-Yen; Buhari, Shaik A.; Hamann, Ute; Försti, Asta; Rüdiger, Thomas; Ulmer, Hans-Ulrich; Jakubowska, Anna; Lubinski, Jan; Jaworska, Katarzyna; Durda, Katarzyna; Sangrajrang, Suleeporn; Gaborieau, Valerie; Brennan, Paul; McKay, James; Vachon, Celine; Slager, Susan; Fostira, Florentia; Pilarski, Robert; Shen, Chen-Yang; Hsiung, Chia-Ni; Wu, Pei-Ei; Hou, Ming-Feng; Swerdlow, Anthony; Ashworth, Alan; Orr, Nick; Schoemaker, Minouk J.; Ponder, Bruce A.J.; Dunning, Alison M.; Easton, Douglas F.

2013-01-01

The 10q26 locus in the second intron of FGFR2 is the locus most strongly associated with estrogen-receptor-positive breast cancer in genome-wide association studies. We conducted fine-scale mapping in case-control studies genotyped with a custom chip (iCOGS), comprising 41 studies (n = 89,050) of European ancestry, 9 Asian ancestry studies (n = 13,983), and 2 African ancestry studies (n = 2,028) from the Breast Cancer Association Consortium. We identified three statistically independent risk signals within the locus. Within risk signals 1 and 3, genetic analysis identified five and two variants, respectively, highly correlated with the most strongly associated SNPs. By using a combination of genetic fine mapping, data on DNase hypersensitivity, and electrophoretic mobility shift assays to study protein-DNA binding, we identified rs35054928, rs2981578, and rs45631563 as putative functional SNPs. Chromatin immunoprecipitation showed that FOXA1 preferentially bound to the risk-associated allele (C) of rs2981578 and was able to recruit ERα to this site in an allele-specific manner, whereas E2F1 preferentially bound the risk variant of rs35054928. The risk alleles were preferentially found in open chromatin and bound by Ser5 phosphorylated RNA polymerase II, suggesting that the risk alleles are associated with changes in transcription. Chromatin conformation capture demonstrated that the risk region was able to interact with the promoter of FGFR2, the likely target gene of this risk region. A role for FOXA1 in mediating breast cancer susceptibility at this locus is consistent with the finding that the FGFR2 risk locus primarily predisposes to estrogen-receptor-positive disease. PMID:24290378

The Role of Cytokines in the Pathophysiology of Suicidal Behavior

PubMed Central

Ganança, Licínia; Oquendo, Maria A.; Tyrka, Audrey R.; Cisneros-Trujillo, Sebastian; Mann, J. John; Sublette, M. Elizabeth

2016-01-01

Objective Immune dysregulation has been implicated in depression and other psychiatric disorders. What is less clear is how immune dysregulation can affect risk of suicidal behavior. We reviewed the scientific literature concerning cytokines related to suicidal ideation, suicidal behavior and suicide, and surveyed clinical and neurobiological factors associated with cytokine levels that may modulate effects of inflammation on suicide risk. Methods We searched PubMed, Embase, Scopus and PsycINFO for relevant studies published from 1980 through February, 2015. Papers were included if they were written in English and focused on cytokine measurements in patients with suicidal behaviors. Results The literature search yielded 22 studies concerning cytokines and suicidal ideation, suicide attempts or suicide completion. The most consistent finding was elevated interleukin (IL)-6, found in 8 out of 14 studies, in CSF, blood, and postmortem brain. In one study, IL-6 in CSF was also found to be higher in violent than nonviolent attempters and to correlate with future suicide completion. Low plasma IL-2 was observed in 2 studies of suicide attempters, while divergent results were seen for tumor necrosis factor (TNF)-α, interferon (IFN)-γ, transforming growth factor (TGF)-β, IL-4, and soluble Il-2 receptors. Conclusions Given the complexity suggested by the heterogenous cytokine findings, putative mediators and moderators of inflammation on suicidal behavior merit further study. Elevated IL-6 was the most robust cytokine finding, associated with suicidal ideation and both nonfatal suicide attempts and suicides. Future studies should evaluate the predictive value of high IL-6, consider how this may alter brain function to impact suicidal behavior, and explore the potential beneficial effects of reducing IL-6 on suicide risk. PMID:26546783

Cross-disease Meta-analysis of Genome-wide Association Studies for Systemic Sclerosis and Rheumatoid Arthritis Reveals IRF4 as a New Common Susceptibility Locus

PubMed Central

López-Isac, Elena; Martín, Jose-Ezequiel; Assassi, Shervin; Simeón, Carmen P; Carreira, Patricia; Ortego-Centeno, Norberto; Freire, Mayka; Beltrán, Emma; Narváez, Javier; Alegre-Sancho, Juan J; Fernández-Gutiérrez, Benjamín; Balsa, Alejandro; Ortiz, Ana M; González-Gay, Miguel A; Beretta, Lorenzo; Santaniello, Alessandro; Bellocchi, Chiara; Lunardi, Claudio; Moroncini, Gianluca; Gabrielli, Armando; Witte, Torsten; Hunzelmann, Nicolas; Distler, Jörg HW; Riekemasten, Gabriella; van der Helm-van Mil, Annete H; de Vries-Bouwstra, Jeska; Magro-Checa, Cesar; Voskuyl, Alexandre E; Vonk, Madelon C; Molberg, Øyvind; Merriman, Tony; Hesselstrand, Roger; Nordin, Annika; Padyukov, Leonid; Herrick, Ariane; Eyre, Steve; Koeleman, Bobby PC; Denton, Christopher P; Fonseca, Carmen; Radstake, Timothy RDJ; Worthington, Jane; Mayes, Maureen D; Martín, Javier

2017-01-01

Objectives Systemic sclerosis (SSc) and rheumatoid arthritis (RA) are autoimmune diseases that share clinical and immunological characteristics. To date, several shared SSc-RA loci have been identified independently. In this study, we aimed to systematically search for new common SSc-RA loci through an inter-disease meta-GWAS strategy. Methods We performed a meta-analysis combining GWAS datasets of SSc and RA using a strategy that allowed identification of loci with both same-direction and opposing-direction allelic effects. The top single-nucleotide polymorphisms (SNPs) were followed-up in independent SSc and RA case-control cohorts. This allowed us to increase the sample size to a total of 8,830 SSc patients, 16,870 RA patients and 43,393 controls. Results The cross-disease meta-analysis of the GWAS datasets identified several loci with nominal association signals (P-value < 5 × 10-6), which also showed evidence of association in the disease-specific GWAS scan. These loci included several genomic regions not previously reported as shared loci, besides risk factors associated with both diseases in previous studies. The follow-up of the putatively new SSc-RA loci identified IRF4 as a shared risk factor for these two diseases (Pcombined = 3.29 × 10-12). In addition, the analysis of the biological relevance of the known SSc-RA shared loci pointed to the type I interferon and the interleukin 12 signaling pathways as the main common etiopathogenic factors. Conclusions Our study has identified a novel shared locus, IRF4, for SSc and RA and highlighted the usefulness of cross-disease GWAS meta-analysis in the identification of common risk loci. PMID:27111665

Protective effects of coffee against oxidative stress induced by the tobacco carcinogen benzo[α]pyrene.

PubMed

Kalthoff, Sandra; Landerer, Steffen; Reich, Julia; Strassburg, Christian P

2017-07-01

Coffee consumption has been epidemiologically associated with a lower risk for liver cirrhosis and cancer. UDP-glucuronosyltransferases (UGT1A) catalyze the detoxification of reactive metabolites thereby acting as indirect antioxidants. Aim of the study was to examine UGT1A regulation in response to Benzo[α]pyrene (BaP) to elucidate the potentially protective effects of coffee on BaP-induced oxidative stress and toxicity. In cell culture (HepG2, KYSE70 cells) and in htgUGT1A-WT mice, UGT1A transcription was activated by BaP, while it was reduced or absent htgUGT1A-SNP (containing 10 commonly occurring UGT1A-SNPs) mice. siRNA-mediated knockdown identified aryl hydrocarbon receptor (AhR) and nuclear factor erythroid2-related factor-2 (Nrf2) as mediators of BaP-induced UGT1A upregulation. Exposure to coffee led to a reduction of BaP-induced production of reactive oxygen species in vitro and in htgUGT1A-WT and -SNP mice. After UGT1A silencing by UGT1A-specific siRNA in cell culture, the coffee-mediated reduction of ROS production was significantly impaired compared to UGT1A expressing cells. A common UGT1A haplotype, prevalent in 9% (homozygous) of the White population, significantly impairs the expression of UGT1A enzymes in response to the putative tobacco carcinogen BaP and is likely to represent a significant risk factor for reduced detoxification and increased genotoxicity. Coffee was demonstrated to inhibit BaP-induced production of oxidative stress by UGT1A activation, and is therefore an attractive candidate for chemoprotection in risk groups for HCC or other tumors. Copyright © 2017 Elsevier Inc. All rights reserved.

Putative effect of alcohol on suicide attempters: an evaluative study in a tertiary medical college.

PubMed

Bhattacharjee, Subir; Bhattacharya, Amit; Thakurta, Rajarshi Guha; Ray, Paramita; Singh, Om Prakash; Sen, Sreyashi

2012-10-01

Alcohol abuse is a known risk factor for suicide. Alcohol increases aggression and impulsivity, which are strongly related to suicidal behavior. Sociocultural factors influence both alcohol use and suicide rates. Studies, conducted in one population, are not applicable to other and the results cannot be generalized. The aim was to study the putative role of alcohol in suicide cases in the rural Indian population by analysis of various sociodemographic variables. This was a cross-sectional study in conducted in a tertiary medical college. Two hundred consecutive patients who survived a suicide attempt were evaluated by a psychiatrist. The data were recorded for sociodemographic variables, psychiatric disorders, suicide intent, lethality of the suicide attempt, and history of alcohol intake prior to the suicide attempt. Using alcohol intake prior to the suicide attempt as a determining dimension, various sociodemographic variables were analyzed for their statistical significance and the role of alcohol in suicide cases was assessed. Seventeen percent suicide attempt survivors had a history of alcohol intake prior to the suicide attempt. Fifteen percent had a history of alcohol use disorder. Alcohol use affected the suicide rate in the male population in the late twenties to mid-thirties age group, illiterate and people with high school education, semiskilled workers, shop owners, and student population. Alcohol dependence, bipolar II disorder, intermittent explosive disorder, and dysthymic disorder had higher rate of suicide attempt with the use of alcohol prior to the suicide attempt. Alcohol users attempted a more lethal suicide attempt and were found to have problems with primary support group and occupational problem as precipitating stressor for suicide attempt. Alcohol use increases the suicide rate, in the specific rural Indian population.

Functional characterization of transcription factor binding sites for HNF1-alpha, HNF3-beta (FOXA2), HNF4-alpha, Sp1 and Sp3 in the human prothrombin gene enhancer.

PubMed

Ceelie, H; Spaargaren-Van Riel, C C; De Jong, M; Bertina, R M; Vos, H L

2003-08-01

Prothrombin is a key component in blood coagulation. Overexpression of prothrombin leads to an increased risk of venous thrombosis. Therefore, the study of the transcriptional regulation of the prothrombin gene may help to identify mechanisms of overexpression. The aim of our study was to localize the regions within the prothrombin enhancer responsible for its activity, to identify the proteins binding to these regions, and to establish their functional importance. We constructed a set of prothrombin promoter 5' deletion constructs containing the firefly luciferase reporter gene, which were transiently transfected in HepG2, HuH7 and HeLa cells. Putative transcription factor (TF) binding sites were evaluated by electrophoretic mobility shift assays. The functional importance of each TF binding site was evaluated by site directed mutagenesis and transient transfection of the mutant constructs. We confirmed the major contribution of the enhancer region to the transcriptional activity of the prothrombin promoter. Analysis of this region revealed putative binding sites for hepatocyte nuclear factor HNF4, HNF3-beta and specificity protein(Sp)1. We identified six different TFs binding to three evolutionary conserved sites in the enhancer: HNF4-alpha (site 1), HNF1-alpha, HNF3-beta and an as yet unidentified TF (site 2) and the ubiquitously expressed TFs Sp1 and Sp3 (site 3). Mutagenesis studies showed that loss of binding of HNF3-beta resulted in a considerable decrease of enhancer activity, whereas loss of HNF4-alpha or Sp1/Sp3 resulted in milder reductions. The prothrombin enhancer plays a major role in regulation of prothrombin expression. Six different TFs are able to bind to this region. At least three of these TFs, HNF4-alpha, HNF3-beta and Sp1/Sp3, are important in regulation of prothrombin expression.

Environmental pollutants as risk factors for neurodegenerative disorders: Alzheimer and Parkinson diseases

PubMed Central

Chin-Chan, Miguel; Navarro-Yepes, Juliana; Quintanilla-Vega, Betzabet

2015-01-01

Neurodegenerative diseases including Alzheimer (AD) and Parkinson (PD) have attracted attention in last decades due to their high incidence worldwide. The etiology of these diseases is still unclear; however the role of the environment as a putative risk factor has gained importance. More worryingly is the evidence that pre- and post-natal exposures to environmental factors predispose to the onset of neurodegenerative diseases in later life. Neurotoxic metals such as lead, mercury, aluminum, cadmium and arsenic, as well as some pesticides and metal-based nanoparticles have been involved in AD due to their ability to increase beta-amyloid (Aβ) peptide and the phosphorylation of Tau protein (P-Tau), causing senile/amyloid plaques and neurofibrillary tangles (NFTs) characteristic of AD. The exposure to lead, manganese, solvents and some pesticides has been related to hallmarks of PD such as mitochondrial dysfunction, alterations in metal homeostasis and aggregation of proteins such as α-synuclein (α-syn), which is a key constituent of Lewy bodies (LB), a crucial factor in PD pathogenesis. Common mechanisms of environmental pollutants to increase Aβ, P-Tau, α-syn and neuronal death have been reported, including the oxidative stress mainly involved in the increase of Aβ and α-syn, and the reduced activity/protein levels of Aβ degrading enzyme (IDE)s such as neprilysin or insulin IDE. In addition, epigenetic mechanisms by maternal nutrient supplementation and exposure to heavy metals and pesticides have been proposed to lead phenotypic diversity and susceptibility to neurodegenerative diseases. This review discusses data from epidemiological and experimental studies about the role of environmental factors in the development of idiopathic AD and PD, and their mechanisms of action. PMID:25914621

THE ENVIRONMENT AND SUSCEPTIBILITY TO SCHIZOPHRENIA

PubMed Central

Brown, Alan S.

2010-01-01

In the present article the putative role of environmental factors in schizophrenia is reviewed and synthesized. Accumulating evidence from recent studies suggests that environmental exposures may play a more significant role in the etiopathogenesis of this disorder than previously thought. This expanding knowledge base is largely a consequence of refinements in the methodology of epidemiologic studies, including birth cohort investigations, and in preclinical research that has been inspired by the evolving literature on animal models of environmental exposures. The bulk of evidence supports a contribution of environmental factors acting during fetal and perinatal life; these include infections, nutritional deficiencies, paternal age, fetal/neonatal hypoxic insults, maternal stress and other exposures. A considerable amount of data supports cannabis use in adolescence, migration, unfavorable neighborhood environments, and possibly infections at different points in the lifespan as risk factors for schizophrenia. Animal models have yielded evidence suggesting that these exposures cause brain and behavioral phenotypes that are analogous to findings observed in patients with schizophrenia. It is suggested that future studies attempt to replicate these findings, identify new risk factors, explore the gestational specificity of environmental insults, elaborate developmental trajectories, and examine relationships between environmental exposures and structural and functional brain anomalies in schizophrenia patients. Future research on gene-environment interactions and epigenetic effects of environmental exposures should shed further light on genes and exposures that may not be identified in the absence of these integrated approaches. Moreover, translational studies should further facilitate the discovery of neurodevelopmental mechanisms that increase susceptibility to schizophrenia. The study of environmental factors in schizophrenia may have important implications for the prevention of this disorder, and offers the potential to complement, and refine, existing efforts on explanatory neurodevelopmental models. PMID:955757

HLA-DQA1 and PLA2R1 polymorphisms and risk of idiopathic membranous nephropathy.

PubMed

Bullich, Gemma; Ballarín, José; Oliver, Artur; Ayasreh, Nadia; Silva, Irene; Santín, Sheila; Díaz-Encarnación, Montserrat M; Torra, Roser; Ars, Elisabet

2014-02-01

Single nucleotide polymorphisms (SNPs) within HLA complex class II HLA-DQ α-chain 1 (HLA-DQA1) and M-type phospholipase A2 receptor (PLA2R1) genes were identified as strong risk factors for idiopathic membranous nephropathy (IMN) development in a recent genome-wide association study. Copy number variants (CNVs) within the Fc gamma receptor III (FCGR3) locus have been associated with several autoimmune diseases, but their role in IMN has not been studied. This study aimed to validate the association of HLA-DQA1 and PLA2R1 risk alleles with IMN in a Spanish cohort, test the putative association of FCGR3A and FCGR3B CNVs with IMN, and assess the use of these genetic factors to predict the clinical outcome of the disease. A Spanish cohort of 89 IMN patients and 286 matched controls without nephropathy was recruited between October of 2009 and July of 2012. Case-control studies for SNPs within HLA-DQA1 (rs2187668) and PLA2R1 (rs4664308) genes and CNVs for FCGR3A and FCGR3B genes were performed. The contribution of these polymorphisms to predict clinical outcome and renal function decline was analyzed. This study validated the association of these HLA-DQA1 and PLA2R1 SNPs with IMN in a Spanish cohort and its increased risk when combining both risk genotypes. No significant association was found between FCGR3 CNVs and IMN. These results revealed that HLA-DQA1 and PLA2R1 genotype combination adjusted for baseline proteinuria strongly predicted response to immunosuppressive therapy. HLA-DQA1 genotype adjusted for proteinuria was also linked with renal function decline. This study confirms that HLA-DQA1 and PLA2R1 genotypes are risk factors for IMN, whereas no association was identified for FCGR3 CNVs. This study provides, for the first time, evidence of the contribution of these HLA-DQA1 and PLA2R1 polymorphisms in predicting IMN response to immunosuppressors and disease progression. Future studies are needed to validate and identify prognostic markers.

Farm- and flock-level risk factors associated with Highly Pathogenic Avian Influenza outbreaks on small holder duck and chicken farms in the Mekong Delta of Viet Nam.

PubMed

Henning, Kate A; Henning, Joerg; Morton, John; Long, Ngo Thanh; Ha, Nguyen Truc; Meers, Joanne

2009-10-01

After 11 consecutive months of control, the Mekong Delta in Viet Nam experienced a wave of Highly Pathogenic Avian Influenza (HPAI) H5N1 outbreaks on small holder poultry farms from December 2006 to January 2007. We conducted a retrospective matched case-control study to investigate farm- and flock-level risk factors for outbreak occurrence during this period. Twenty-two case farms were selected from those where clinical signs consistent with HPAI H5N1 had been present and HPAI H5N1 had been confirmed with a positive real-time PCR test from samples obtained from affected birds. For every case farm enrolled, two control farms were selected matched on time of outbreak occurrence, farm location and species. Veterinarians conducted interviews with farmers, to collect information on household demographics, farm characteristics, husbandry practices, trading practices, poultry health, vaccination and biosecurity. Exact stratified logistic regression models were used to assess putative risk factors associated with a flock having or not having a HPAI outbreak. Nested analyses were also performed, restricted to subsets of farms using scavenging, confinement or supplementary feeding practices. Risk of an outbreak of HPAI H5N1 was increased in flocks that had received no vaccination (odds ratio (OR)=20.2; 95% confidence interval (CI): 1.0, +infinity) or only one vaccination (OR=85.2; 95% CI: 6.5, +infinity) of flocks compared to two vaccinations, and in flocks on farms that had family and friends visiting (OR=8.2; 95% CI: 1.0, +infinity) and geese present (OR=11.5; 95% CI: 1.1, +infinity). The subset analysis using only flocks that scavenged showed that sharing of scavenging areas with flocks from other farms was associated with increased risk of an outbreak (OR=10.9; 95% CI: 1.4, 492.9). We conclude that none or only one vaccination, visitors to farms, the presence of geese on farms and sharing of scavenging areas with ducks from other farms increase the risk of HPAI H5N1 outbreaks in poultry flocks in Viet Nam.

NSR-seq transcriptional profiling enables identification of a gene signature of Plasmodium falciparum parasites infecting children.

PubMed

Vignali, Marissa; Armour, Christopher D; Chen, Jingyang; Morrison, Robert; Castle, John C; Biery, Matthew C; Bouzek, Heather; Moon, Wonjong; Babak, Tomas; Fried, Michal; Raymond, Christopher K; Duffy, Patrick E

2011-03-01

Malaria caused by Plasmodium falciparum results in approximately 1 million annual deaths worldwide, with young children and pregnant mothers at highest risk. Disease severity might be related to parasite virulence factors, but expression profiling studies of parasites to test this hypothesis have been hindered by extensive sequence variation in putative virulence genes and a preponderance of host RNA in clinical samples. We report here the application of RNA sequencing to clinical isolates of P. falciparum, using not-so-random (NSR) primers to successfully exclude human ribosomal RNA and globin transcripts and enrich for parasite transcripts. Using NSR-seq, we confirmed earlier microarray studies showing upregulation of a distinct subset of genes in parasites infecting pregnant women, including that encoding the well-established pregnancy malaria vaccine candidate var2csa. We also describe a subset of parasite transcripts that distinguished parasites infecting children from those infecting pregnant women and confirmed this observation using quantitative real-time PCR and mass spectrometry proteomic analyses. Based on their putative functional properties, we propose that these proteins could have a role in childhood malaria pathogenesis. Our study provides proof of principle that NSR-seq represents an approach that can be used to study clinical isolates of parasites causing severe malaria syndromes as well other blood-borne pathogens and blood-related diseases.

NSR-seq transcriptional profiling enables identification of a gene signature of Plasmodium falciparum parasites infecting children

PubMed Central

Vignali, Marissa; Armour, Christopher D.; Chen, Jingyang; Morrison, Robert; Castle, John C.; Biery, Matthew C.; Bouzek, Heather; Moon, Wonjong; Babak, Tomas; Fried, Michal; Raymond, Christopher K.; Duffy, Patrick E.

2011-01-01

Malaria caused by Plasmodium falciparum results in approximately 1 million annual deaths worldwide, with young children and pregnant mothers at highest risk. Disease severity might be related to parasite virulence factors, but expression profiling studies of parasites to test this hypothesis have been hindered by extensive sequence variation in putative virulence genes and a preponderance of host RNA in clinical samples. We report here the application of RNA sequencing to clinical isolates of P. falciparum, using not-so-random (NSR) primers to successfully exclude human ribosomal RNA and globin transcripts and enrich for parasite transcripts. Using NSR-seq, we confirmed earlier microarray studies showing upregulation of a distinct subset of genes in parasites infecting pregnant women, including that encoding the well-established pregnancy malaria vaccine candidate var2csa. We also describe a subset of parasite transcripts that distinguished parasites infecting children from those infecting pregnant women and confirmed this observation using quantitative real-time PCR and mass spectrometry proteomic analyses. Based on their putative functional properties, we propose that these proteins could have a role in childhood malaria pathogenesis. Our study provides proof of principle that NSR-seq represents an approach that can be used to study clinical isolates of parasites causing severe malaria syndromes as well other blood-borne pathogens and blood-related diseases. PMID:21317536

Factors Associated with Recent HIV Testing among Heterosexuals at High Risk for HIV Infection in New York City.

PubMed

Gwadz, Marya; Cleland, Charles M; Kutnick, Alexandra; Leonard, Noelle R; Ritchie, Amanda S; Lynch, Laura; Banfield, Angela; McCright-Gill, Talaya; Del Olmo, Montserrat; Martinez, Belkis

2016-01-01

The Centers for Disease Control and Prevention recommends persons at high risk for HIV infection in the United States receive annual HIV testing to foster early HIV diagnosis and timely linkage to health care. Heterosexuals make up a significant proportion of incident HIV infections (>25%) but test for HIV less frequently than those in other risk categories. Yet factors that promote or impede annual HIV testing among heterosexuals are poorly understood. The present study examines individual/attitudinal-, social-, and structural-level factors associated with past-year HIV testing among heterosexuals at high risk for HIV. Participants were African-American/Black and Hispanic heterosexual adults (N = 2307) residing in an urban area with both high poverty and HIV prevalence rates. Participants were recruited by respondent-driven sampling in 2012-2015 and completed a computerized structured assessment battery covering background factors, multi-level putative facilitators of HIV testing, and HIV testing history. Separate logistic regression analysis for males and females identified factors associated with past-year HIV testing. Participants were mostly male (58%), African-American/Black (75%), and 39 years old on average (SD = 12.06 years). Lifetime homelessness (54%) and incarceration (62%) were common. Half reported past-year HIV testing (50%) and 37% engaged in regular, annual HIV testing. Facilitators of HIV testing common to both genders included sexually transmitted infection (STI) testing or STI diagnosis, peer norms supporting HIV testing, and HIV testing access. Among women, access to general medical care and extreme poverty further predicted HIV testing, while recent drug use reduced the odds of past-year HIV testing. Among men, past-year HIV testing was also associated with lifetime incarceration and substance use treatment. The present study identified gaps in rates of HIV testing among heterosexuals at high risk for HIV, and both common and gender-specific facilitators of HIV testing. Findings suggest a number of avenues for increasing HIV testing rates, including increasing the number and types of settings offering high-quality HIV testing; promoting STI as well as HIV testing; better integrating STI and HIV testing systems; implementing peer-driven social/behavioral intervention approaches to harness the positive influence of social networks and reduce unfavorable shared peer norms; and specialized approaches for women who use drugs.

Brain injury, neuroinflammation and Alzheimer's disease.

PubMed

Breunig, Joshua J; Guillot-Sestier, Marie-Victoire; Town, Terrence

2013-01-01

With as many as 300,000 United States troops in Iraq and Afghanistan having suffered head injuries (Miller, 2012), traumatic brain injury (TBI) has garnered much recent attention. While the cause and severity of these injuries is variable, severe cases can lead to lifelong disability or even death. While aging is the greatest risk factor for Alzheimer's disease (AD), it is now becoming clear that a history of TBI predisposes the individual to AD later in life (Sivanandam and Thakur, 2012). In this review article, we begin by defining hallmark pathological features of AD and the various forms of TBI. Putative mechanisms underlying the risk relationship between these two neurological disorders are then critically considered. Such mechanisms include precipitation and 'spreading' of cerebral amyloid pathology and the role of neuroinflammation. The combined problems of TBI and AD represent significant burdens to public health. A thorough, mechanistic understanding of the precise relationship between TBI and AD is of utmost importance in order to illuminate new therapeutic targets. Mechanistic investigations and the development of preclinical therapeutics are reliant upon a clearer understanding of these human diseases and accurate modeling of pathological hallmarks in animal systems.

Epigenetics and obesity: the devil is in the details.

PubMed

Franks, Paul W; Ling, Charlotte

2010-12-21

Obesity is a complex disease with multiple well-defined risk factors. Nevertheless, susceptibility to obesity and its sequelae within obesogenic environments varies greatly from one person to the next, suggesting a role for gene × environment interactions in the etiology of the disorder. Epigenetic regulation of the human genome provides a putative mechanism by which specific environmental exposures convey risk for obesity and other human diseases and is one possible mechanism that underlies the gene × environment/treatment interactions observed in epidemiological studies and clinical trials. A study published in BMC Medicine this month by Wang et al. reports on an examination of DNA methylation in peripheral blood leukocytes of lean and obese adolescents, comparing methylation patterns between the two groups. The authors identified two genes that were differentially methylated, both of which have roles in immune function. Here we overview the findings from this study in the context of those emerging from other recent genetic and epigenetic studies, discuss the strengths and weaknesses of the study and speculate on the future of epigenetics in chronic disease research.

The release of genetically modified crops into the environment. Part II. Overview of ecological risk assessment.

PubMed

Conner, Anthony J; Glare, Travis R; Nap, Jan-Peter

2003-01-01

Despite numerous future promises, there is a multitude of concerns about the impact of GM crops on the environment. Key issues in the environmental assessment of GM crops are putative invasiveness, vertical or horizontal gene flow, other ecological impacts, effects on biodiversity and the impact of presence of GM material in other products. These are all highly interdisciplinary and complex issues. A crucial component for a proper assessment is defining the appropriate baseline for comparison and decision. For GM crops, the best and most appropriately defined reference point is the impact of plants developed by traditional breeding. The latter is an integral and accepted part of agriculture. In many instances, the putative impacts identified for GM crops are very similar to the impacts of new cultivars derived from traditional breeding. When assessing GM crops relative to existing cultivars, the increased knowledge base underpinning the development of GM crops will provide greater confidence in the assurances plant science can give on the risks of releasing such crops.

Germline mutations in 40 cancer susceptibility genes among Chinese patients with high hereditary risk breast cancer.

PubMed

Li, Junyan; Jing, Ruilin; Wei, Hongyi; Wang, Minghao; Qi, Xiaowei; Liu, Haoxi; Liu, Jian; Ou, Jianghua; Jiang, Weihua; Tian, Fuguo; Sheng, Yuan; Li, Hengyu; Xu, Hong; Zhang, Ruishan; Guan, Aihua; Liu, Ke; Jiang, Hongchuan; Ren, Yu; He, Jianjun; Huang, Weiwei; Liao, Ning; Cai, Xiangjun; Ming, Jia; Ling, Rui; Xu, Yan; Hu, Chunyan; Zhang, Jianguo; Guo, Baoliang; Ouyang, Lizhi; Shuai, Ping; Liu, Zhenzhen; Zhong, Ling; Zeng, Zhen; Zhang, Ting; Xuan, Zhaoling; Tan, Xuanni; Liang, Junbin; Pan, Qinwen; Chen, Li; Zhang, Fan; Fan, Linjun; Zhang, Yi; Yang, Xinhua; Li, Jingbo; Chen, Chongjian; Jiang, Jun

2018-05-12

Multigene panel testing of breast cancer predisposition genes have been extensively conducted in Europe and America, which is relatively rare in Asia however. In this study, we assessed the frequency of germline mutations in 40 cancer predisposition genes, including BRCA1 and BRCA2, among a large cohort of Chinese patients with high hereditary risk of BC. From 2015 to 2016, consecutive BC patients from 26 centers of China with high hereditary risk were recruited (n=937). Clinical information was collected and next-generation sequencing (NGS) was performed using blood samples of participants to identify germline mutations. In total, we acquired 223 patients with putative germline mutations, including 159 in BRCA1/2, 61 in 15 other BC susceptibility genes and 3 in both BRCA1/2 and non-BRCA1/2 gene. Major mutant non-BRCA1/2 genes were TP53 (n=18), PALB2 (n=11), CHEK2 (n=6), ATM (n=6), and BARD1 (n=5). No factors predicted pathologic mutations in non-BRCA1/2 genes when treated as a whole. TP53 mutations were associated with HER-2 positive BC and younger age at diagnosis; and CHEK2 and PALB2 mutations were enriched in patients with luminal BC. Among high hereditary risk Chinese BC patients, 23.8% contained germline mutations, including 6.8% in non-BRCA1/2 genes. TP53 and PALB2 had a relatively high mutation rates (1.9% and 1.2%). Although no factors predicted for detrimental mutations in non-BRCA1/2 genes, some clinical features were associated with mutations of several particular genes. This article is protected by copyright. All rights reserved. © 2018 UICC.

Predicting the onset and persistence of episodes of depression in primary health care. The predictD-Spain study: Methodology

PubMed Central

Bellón, Juan Ángel; Moreno-Küstner, Berta; Torres-González, Francisco; Montón-Franco, Carmen; GildeGómez-Barragán, María Josefa; Sánchez-Celaya, Marta; Díaz-Barreiros, Miguel Ángel; Vicens, Catalina; de Dios Luna, Juan; Cervilla, Jorge A; Gutierrez, Blanca; Martínez-Cañavate, María Teresa; Oliván-Blázquez, Bárbara; Vázquez-Medrano, Ana; Sánchez-Artiaga, María Soledad; March, Sebastia; Motrico, Emma; Ruiz-García, Victor Manuel; Brangier-Wainberg, Paulette Renée; del Mar Muñoz-García, María; Nazareth, Irwin; King, Michael

2008-01-01

Background The effects of putative risk factors on the onset and/or persistence of depression remain unclear. We aim to develop comprehensive models to predict the onset and persistence of episodes of depression in primary care. Here we explain the general methodology of the predictD-Spain study and evaluate the reliability of the questionnaires used. Methods This is a prospective cohort study. A systematic random sample of general practice attendees aged 18 to 75 has been recruited in seven Spanish provinces. Depression is being measured with the CIDI at baseline, and at 6, 12, 24 and 36 months. A set of individual, environmental, genetic, professional and organizational risk factors are to be assessed at each follow-up point. In a separate reliability study, a proportional random sample of 401 participants completed the test-retest (251 researcher-administered and 150 self-administered) between October 2005 and February 2006. We have also checked 118,398 items for data entry from a random sample of 480 patients stratified by province. Results All items and questionnaires had good test-retest reliability for both methods of administration, except for the use of recreational drugs over the previous six months. Cronbach's alphas were good and their factorial analyses coherent for the three scales evaluated (social support from family and friends, dissatisfaction with paid work, and dissatisfaction with unpaid work). There were 191 (0.16%) data entry errors. Conclusion The items and questionnaires were reliable and data quality control was excellent. When we eventually obtain our risk index for the onset and persistence of depression, we will be able to determine the individual risk of each patient evaluated in primary health care. PMID:18657275

Fetomaternal hemorrhage during external cephalic version.

PubMed

Boucher, Marc; Marquette, Gerald P; Varin, Jocelyne; Champagne, Josette; Bujold, Emmanuel

2008-07-01

To estimate the frequency and volume of fetomaternal hemorrhage during external cephalic version for term breech singleton fetuses and to identify risk factors involved with this complication. A prospective observational study was performed including all patients undergoing a trial of external cephalic version for a breech presentation of at least 36 weeks of gestation between 1987 and 2001 in our center. A search for fetal erythrocytes using the standard Kleihauer-Betke test was obtained before and after each external cephalic version. The frequency and volume of fetomaternal hemorrhage were calculated. Putative risk factors for fetomaternal hemorrhage were evaluated by chi(2) test and Mann-Whitney U test. A Kleihauer-Betke test result was available before and after 1,311 trials of external cephalic version. The Kleihauer-Betke test was positive in 67 (5.1%) before the procedure. Of the 1,244 women with a negative Kleihauer-Betke test before external cephalic version, 30 (2.4%) had a positive Kleihauer-Betke test after the procedure. Ten (0.8%) had an estimated fetomaternal hemorrhage greater than 1 mL, and one (0.08%) had an estimated fetomaternal hemorrhage greater than 30 mL. The risk of fetomaternal hemorrhage was not influenced by parity, gestational age, body mass index, number of attempts at version, placental location, or amniotic fluid index. The risk of detectable fetomaternal hemorrhage during external cephalic version was 2.4%, with fetomaternal hemorrhage more than 30 mL in less than 0.1% of cases. These data suggest that the performance of a Kleihauer-Betke test is unwarranted in uneventful external cephalic version and that in Rh-negative women, no further Rh immune globulin is necessary other than the routine 300-microgram dose at 28 weeks of gestation and postpartum. II.

Prevalence of latent tuberculosis infection and associated risk factors among 3,374 healthcare students in Italy.

PubMed

Lamberti, Monica; Muoio, Mariarosaria; Monaco, Maria Grazia Lourdes; Uccello, Rossella; Sannolo, Nicola; Mazzarella, Gennaro; Garzillo, Elpidio Maria; Arnese, Anonio; La Cerra, Giuseppe; Coppola, Nicola

2014-01-01

The risk of tuberculosis (TB) in healthcare personnel (HCP) is related to its incidence in the general population. Healthcare students involved in clinical training could be exposed to occupational risks similar to those that HCP face. The prevalence of latent tuberculosis infection (LTBI) among undergraduate healthcare students with different working seniority in Italy was analysed. A cross-sectional study under a screening programme for LTBI among undergraduate and postgraduate students attending Medical School at the Second University of Naples was conducted between January 2012 and December 2013 with clinical evaluations, tuberculin skin testing (TST) and, in positive TST students, Interferon-γ release assays (IGRA). Putative risk factors for LTBI were assessed by means of a standardised questionnaire. 3,374 students attending the Medical School of the Second University of Naples were submitted to a screening programme for TBC. 3,331 performed TST as a first-level test and 43 performed a Quantiferon test (QFT). 128 students were TST-positive and continued the diagnostic work with QFT, which was positive in 34 students. Of the 43 subjects who took the QFT as a first-level test only 1 was positive. In 35 students positive to the QFT test we formulated the diagnosis of LTBI by clinical and radiographic results. A correlation was found between age, non-Italian born persons, studying age, post-medical school status and LTBI. The prevalence of LTBI among healthcare students in our study was very low. In countries with a low incidence of TB, the screening programmes of healthcare students can be useful for early identification and treatment of sporadic cases of LTBI.

Profiling Antibody Responses to Infections by Chlamydia abortus Enables Identification of Potential Virulence Factors and Candidates for Serodiagnosis

PubMed Central

Forsbach-Birk, Vera; Foddis, Corinna; Simnacher, Ulrike; Wilkat, Max; Longbottom, David; Walder, Gernot; Benesch, Christiane; Ganter, Martin; Sachse, Konrad; Essig, Andreas

2013-01-01

Enzootic abortion of ewes (EAE) due to infection with the obligate intracellular pathogen Chlamydia (C.) abortus is an important zoonosis leading to considerable economic loss to agriculture worldwide. The pathogen can be transmitted to humans and may lead to serious infection in pregnant women. Knowledge about epidemiology, clinical course and transmission to humans is hampered by the lack of reliable diagnostic tools. Immunoreactive proteins, which are expressed in infected animals and humans, may serve as novel candidates for diagnostic marker proteins and represent putative virulence factors. In order to broaden the spectrum of immunogenic C. abortus proteins we applied 2D immunoblot analysis and screening of an expression library using human and animal sera. We have identified 48 immunoreactive proteins representing potential diagnostic markers and also putative virulence factors, such as CAB080 (homologue of the “macrophage infectivity potentiator”, MIP), CAB167 (homologue of the “translocated actin recruitment protein”, TARP), CAB712 (homologue of the “chlamydial protease-like activity factor”, CPAF), CAB776 (homologue of the “Polymorphic membrane protein D”, PmpD), and the “hypothetical proteins” CAB063, CAB408 and CAB821, which are predicted to be type III secreted. We selected two putative virulence factors for further characterization, i.e. CAB080 (cMIP) and CAB063, and studied their expression profiles at transcript and protein levels. Analysis of the subcellular localization of both proteins throughout the developmental cycle revealed CAB063 being the first C. abortus protein shown to be translocated to the host cell nucleus. PMID:24260366

Helicobacter pylori and non-malignant diseases.

PubMed

Matysiak-Budnik, Tamara; Laszewicz, Wiktor; Lamarque, Dominique; Chaussade, Stanislas

2006-10-01

The prevalence of Helicobacter pylori-associated peptic ulcers, in particular duodenal ulcers, is decreasing following decreasing prevalence of H. pylori infection, while the frequency of non-steroidal anti-inflammatory drugs (NSAIDs)-induced and H. pylori-negative idiopathic ulcers is increasing. The incidence of bleeding ulcers has been stable during the last decades. Several putative H. pylori virulence genes, i.e., cag, vacA, babA, or dupA, as well as host-related genetic factors like IL-1beta and TNFalpha-gene polymorphism, have been proposed as risk factors for duodenal ulcer. H. pylori eradication may prevent NSAID complications, in particular, when it is performed before introduction of NSAIDs. There is a complex association between H. pylori and gastroesophageal reflux disease (GERD), and the impact of H. pylori eradication on the appearance of GERD symptoms depends on various host- and bacteria-related factors. Eradication of H. pylori in GERD is recommended in patients before instauration of a long-term PPI treatment to prevent the development of gastric atrophy. A small proportion (10%) of non-ulcer dyspepsia cases may be attributed to H. pylori and may benefit from eradication treatment. A test-and-treat strategy is more cost-effective than prompt endoscopy in the initial management of dyspepsia.

Diet and endometrial cancer: a focus on the role of fruit and vegetable intake, Mediterranean diet and dietary inflammatory index in the endometrial cancer risk.

PubMed

Ricceri, Fulvio; Giraudo, Maria Teresa; Fasanelli, Francesca; Milanese, Dario; Sciannameo, Veronica; Fiorini, Laura; Sacerdote, Carlotta

2017-11-13

Endometrial cancer is the fourth most common cancer in European women. The major risk factors for endometrial cancer are related to the exposure of endometrium to estrogens not opposed to progestogens, that can lead to a chronic endometrial inflammation. Diet may play a role in cancer risk by modulating chronic inflammation. In the framework of a case-control study, we recruited 297 women with newly diagnosed endometrial cancer and 307 controls from Northern Italy. Using logistic regression, we investigated the role of fruit and vegetable intake, adherence to the Mediterranean diet (MD), and the dietary inflammatory index (DII) in endometrial cancer risk. Women in the highest quintile of vegetable intake had a statistically significantly lower endometrial cancer risk (adjusted OR 5th quintile vs 1st quintile: 0.34, 95% CI 0.17-0.68). Women with high adherence to the MD had a risk of endometrial cancer that was about half that of women with low adherence to the MD (adjusted OR: 0.51, 95% CI 0.39-0.86). A protective effect was detected for all the lower quintiles of DII, with the highest protective effect seen for the lowest quintile (adjusted OR 5th quintile vs 1st quintile: 3.28, 95% CI 1.30-8.26). These results suggest that high vegetable intake, adherence to the MD, and a low DII are related to a lower endometrial cancer risk, with several putative connected biological mechanisms that strengthen the biological plausibility of this association.

Comparison of the geographical distribution of feline immunodeficiency virus and feline leukemia virus infections in the United States of America (2000-2011).

PubMed

Chhetri, Bimal K; Berke, Olaf; Pearl, David L; Bienzle, Dorothee

2013-01-05

Although feline immunodeficiency virus (FIV) and feline leukemia virus (FeLV) have similar risk factors and control measures, infection rates have been speculated to vary in geographic distribution over North America. Since both infections are endemic in North America, it was assumed as a working hypothesis that their geographic distributions were similar. Hence, the purpose of this exploratory analysis was to investigate the comparative geographical distribution of both viral infections. Counts of FIV (n=17,108) and FeLV (n=30,017) positive serology results (FIV antibody and FeLV ELISA) were obtained for 48 contiguous states and District of Columbia of the United States of America (US) from the IDEXX Laboratories website. The proportional morbidity ratio of FIV to FeLV infection was estimated for each administrative region and its geographic distribution pattern was visualized by a choropleth map. Statistical evidence of an excess in the proportional morbidity ratio from unity was assessed using the spatial scan test under the normal probability model. This study revealed distinct spatial distribution patterns in the proportional morbidity ratio suggesting the presence of one or more relevant and geographically varying risk factors. The disease map indicates that there is a higher prevalence of FIV infections in the southern and eastern US compared to FeLV. In contrast, FeLV infections were observed to be more frequent in the western US compared to FIV. The respective excess in proportional morbidity ratio was significant with respect to the spatial scan test (p < 0.05). The observed variability in the geographical distribution of the proportional morbidity ratio of FIV to FeLV may be related to the presence of an additional or unique, but yet unknown, spatial risk factor. Putative factors may be geographic variations in specific virus strains and rate of vaccination. Knowledge of these factors and the geographical distributions of these infections can inform recommendations for testing, management and prevention. However, further studies are required to investigate the potential association of these factors with FIV and FeLV.

Gene flow in complex landscapes: Testing multiple hypotheses with causal modeling

Treesearch

Samuel A. Cushman; Kevin S. McKelvey; Jim Hayden; Michael K. Schwartz

2006-01-01

Predicting population-level effects of landscape change depends on identifying factors that influence population connectivity in complex landscapes. However, most putative movement corridors and barriers have not been based on empirical data. In this study, we identify factors that influence connectivity by comparing patterns of genetic similarity among 146 black bears...

Carotenoid biosynthesis in bacteria: In vitro studies of a crt/bch transcription factor from Rhodobacter capsulatus and carotenoid enzymes from Erwinia herbicola

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

O'Brien, D.A.

1992-11-01

A putative transcription factor in Rhodobactor capsulatus which binds upstream of the crt and bch pigment biosynthesis operons and appears to play a role in the adaptation of the organism from the aerobic to the anaerobic-photosynthetic growth mode was characterized. Chapter 2 describes the identification of this factor through an in vitro mobility shift assay, as well as the determination of its binding properties and sequence specificity. Chapter 3 focuses on the isolation of this factor. Biochemistry of later carotenoid biosynthesis enzymes derived from the non-photosynthetic bacterium, Erwinia herbicola. Chapter 4 describes the separate overexpression and in vitro analysis ofmore » two enzymes involved in the main sequence of the carotenoid biosynthesis pathway, lycopene cyclase and 5-carotene hydroxylase. Chapter 5 examines the overexpression and enzymology of functionally active zeaxanthin glucosyltransferase, an enzyme which carries out a more unusual transformation, converting a carotenoid into its more hydrophilic mono- and diglucoside derivatives. In addition, amino acid homology with other glucosyltransferases suggests a putative binding site for the UDP-activated glucose substrate.« less

PlantTFDB: a comprehensive plant transcription factor database

PubMed Central

Guo, An-Yuan; Chen, Xin; Gao, Ge; Zhang, He; Zhu, Qi-Hui; Liu, Xiao-Chuan; Zhong, Ying-Fu; Gu, Xiaocheng; He, Kun; Luo, Jingchu

2008-01-01

Transcription factors (TFs) play key roles in controlling gene expression. Systematic identification and annotation of TFs, followed by construction of TF databases may serve as useful resources for studying the function and evolution of transcription factors. We developed a comprehensive plant transcription factor database PlantTFDB (http://planttfdb.cbi.pku.edu.cn), which contains 26 402 TFs predicted from 22 species, including five model organisms with available whole genome sequence and 17 plants with available EST sequences. To provide comprehensive information for those putative TFs, we made extensive annotation at both family and gene levels. A brief introduction and key references were presented for each family. Functional domain information and cross-references to various well-known public databases were available for each identified TF. In addition, we predicted putative orthologs of those TFs among the 22 species. PlantTFDB has a simple interface to allow users to search the database by IDs or free texts, to make sequence similarity search against TFs of all or individual species, and to download TF sequences for local analysis. PMID:17933783

Sites of release of Putative Sex Pheromone and Sexual Behaviour in Female Carcinus maenas(Crustacea: Decapoda)

NASA Astrophysics Data System (ADS)

Bamber, S. D.; Naylor, E.

1997-02-01

Pre-moult female Carcinus maenasurine was confirmed as a source of putative sex pheromone. The sexual and temporal specificity of bioactivity in pre-moult female urine was demonstrated when urine samples taken from inter-moult and pre-moult male crabs, and inter-moult females, failed to generate a sexual response from receptive males. Detection sensitivity of male crabs to pre-moult female urine was established at a dilution factor of 1 μl of urine in 10 ml of seawater. Experimental blockage of the site of urine release (the antennal gland opercula) failed to diminish the chemical attractiveness of pre-moult female crabs to test males, implicating at least one further site of putative pheromone release. Observations of female sexual behaviour demonstrated an active role by pre-moult and post-moult female crabs when introduced to male crabs whose locomotor movement had been temporarily restricted.

[Isolation of ABA-regulated genes in Oryza sativa through fluorescent differential display PCR (FDD-PCR)].

PubMed

Xu, Shou Ling; Shen, Si Shi; Xu, Zhi Hong; Xue, Hong Wei

2002-12-01

Abscisic acid (ABA) was critical in plant seed development and response to environmental factors such as stress situations. To study the possible ABA related signaling transduction pathways, we tried to isolate the ABA-regulated genes through fluorescent differential display PCR (FDD-PCR) technology using rice seedling as materials (treated with ABA for 2, 4, 8 and 12h). In the 17 fragments isolated, 14 and 3 clones were up-and down-regulated respectively. Sequence analyses revealed that the encoded proteins were involved in photosynthesis (7 fragments), signal transduction (1 fragments), transcription (2 fragments), metabolism and resistance (6 fragments), and unknown protein (1 fragments). 3 clones, encoding putative alpha/beta hydrolase fold, putative vacuolar H+ -ATPase B subunit, putative tyrosine phosphatase, were confirmed to be regulated under ABA treatment by RT-PCR and northern blot analysis. FDD-PCR and possible functional mechanisms of ABA were discussed.

Understanding the role of injury/illness sensitivity and anxiety sensitivity in (automatic) pain processing: an examination using the extrinsic affective simon task.

PubMed

Vancleef, Linda M G; Peters, Madelon L; Gilissen, Susan M P; De Jong, Peter J

2007-07-01

Three fundamental fears are assumed to underlie psychopathology: Anxiety Sensitivity (AS), Injury/illness sensitivity (IS), and Fear of Negative Evaluation (FNE). Both AS and IS may form risk factors for the development and exacerbation of chronic pain. The current research examines the relation between these fears and automatic threat appraisal for pain-related stimuli. Study 1 (n=48) additionally examined content-specific associations of AS and FNE with the automatic threat appraisal of, respectively, panic and social evaluative cues. Study 2 (n=60) additionally focused on the association of IS and AS with the engagement in health protecting behavior, and the use of health care services. Both studies found evidence for an automatic threat appraisal of aversive stimuli. Study 2 demonstrated a positive association between the automatic threat appraisal for pain-related stimuli and individuals' IS levels. IS was found to be the single best predictor of the tendency to engage in health protecting behavior, whereas AS was the single best predictor of the reported use of health care services. This study contributes to the field of knowledge on putative risk factors for chronic pain. Results demonstrate an automatic threat appraisal toward pain-related stimuli that is related to vulnerability traits for pain. This automatic threat appraisal might initiate relatively spontaneous (nonstrategic) pain-maintaining behavioral responses.

Motivation and personality: relationships between putative motive dimensions and the five factor model of personality.

PubMed

Bernard, Larry C

2010-04-01

There are few multidimensional measures of individual differences in motivation available. The Assessment of Individual Motives-Questionnaire assesses 15 putative dimensions of motivation. The dimensions are based on evolutionary theory and preliminary evidence suggests the motive scales have good psychometric properties. The scales are reliable and there is evidence of their consensual validity (convergence of self-other ratings) and behavioral validity (relationships with self-other reported behaviors of social importance). Additional validity research is necessary, however, especially with respect to current models of personality. The present study tested two general and 24 specific hypotheses based on proposed evolutionary advantages/disadvantages and fitness benefits/costs of the five-factor model of personality together with the new motive scales in a sample of 424 participants (M age=28.8 yr., SD=14.6). Results were largely supportive of the hypotheses. These results support the validity of new motive dimensions and increase understanding of the five-factor model of personality.

Neurocircuitry underlying risk and resilience to social anxiety disorder

PubMed Central

Clauss, Jacqueline A.; Avery, Suzanne N.; VanDerKlok, Ross M.; Rogers, Baxter P.; Cowan, Ronald L.; Benningfield, Margaret M.; Blackford, Jennifer Urbano

2015-01-01

Background Almost half of children with an inhibited temperament will develop social anxiety disorder by late adolescence. Importantly, this means that half of children with an inhibited temperament will not develop social anxiety disorder. Studying adults with an inhibited temperament provides a unique opportunity to identify neural signatures of both risk and resilience to social anxiety disorder. Methods Functional MRI was used to measure brain activation during the anticipation of viewing fear faces in 34 young adults (17 inhibited, 17 uninhibited). To identify neural signatures of risk, we tested for group differences in functional activation and connectivity in regions implicated in social anxiety disorder, including the prefrontal cortex, amygdala, and insula. To identify neural signatures of resilience, we tested correlations between brain activation and both emotion regulation and social anxiety scores. Results Inhibited subjects had greater activation of a prefrontal network when anticipating viewing fear faces, relative to uninhibited subjects. No group differences were identified in the amygdala. Inhibited subjects had more negative connectivity between the rostral anterior cingulate cortex (ACC) and the bilateral amygdala. Within the inhibited group, those with fewer social anxiety symptoms and better emotion regulation skills had greater ACC activation and greater functional connectivity between the ACC and amygdala. Conclusions These finding suggest that engaging regulatory prefrontal regions during anticipation may be a protective factor, or putative neural marker of resilience, in high-risk individuals. Cognitive training targeting prefrontal cortex function may provide protection against anxiety, especially in high-risk individuals, such as those with inhibited temperament. PMID:24753211

Chronic Pancreatitis and Pancreatic Cancer Risk: A Systematic Review and Meta-analysis.

PubMed

Kirkegård, Jakob; Mortensen, Frank Viborg; Cronin-Fenton, Deirdre

2017-09-01

Chronic pancreatitis is a putative risk factor for pancreatic cancer. The aim of this study was to examine the magnitude and temporality of this association. We searched MEDLINE and EMBASE for observational studies investigating the association between chronic pancreatitis and pancreatic cancer. We computed overall effect estimates (EEs) with associated 95% confidence intervals (CIs) using a random-effects meta-analytic model. The EEs were stratified by length of follow-up from chronic pancreatitis diagnosis to pancreatic cancer (lag period). Robustness of the results was examined in sensitivity analyses. We identified 13 eligible studies. Pooled EEs for pancreatic cancer in patients with chronic pancreatitis were 16.16 (95% CI: 12.59-20.73) for patients diagnosed with pancreatic cancer within 2 years from their chronic pancreatitis diagnosis. The risk of pancreatic cancer in patients with chronic pancreatitis decreased when the lag period was increased to 5 years (EE: 7.90; 95% CI: 4.26-14.66) or a minimum of 9 years (EE: 3.53; 95% CI: 1.69-7.38). In conclusion, chronic pancreatitis increases the risk of pancreatic cancer, but the association diminishes with long-term follow-up. Five years after diagnosis, chronic pancreatitis patients have a nearly eight-fold increased risk of pancreatic cancer. We suggest that common practice on inducing a 2-year lag period in these studies may not be sufficient. We also recommend a close follow-up in the first years following a diagnosis of chronic pancreatitis to avoid overlooking a pancreatic cancer.

Do Child Abuse and Maltreatment Increase Risk of Schizophrenia?

PubMed Central

Sideli, Lucia; Mule, Alice; La Barbera, Daniele

2012-01-01

Introduction IntroductionaaAlthough childhood abuse is a recognised risk factor for depression, post-traumatic stress disorder, and substance misuse, its role in the aetiology of psychotic disorder remained controversial. This is in part because the putative effect of childhood trauma on psychosis has been mostly evaluated by small, cross sectional, uncontrolled studies that raised methodological issues. Methods Papers concerning the association between childhood trauma and psychotic disorders (to November, 2011) were identified using a comprehensive search of PubMed, Psychinfo, and Scopus and analysing reference list of relevant papers. A narrative synthesis was used to summarise results. Results An association between childhood abuse and psychotic symptoms was consistently reported by large cross sectional surveys with an effect ranging from 1.7 to 15. However, we cannot conclude that the relationship is causal as lack of longitudinal studies prevent us from fully excluding alternative explanations such as reverse causality. Gender, cannabis use, and depressive and post-traumatic stress disorder symptoms appear to moderate the effect of childhood trauma on psychotic disorders. However, specificity of childhood abuse in psychotic disorders and, particularly, in schizophrenia has not been demonstrated. Conclusion Although the association between childhood abuse and psychosis has been replicated, the etiological role of such early adversity has yet to be fully clarified. So far none of the studies reported support the hypothesis that childhood abuse is either sufficient or necessary to develop a psychotic disorder. It seems likely that any effect of childhood abuse on schizophrenia needs to be understood in terms of genetic susceptibility and interaction with other environmental risk factors. PMID:22707958

Family correlates of childhood binge eating: A systematic review.

PubMed

Saltzman, Jaclyn A; Liechty, Janet M

2016-08-01

Binge Eating Disorder is the most prevalent eating disorder in the US, and binge eating has been identified in children as young as five. As part of a larger registered systematic review, we identified family correlates of binge eating in children (C-BE) aged 12 and under. Using established guidelines, we searched PubMed and PsycInfo for peer-reviewed studies published in English between 1980 and April 2015 that examined family correlates and predictors of C-BE. This yielded 736 records for review; after exclusions fifteen studies were reviewed. Risk of bias was assessed. A risk factor typology was used to classify correlates. Nine of the included studies were cross-sectional and six longitudinal. Family weight teasing and parent emotional unresponsiveness were correlates of C-BE. Parent weight, education/socio-economic situation, and parent race/ethnicity were not associated with C-BE in any study reviewed. There was insufficient or unclear evidence regarding associations between C-BE and parent disordered eating, weight or thinness concern, harsh discipline, maternal dieting, attachment security, and mealtimes and feeding practices. Limitations included too few studies on many of the correlates to summarize, inconsistency of findings, homogenous samples, and predominately cross-sectional designs. Weight-related teasing in families and parental emotional unresponsiveness are correlates of C-BE and important areas to address in parent education and eating disorder prevention programs with families. Further longitudinal studies on putative risk factors for binge eating in childhood are needed to address current limitations, enable synthesis across studies, and inform public health efforts to prevent binge eating problems in children. Copyright © 2016 Elsevier Ltd. All rights reserved.

Vascular effects of wine polyphenols.

PubMed

Dell'Agli, Mario; Buscialà, Alessandra; Bosisio, Enrica

2004-09-01

Moderate consumption of red wine has been putatively associated with lowering the risk of developing coronary heart disease. This beneficial effect is mainly attributed to the occurrence of polyphenol compounds such as anthocyanosides (ACs), catechins, proanthocyanidins (PAs), stilbenes and other phenolics in red wine. This review focuses on the vascular effects of red wine polyphenols (RWPs), with emphasis on anthocyanosides and proanthocyanidins. From in vitro studies, the effect of red wine polyphenols on the vascular tone is thought to be due to short- and long-term mechanisms. NO-mediated vasorelaxation represents the short-term response to wine polyphenols, which exert the effect by increasing the influx of extracellular Ca(2+), and the mobilization of intracellular Ca(2+) in endothelial cells. Polyphenolic compounds may also have long-term properties, as they increase endothelial NO synthase expression acting on the promoter activity. In addition, they decrease the expression of adhesion molecules and growth factors, involved in migration and proliferation of vascular smooth muscle cells. Moreover, they inhibit platelet aggregation. However, a paucity of data as regards the bioavailability and metabolism of these compounds in human studies is a limiting factor to proving their efficacy in vivo.

PINK1 deficiency impairs mitochondrial homeostasis and promotes lung fibrosis

PubMed Central

Bueno, Marta; Lai, Yen-Chun; Romero, Yair; Brands, Judith; St. Croix, Claudette M.; Kamga, Christelle; Corey, Catherine; Herazo-Maya, Jose D.; Sembrat, John; Lee, Janet S.; Duncan, Steve R.; Rojas, Mauricio; Shiva, Sruti; Chu, Charleen T.; Mora, Ana L.

2014-01-01

Although aging is a known risk factor for idiopathic pulmonary fibrosis (IPF), the pathogenic mechanisms that underlie the effects of advancing age remain largely unexplained. Some age-related neurodegenerative diseases have an etiology that is related to mitochondrial dysfunction. Here, we found that alveolar type II cells (AECIIs) in the lungs of IPF patients exhibit marked accumulation of dysmorphic and dysfunctional mitochondria. These mitochondrial abnormalities in AECIIs of IPF lungs were associated with upregulation of ER stress markers and were recapitulated in normal mice with advancing age in response to stimulation of ER stress. We found that impaired mitochondria in IPF and aging lungs were associated with low expression of PTEN-induced putative kinase 1 (PINK1). Knockdown of PINK1 expression in lung epithelial cells resulted in mitochondria depolarization and expression of profibrotic factors. Moreover, young PINK1-deficient mice developed similarly dysmorphic, dysfunctional mitochondria in the AECIIs and were vulnerable to apoptosis and development of lung fibrosis. Our data indicate that PINK1 deficiency results in swollen, dysfunctional mitochondria and defective mitophagy, and promotes fibrosis in the aging lung. PMID:25562319

Sedentary behavior and sleep: paradoxical effects in association with childhood obesity.

PubMed

Must, A; Parisi, S M

2009-04-01

Sedentary behavior and sleep may be working in concert to increase the likelihood of a child becoming overweight, but in paradoxical ways. Reduction of sedentary behavior (that is, media screen time) has been extensively researched and touted as an intervention target. Inadequate sleep as a putative risk factor for obesity is only beginning to be explored. In this paper, we review the current state of research regarding these factors, and describe the existing evidence and mechanisms proposed to explain these relationships. Whereas the association between weight and sedentary behavior has been consistently shown in observational studies, effect sizes are small, and multiple mechanisms appear to be operating. Recent cross-sectional and longitudinal evidence suggests a link between short sleep duration and weight. Possible mechanisms here include direct metabolic effects as well as indirect behavioral pathways, including the presence of electronic media in children's bedrooms. Measurement issues present a challenge to both areas of research. Prospective studies that include more accurate measures of both sedentary behavior and of sleep will be needed to clarify causal pathways.

Predicting depression from illness severity in cardiovascular disease patients: self-efficacy beliefs, illness perception, and perceived social support as mediators.

PubMed

Greco, A; Steca, P; Pozzi, R; Monzani, D; D'Addario, M; Villani, A; Rella, V; Giglio, A; Malfatto, G; Parati, G

2014-04-01

Many studies have investigated the relationships between cardiovascular diseases and patients' depression; nevertheless, few is still known as regard the impact of illness severity on depression and whether psychosocial variables mediate this association. The aim of this study is to investigate the putative mediating role of illness representations, self-efficacy beliefs, and perceived social support on the relationship between illness severity and depression. A total of 75 consecutive patients with cardiovascular disease (80 % men; mean age = 65.44, SD = 10.20) were enrolled in an Italian hospital. Illness severity was measured in terms of left ventricular ejection fraction, whereas psychological factors were assessed using self-report questionnaires. The relationship between left ventricular ejection fraction and depression was mediated by identity illness perception, self-efficacy beliefs in managing cardiac risk factors, and perceived social support. The treatment of depression in cardiovascular disease patients may therefore benefit from a psychological intervention focused on patients' illness representations, self-efficacy beliefs, and their perceived social support.

Expressed sequence tags (ESTs) and phylogenetic analysis of floral genes from a paleoherb species, Asarum caudigerum.

PubMed

Zhao, Yinhe; Wang, Guoying; Zhang, Jinpeng; Yang, Junbo; Peng, Shang; Gao, Lianming; Li, Chengyun; Hu, Jinyong; Li, Dezhu; Gao, Lizhi

2006-07-01

Asarum caudigerum (Aristolochiaceae) is an important species of paleoherb in relation to understanding the origin and evolution of angiosperm flowers, due to its basal position in the angiosperms. The aim of this study was to isolate floral-related genes from A. caudigerum, and to infer evolutionary relationships among florally expression-related genes, to further illustrate the origin and diversification of flowers in angiosperms. A subtracted floral cDNA library was constructed from floral buds using suppression subtractive hybridization (SSH). The cDNA of floral buds and leaves at the seedling stage were used as a tester and a driver, respectively. To further identify the function of putative MADS-box transcription factors, phylogenetic trees were reconstructed in order to infer evolutionary relationships within the MADS-box gene family. In the forward-subtracted floral cDNA library, 1920 clones were randomly sequenced, from which 567 unique expressed sequence tags (ESTs) were obtained. Among them, 127 genes failed to show significant similarity to any published sequences in GenBank and thus are putatively novel genes. Phylogenetic analysis indicated that a total of 29 MADS-box transcription factors were members of the APETALA3(AP3) subfamily, while nine others were putative MADS-box transcription factors that formed a cluster with MADS-box genes isolated from Amborella, the basal-most angiosperm, and those from the gymnosperms. This suggests that the origin of A. caudigerum is intermediate between the angiosperms and gymnosperms.

Transcriptome-Wide Survey and Expression Profile Analysis of Putative Chrysanthemum HD-Zip I and II Genes

PubMed Central

Song, Aiping; Li, Peiling; Xin, Jingjing; Chen, Sumei; Zhao, Kunkun; Wu, Dan; Fan, Qingqing; Gao, Tianwei; Chen, Fadi; Guan, Zhiyong

2016-01-01

The homeodomain-leucine zipper (HD-Zip) transcription factor family is a key transcription factor family and unique to the plant kingdom. It consists of a homeodomain and a leucine zipper that serve in combination as a dimerization motif. The family can be classified into four subfamilies, and these subfamilies participate in the development of hormones and mediation of hormone action and are involved in plant responses to environmental conditions. However, limited information on this gene family is available for the important chrysanthemum ornamental species (Chrysanthemum morifolium). Here, we characterized 17 chrysanthemum HD-Zip genes based on transcriptome sequences. Phylogenetic analyses revealed that 17 CmHB genes were distributed in the HD-Zip subfamilies I and II and identified two pairs of putative orthologous proteins in Arabidopsis and chrysanthemum and four pairs of paralogous proteins in chrysanthemum. The software MEME was used to identify 7 putative motifs with E values less than 1e-3 in the chrysanthemum HD-Zip factors, and they can be clearly classified into two groups based on the composition of the motifs. A bioinformatics analysis predicted that 8 CmHB genes could be targeted by 10 miRNA families, and the expression of these 17 genes in response to phytohormone treatments and abiotic stresses was characterized. The results presented here will promote research on the various functions of the HD-Zip gene family members in plant hormones and stress responses. PMID:27196930

Serum Phosphorus and Risk of Cardiovascular Disease, All-Cause Mortality, or Graft Failure in Kidney Transplant Recipients: An Ancillary Study of the FAVORIT Trial Cohort.

PubMed

Merhi, Basma; Shireman, Theresa; Carpenter, Myra A; Kusek, John W; Jacques, Paul; Pfeffer, Marc; Rao, Madhumathi; Foster, Meredith C; Kim, S Joseph; Pesavento, Todd E; Smith, Stephen R; Kew, Clifton E; House, Andrew A; Gohh, Reginald; Weiner, Daniel E; Levey, Andrew S; Ix, Joachim H; Bostom, Andrew

2017-09-01

Mild hyperphosphatemia is a putative risk factor for cardiovascular disease [CVD], loss of kidney function, and mortality. Very limited data are available from sizable multicenter kidney transplant recipient (KTR) cohorts assessing the potential relationships between serum phosphorus levels and the development of CVD outcomes, transplant failure, or all-cause mortality. Cohort study. The Folic Acid for Vascular Outcome Reduction in Transplantation (FAVORIT) Trial, a large, multicenter, multiethnic, controlled clinical trial that provided definitive evidence that high-dose vitamin B-based lowering of plasma homocysteine levels did not reduce CVD events, transplant failure, or total mortality in stable KTRs. Serum phosphorus levels were determined in 3,138 FAVORIT trial participants at randomization. During a median follow-up of 4.0 years, the cohort had 436 CVD events, 238 transplant failures, and 348 deaths. Proportional hazards modeling revealed that each 1-mg/dL higher serum phosphorus level was not associated with a significant increase in CVD risk (HR, 1.06; 95% CI, 0.92-1.22), but increased transplant failure (HR, 1.36; 95% CI, 1.15-1.62) and total mortality risk associations (HR, 1.21; 95% CI, 1.04-1.40) when adjusted for treatment allocation, traditional CVD risk factors, kidney measures, type of kidney transplant, transplant vintage, and use of calcineurin inhibitors, steroids, or lipid-lowering drugs. These associations were strengthened in models without kidney measures: CVD (HR, 1.14; 95% CI, 1.00-1.31), transplant failure (HR, 1.72; 95% CI, 1.46-2.01), and mortality (HR, 1.34; 95% CI, 1.15-1.54). We lacked data for concentrations of parathyroid hormone, fibroblast growth factor 23, or vitamin D metabolites. Serum phosphorus level is marginally associated with CVD and more strongly associated with transplant failure and total mortality in long-term KTRs. A randomized controlled clinical trial in KTRs that assesses the potential impact of phosphorus-lowering therapy on these hard outcomes may be warranted. Copyright © 2017 National Kidney Foundation, Inc. All rights reserved.

Serum Phosphorus and Risk of Cardiovascular Disease, All-Cause Mortality, or Graft Failure in Kidney Transplant Recipients: An Ancillary Study of the FAVORIT Trial Cohort

PubMed Central

Merhi, Basma; Shireman, Theresa; Carpenter, Myra A.; Kusek, John W.; Jacques, Paul; Pfeffer, Marc; Rao, Madhumathi; Foster, Meredith C.; Kim, S. Joseph; Pesavento, Todd E.; Smith, Stephen R.; Kew, Clifton E.; House, Andrew A.; Gohh, Reginald; Weiner, Daniel E.; Levey, Andrew S.; Ix, Joachim H.; Bostom, Andrew

2017-01-01

Background Mild hyperphosphatemia is a putative risk factor for cardiovascular disease [CVD], loss of kidney function, and mortality. Very limited data are available from sizable multicenter kidney transplant recipient (KTR) cohorts assessing the potential relationships between serum phosphorus levels and the development of CVD outcomes, transplant failure, or all-cause mortality. Study Design Cohort study. Setting & Participants The Folic Acid for Vascular Outcome Reduction in Transplantation (FAVORIT) Trial, a large, multicenter, multiethnic, controlled clinical trial that provided definitive evidence that high-dose vitamin B–based lowering of plasma homocysteine levels did not reduce CVD events, transplant failure, or total mortality in stable KTRs. Predictor Serum phosphorus levels were determined in 3,138 FAVORIT trial participants at randomization. Results During a median follow-up of 4.0 years, the cohort had 436 CVD events, 238 transplant failures, and 348 deaths. Proportional hazards modeling revealed that each 1-mg/dL higher serum phosphorus level was not associated with a significant increase in CVD risk (HR, 1.06; 95% CI, 0.92–1.22), but increased transplant failure (HR, 1.36; 95% CI, 1.15–1.62) and total mortality risk associations (HR, 1.21; 95% CI, 1.04–1.40) when adjusted for treatment allocation, traditional CVD risk factors, kidney measures, type of kidney transplant, transplant vintage, and use of calcineurin inhibitors, steroids, or lipid-lowering drugs. These associations were strengthened in models without kidney measures: CVD (HR, 1.14; 95% CI, 1.00–1.31), transplant failure (HR, 1.72; 95% CI, 1.46–2.01), and mortality (HR, 1.34; 95% CI, 1.15–1.54). Limitations We lacked data for concentrations of parathyroid hormone, fibroblast growth factor 23, or vitamin D metabolites. Conclusions Serum phosphorus level is marginally associated with CVD and more strongly associated with transplant failure and total mortality in long-term KTRs. A randomized controlled clinical trial in KTRs that assesses the potential impact of phosphorus-lowering therapy on these hard outcomes may be warranted. PMID:28579423

In vitro activity of almond skin polyphenols for scavenging free radicals and inducing quinone reductase

USDA-ARS?s Scientific Manuscript database

Observational studies and clinical trials suggest nut intake, including almonds, is associated with an enhancement in antioxidant defense and a reduction in risk of cancer and cardiovascular disease. Almond skins are rich in polyphenols (ASP) that may contribute to these putative benefits. To assess...

AGE-RELATED DIFFERENCES IN SUSCEPTIBILITY TO CARCINOGENESIS - A QUANTITATIVE ANALYSIS OF EMPIRICAL ANIMAL BIOASSAY DATA

EPA Science Inventory

As part of its revision of cancer risk assessment guidelines, the U.S. Environmental Protection Agency has assembled and analyzed animal cancer bioassay data for exposures to mutagenic and putatively non-mutagenic chemicals over different periods of life. This paper reports an i...

Gene-environment interactions in cancer epidemiology: a National Cancer Institute Think Tank report.

PubMed

Hutter, Carolyn M; Mechanic, Leah E; Chatterjee, Nilanjan; Kraft, Peter; Gillanders, Elizabeth M

2013-11-01

Cancer risk is determined by a complex interplay of genetic and environmental factors. Genome-wide association studies (GWAS) have identified hundreds of common (minor allele frequency [MAF] > 0.05) and less common (0.01 < MAF < 0.05) genetic variants associated with cancer. The marginal effects of most of these variants have been small (odds ratios: 1.1-1.4). There remain unanswered questions on how best to incorporate the joint effects of genes and environment, including gene-environment (G × E) interactions, into epidemiologic studies of cancer. To help address these questions, and to better inform research priorities and allocation of resources, the National Cancer Institute sponsored a "Gene-Environment Think Tank" on January 10-11, 2012. The objective of the Think Tank was to facilitate discussions on (1) the state of the science, (2) the goals of G × E interaction studies in cancer epidemiology, and (3) opportunities for developing novel study designs and analysis tools. This report summarizes the Think Tank discussion, with a focus on contemporary approaches to the analysis of G × E interactions. Selecting the appropriate methods requires first identifying the relevant scientific question and rationale, with an important distinction made between analyses aiming to characterize the joint effects of putative or established genetic and environmental factors and analyses aiming to discover novel risk factors or novel interaction effects. Other discussion items include measurement error, statistical power, significance, and replication. Additional designs, exposure assessments, and analytical approaches need to be considered as we move from the current small number of success stories to a fuller understanding of the interplay of genetic and environmental factors. © 2013 WILEY PERIODICALS, INC.

Factors Associated with Cross-Contamination of Hides of Scottish Cattle by Escherichia coli O157▿

PubMed Central

Mather, A. E.; Reid, S. W. J.; McEwen, S. A.; Ternent, H. E.; Reid-Smith, R. J.; Boerlin, P.; Taylor, D. J.; Steele, W. B.; Gunn, G. J.; Mellor, D. J.

2008-01-01

The putative source of hide contamination for 236 cattle in Scotland followed from the farm through to slaughter was determined using phage and verocytotoxin type data. The majority of cattle (84%) were found to have subtypes of Escherichia coli O157 on their hide that had not been found previously in any animal from the farm of origin, strongly suggesting that contamination occurred once animals had left the farm of origin. Using logistic regression analysis, several variables and factors were found to be strongly associated (P < 0.01) with cross-contamination of cattle hides at the univariate level; commercial transport to slaughter, transport with other animals, use of a crush, line automation, and increasing slaughterhouse throughput were all risk factors, while feeding hay in lairage, processing an animal earlier in a slaughter cohort, and cleaning the landing area poststunning were protective. In the multivariable model, with the slaughterhouse and the farm group included as random effects, factors associated with the cross-contamination of cattle hides were identified. Transport to the slaughterhouse by a commercial hauler had a borderline-significant association with increased odds of an animal having a cross-contaminated hide (odds ratio [OR] [95% confidence interval {CI}] = 5.7 [0.99, 33.0]; P = 0.05). At the slaughterhouse, providing hay to cattle waiting in lairage (OR [95% CI] = 0.04 [<0.01, 1.04]; P = 0.05) and cleaning the landing area (OR [95% CI] = 0.03 [<0.01, 1.15,]; P = 0.06) also had a borderline-significant association with decreased odds of an animal having a cross-contaminated hide. Although the prevalence of carcass contamination remains very low, targeted intervention at the preslaughter stage may have the potential to reduce further the risk to public health. PMID:18723662

Gene-Environment Interactions in Cancer Epidemiology: A National Cancer Institute Think Tank Report

PubMed Central

Hutter, Carolyn M.; Mechanic, Leah E.; Chatterjee, Nilanjan; Kraft, Peter; Gillander, Elizabeth M.

2014-01-01

Cancer risk is determined by a complex interplay of genetic and environmental factors. Genome-wide association studies (GWAS) have identified hundreds of common (minor allele frequency [MAF]>0.05) and less common (0.01

The VicGeneration study - a birth cohort to examine the environmental, behavioural and biological predictors of early childhood caries: background, aims and methods

PubMed Central

2010-01-01

Background Dental caries (decay) during childhood is largely preventable however it remains a significant and costly public health concern, identified as the most prevalent chronic disease of childhood. Caries in children aged less than five years (early childhood caries) is a rapid and progressive disease that can be painful and debilitating, and significantly increases the likelihood of poor child growth, development and social outcomes. Early childhood caries may also result in a substantial social burden on families and significant costs to the public health system. A disproportionate burden of disease is also experienced by disadvantaged populations. Methods/Design This study involves the establishment of a birth cohort in disadvantaged communities in Victoria, Australia. Children will be followed for at least 18 months and the data gathered will explore longitudinal relationships and generate new evidence on the natural history of early childhood caries, the prevalence of the disease and relative contributions of risk and protective biological, environmental and behavioural factors. Specifically, the study aims to: 1. Describe the natural history of early childhood caries (at ages 1, 6, 12 and 18 months), tracking pathways from early bacterial colonisation, through non-cavitated enamel white spot lesions to cavitated lesions extending into dentine. 2. Enumerate oral bacterial species in the saliva of infants and their primary care giver. 3. Identify the strength of concurrent associations between early childhood caries and putative risk and protective factors, including biological (eg microbiota, saliva), environmental (fluoride exposure) and socio-behavioural factors (proximal factors such as: feeding practices and oral hygiene; and distal factors such as parental health behaviours, physical health, coping and broader socio-economic conditions). 4. Quantify the longitudinal relationships between these factors and the development and progression of early childhood caries from age 1-18 months. Discussion There is currently a lack of research describing the natural history of early childhood caries in very young children, or exploring the interactions between risk and protective factors that extend to include contemporary measures of socio-behavioural factors. This study will generate knowledge about pathways, prevalence and preventive opportunities for early childhood caries, the most prevalent child health inequality. PMID:20181292

Identification of putative adhesins of Actinobacillus suis and their homologues in other members of the family Pasteurellaceae.

PubMed

Bujold, Adina R; MacInnes, Janet I

2015-11-14

Actinobacillus suis disease has been reported in a wide range of vertebrate species, but is most commonly found in swine. A. suis is a commensal of the tonsils of the soft palate of swine, but in the presence of unknown stimuli it can invade the bloodstream, causing septicaemia and sequelae such as meningitis, arthritis, and death. It is genotypically and phenotypically similar to A. pleuropneumoniae, the causative agent of pleuropneumonia, and to other members of the family Pasteurellaceae that colonise tonsils. At present, very little is known about the genes involved in attachment, colonisation, and invasion by A. suis (or related members of the tonsil microbiota). Bioinformatic analyses of the A. suis H91-0380 genome were done using BASys and blastx in GenBank. Forty-seven putative adhesin-associated genes predicted to encode 24 putative adhesins were discovered. Among these are 6 autotransporters, 25 fimbriae-associated genes (encoding 3 adhesins), 12 outer membrane proteins, and 4 additional genes (encoding 3 adhesins). With the exception of 2 autotransporter-encoding genes (aidA and ycgV), both with described roles in virulence in other species, all of the putative adhesin-associated genes had homologues in A. pleuropneumoniae. However, the majority of the closest homologues of the A. suis adhesins are found in A. ureae and A. capsulatus--species not known to infect swine, but both of which can cause systemic infections. A. suis and A. pleuropneumoniae share many of the same putative adhesins, suggesting that the different diseases, tissue tropism, and host range of these pathogens are due to subtle genetic differences, or perhaps differential expression of virulence factors during infection. However, many of the putative adhesins of A. suis share even greater homology with those of other pathogens within the family Pasteurellaceae. Similar to A. suis, these pathogens (A. capsulatus and A. ureae) cause systemic infections and it is tempting to speculate that they employ similar strategies to invade the host, but more work is needed before that assertion can be made. This work begins to examine adhesin-associated factors that allow some members of the family Pasteurellaceae to invade the bloodstream while others cause a more localised infection.

Progress and Future Directions in Research on the Psychosis Prodrome: A Review for Clinicians

PubMed Central

Woodberry, Kristen A; Shapiro, Daniel I; Bryant, Caitlin; Seidman, Larry J.

2016-01-01

The psychosis prodrome, or period of clinical and functional decline leading up to acute psychosis, offers a unique opportunity for identifying mechanisms of psychosis onset and testing early intervention strategies. We summarize major findings and emerging directions in prodromal research and provide recommendations for clinicians working with individuals suspected to be at high risk for psychosis. The past two decades of research have led to three major advances. First, tools and criteria have been developed that can reliably identify imminent risk for a psychotic disorder. Second, longitudinal clinical and psychobiological data from large multisite studies are strengthening individual risk assessment and offering insights into potential mechanisms of illness onset. Third, psychosocial and pharmacological interventions are demonstrating promise for delaying or preventing the onset of psychosis in help-seeking, high-risk individuals. The dynamic psychobiological processes implicated in both risk and onset of psychosis, including altered gene expression, cognitive dysfunction, inflammation, gray and white matter brain changes, and vulnerability-stress interactions suggest a wide range of potential treatment targets and strategies. The expansion of resources devoted to early intervention and prodromal research worldwide raises hope for investigating them. Future directions include identifying psychosis-specific risk and resilience factors in children, adolescents, and non-help-seeking community samples, improving study designs to test hypothesized mechanisms of change, and intervening with strategies that better engage youth, their environmental contexts, and neurodevelopmental targets to improve functional outcomes. Prospective research on putatively prodromal samples has the potential to substantially reshape our understanding of mental illness and our efforts to combat it. PMID:26954594

Variability in PAH-DNA adduct measurements in peripheral mononuclear cells: implications for quantitative cancer risk assessment.

PubMed

Dickey, C; Santella, R M; Hattis, D; Tang, D; Hsu, Y; Cooper, T; Young, T L; Perera, F P

1997-10-01

Biomarkers such as DNA adducts have significant potential to improve quantitative risk assessment by characterizing individual differences in metabolism of genotoxins and DNA repair and accounting for some of the factors that could affect interindividual variation in cancer risk. Inherent uncertainty in laboratory measurements and within-person variability of DNA adduct levels over time are putatively unrelated to cancer risk and should be subtracted from observed variation to better estimate interindividual variability of response to carcinogen exposure. A total of 41 volunteers, both smokers and nonsmokers, were asked to provide a peripheral blood sample every 3 weeks for several months in order to specifically assess intraindividual variability of polycyclic aromatic hydrocarbon (PAH)-DNA adduct levels. The intraindividual variance in PAH-DNA adduct levels, together with measurement uncertainty (laboratory variability and unaccounted for differences in exposure), constituted roughly 30% of the overall variance. An estimated 70% of the total variance was contributed by interindividual variability and is probably representative of the true biologic variability of response to carcinogenic exposure in lymphocytes. The estimated interindividual variability in DNA damage after subtracting intraindividual variability and measurement uncertainty was 24-fold. Inter-individual variance was higher (52-fold) in persons who constitutively lack the Glutathione S-Transferase M1 (GSTM1) gene which is important in the detoxification pathway of PAH. Risk assessment models that do not consider the variability of susceptibility to DNA damage following carcinogen exposure may underestimate risks to the general population, especially for those people who are most vulnerable.

Distribution of Putative Virulence Genes in Streptococcus mutans Strains Does Not Correlate with Caries Experience▿†‖

PubMed Central

Argimón, Silvia; Caufield, Page W.

2011-01-01

Streptococcus mutans, a member of the human oral flora, is a widely recognized etiological agent of dental caries. The cariogenic potential of S. mutans is related to its ability to metabolize a wide variety of sugars, form a robust biofilm, produce copious amounts of lactic acid, and thrive in the acid environment that it generates. The remarkable genetic variability present within the species is reflected at the phenotypic level, notably in the differences in the cariogenic potential between strains. However, the genetic basis of these differences is yet to be elucidated. In this study, we surveyed by PCR and DNA hybridization the distribution of putative virulence genes, genomic islands, and insertion sequences across a collection of 33 strains isolated from either children with severe early childhood caries (S-ECC) or those who were caries free (CF). We found this genetically diverse group of isolates to be remarkably homogeneous with regard to the distribution of the putative virulence genes and genetic elements analyzed. Our findings point to the role of other factors in the pathogenesis of S-ECC, such as uncharacterized virulence genes, differences in gene expression and/or enzymatic activity, cooperation between S. mutans strains or with other members of the oral biota, and host factors. PMID:21209168

Identifying novel genes and chemicals related to nasopharyngeal cancer in a heterogeneous network.

PubMed

Li, Zhandong; An, Lifeng; Li, Hao; Wang, ShaoPeng; Zhou, You; Yuan, Fei; Li, Lin

2016-05-05

Nasopharyngeal cancer or nasopharyngeal carcinoma (NPC) is the most common cancer originating in the nasopharynx. The factors that induce nasopharyngeal cancer are still not clear. Additional information about the chemicals or genes related to nasopharyngeal cancer will promote a better understanding of the pathogenesis of this cancer and the factors that induce it. Thus, a computational method NPC-RGCP was proposed in this study to identify the possible relevant chemicals and genes based on the presently known chemicals and genes related to nasopharyngeal cancer. To extensively utilize the functional associations between proteins and chemicals, a heterogeneous network was constructed based on interactions of proteins and chemicals. The NPC-RGCP included two stages: the searching stage and the screening stage. The former stage is for finding new possible genes and chemicals in the heterogeneous network, while the latter stage is for screening and removing false discoveries and selecting the core genes and chemicals. As a result, five putative genes, CXCR3, IRF1, CDK1, GSTP1, and CDH2, and seven putative chemicals, iron, propionic acid, dimethyl sulfoxide, isopropanol, erythrose 4-phosphate, β-D-Fructose 6-phosphate, and flavin adenine dinucleotide, were identified by NPC-RGCP. Extensive analyses provided confirmation that the putative genes and chemicals have significant associations with nasopharyngeal cancer.

Identifying novel genes and chemicals related to nasopharyngeal cancer in a heterogeneous network

PubMed Central

Li, Zhandong; An, Lifeng; Li, Hao; Wang, ShaoPeng; Zhou, You; Yuan, Fei; Li, Lin

2016-01-01

Nasopharyngeal cancer or nasopharyngeal carcinoma (NPC) is the most common cancer originating in the nasopharynx. The factors that induce nasopharyngeal cancer are still not clear. Additional information about the chemicals or genes related to nasopharyngeal cancer will promote a better understanding of the pathogenesis of this cancer and the factors that induce it. Thus, a computational method NPC-RGCP was proposed in this study to identify the possible relevant chemicals and genes based on the presently known chemicals and genes related to nasopharyngeal cancer. To extensively utilize the functional associations between proteins and chemicals, a heterogeneous network was constructed based on interactions of proteins and chemicals. The NPC-RGCP included two stages: the searching stage and the screening stage. The former stage is for finding new possible genes and chemicals in the heterogeneous network, while the latter stage is for screening and removing false discoveries and selecting the core genes and chemicals. As a result, five putative genes, CXCR3, IRF1, CDK1, GSTP1, and CDH2, and seven putative chemicals, iron, propionic acid, dimethyl sulfoxide, isopropanol, erythrose 4-phosphate, β-D-Fructose 6-phosphate, and flavin adenine dinucleotide, were identified by NPC-RGCP. Extensive analyses provided confirmation that the putative genes and chemicals have significant associations with nasopharyngeal cancer. PMID:27149165

The role of sexual behavior in head and neck cancer: implications for prevention and therapy

PubMed Central

Rettig, Eleni; Kiess, Ana Ponce; Fakhry, Carole

2015-01-01

HPV-positive oropharyngeal squamous cell carcinoma (HPV-OSCC) is associated with oral sexual behaviors. The sharp rise in incidence of HPV-OSCC in the USA has been attributed to changes in sexual norms over the past five decades, with lower age at sexual debut and higher numbers of sexual partners per individual. In addition, variations in HPV-OSCC prevalence by race, age cohort and gender may be attributable to differences in oral sexual behaviors among these groups. Oral HPV infection is the putative precursor to HPV-OSCC. Risk factors for oral HPV incidence, prevalence, clearance and persistence are crucial to understanding how, and in whom, oral HPV infection progresses to malignancy. Future investigation should focus on elucidating the natural history of oral HPV infection persistence and malignant transformation, developing effective screening tools and exploring opportunities for prevention such as vaccination and public health education. PMID:25193346

Assessment of gastrointestinal nematode infection, anthelmintic usage and husbandry practices on two small-scale goat farms in Malaysia.

PubMed

Wong, Flora; Sargison, Neil

2018-03-01

Haemonchosis is a common problem on goat farms in tropical countries such as Malaysia. Prevention of production losses generally depends on the use of anthelmintic drugs, but is threatened by the emergence of anthelmintic resistance. This study investigates anthelmintic efficacy on small-scale Malaysian goat farms and describes putative risk factors. Adult goats had moderate to high pre-treatment faecal trichostrongyle egg counts, despite being housed on slatted floors and fed on cut-and-carry forage, raising questions about the source of nematode infection. Our results show multiple resistance to benzimidazole and macrocyclic lactone anthelmintic drugs and allow us to discuss the genetic origins of resistance with reference to farm husbandry and management. We conclude that improvement in Malaysian goat production efficiency will require the development of sustainable helminth control strategies, underpinned by a better understanding of the origins and population genetics of anthelmintic resistance.

Maternal depression and trait anger as risk factors for escalated physical discipline.

PubMed

Shay, Nicole L; Knutson, John F

2008-02-01

To test the hypothesized anger-mediated relation between maternal depression and escalation of physical discipline, 122 economically disadvantaged mothers were assessed for current and lifetime diagnoses of depression using the Current Depressive Episode, Past Depression, and Dysthymia sections of the Structured Clinical Interview for DSM-IV (SCID) and a measure of current depressive symptoms, the Beck Depression Inventory-Second Edition (BDI-II). Escalation of physical discipline was assessed using a video analog parenting task; maternal anger not specific to discipline was assessed using the Spielberger Trait Anger Expression Inventory. Reports of anger were associated with the diagnosis of depression and depressive symptoms. Bootstrap analyses of indirect effects indicated that the link between depression and escalated discipline was mediated by anger. Parallel analyses based on BDI-II scores identified a marginally significant indirect effect of depression on discipline. Findings suggest that anger and irritability are central to the putative link between depression and harsh discipline.

The role of sexual behavior in head and neck cancer: implications for prevention and therapy.

PubMed

Rettig, Eleni; Kiess, Ana Ponce; Fakhry, Carole

2015-01-01

HPV-positive oropharyngeal squamous cell carcinoma (HPV-OSCC) is associated with oral sexual behaviors. The sharp rise in incidence of HPV-OSCC in the USA has been attributed to changes in sexual norms over the past five decades, with lower age at sexual debut and higher numbers of sexual partners per individual. In addition, variations in HPV-OSCC prevalence by race, age cohort and gender may be attributable to differences in oral sexual behaviors among these groups. Oral HPV infection is the putative precursor to HPV-OSCC. Risk factors for oral HPV incidence, prevalence, clearance and persistence are crucial to understanding how, and in whom, oral HPV infection progresses to malignancy. Future investigation should focus on elucidating the natural history of oral HPV infection persistence and malignant transformation, developing effective screening tools and exploring opportunities for prevention such as vaccination and public health education.

Distribution and abundance of host-seeking Culex species at three proximate locations with different levels of West Nile virus activity

USGS Publications Warehouse

Rochlin, I.; Ginsberg, H.S.; Campbell, S.R.

2009-01-01

Culex species were monitored at three proximate sites with historically different West Nile virus (WNV) activities. The site with human WNV transmission (epidemic) had the lowest abundance of the putative bridge vectors, Culex pipiens and Cx. salinarius. The site with horse cases but not human cases (epizootic) had the highest percent composition of Cx. salinarius, whereas the site with WNV-positive birds only (enzootic) had the highest Cx. pipiens abundance and percent composition. A total of 29 WNV-positive Culex pools were collected at the enzootic site, 17 at the epidemic site, and 14 at the epizootic site. Published models of human risk using Cx. pipiens and Cx. salinarius as the primary bridge vectors did not explain WNV activity at our sites. Other variables, such as additional vector species, environmental components, and socioeconomic factors, need to be examined to explain the observed patterns of WNV epidemic activity.

Working memory mediates the effects of gestational age at birth on expressive language development in children.

PubMed

Riva, Valentina; Cantiani, Chiara; Dionne, Ginette; Marini, Andrea; Mascheretti, Sara; Molteni, Massimo; Marino, Cecilia

2017-07-01

This study tested the role of temporary memory, measured by phonological short-term memory (pSTM) and verbal working memory (vWM), as a mediator of the effect of 3 putative risk factors (i.e., socioeconomic status, home literacy environment, birth gestational age) upon expressive and receptive language. A community-based sample of 646 Italian children aged 6-11 years was assessed with a comprehensive battery of language and cognitive tests. A mediation analysis was used to examine whether memory mediates environmental/biological effects on language. The results demonstrated a developmental cascade of effects, whereby the duration of pregnancy drives vWM functioning that, in turn, may affect expressive linguistic outcome Conclusion: Treatments focused on vWM, specifically to preterm children, may improve their language development, with enduring consequences on educational and psychosocial outcomes. (PsycINFO Database Record (c) 2017 APA, all rights reserved).

Primary sclerosing cholangitis and the microbiota: current knowledge and perspectives on etiopathogenesis and emerging therapies.

PubMed

Tabibian, James H; O'Hara, Steven P; Lindor, Keith D

2014-08-01

Primary sclerosing cholangitis (PSC) is a chronic, fibroinflammatory, cholestatic liver disease of unknown etiopathogenesis. PSC generally progresses to liver cirrhosis, is a major risk factor for hepatobiliary and colonic neoplasia, and confers a median survival to death or liver transplantation of only 12 years. Although it is well recognized that approximately 75% of patients with PSC also have inflammatory bowel disease (IBD), the significance of this association remains elusive. Accumulating evidence now suggests a potentially important role for the intestinal microbiota, and enterohepatic circulation of molecules derived therefrom, as a putative mechanistic link between PSC and IBD and a central pathobiological driver of PSC. In this concise review, we provide a summary of and perspectives regarding the relevant basic, translational, and clinical data, which, taken together, encourage further investigation of the role of the microbiota and microbial metabolites in the etiopathogenesis of PSC and as a potential target for novel pharmacotherapies.

Articular cartilage and subchondral bone in the pathogenesis of osteoarthritis.

PubMed

Goldring, Mary B; Goldring, Steven R

2010-03-01

The articular surface plays an essential role in load transfer across the joint, and conditions that produce increased load transfer or altered patterns of load distribution accelerate the development of osteoarthritis (OA). Current knowledge segregates the risk factors into two fundamental mechanisms related to the adverse effects of "abnormal" loading on normal cartilage or "normal" loading on abnormal cartilage. Although chondrocytes can modulate their functional state in response to loading, their capacity to repair and modify the surrounding extracellular matrix is limited in comparison to skeletal cells in bone. This differential adaptive capacity underlies the more rapid appearance of detectable skeletal changes, especially after acute injuries that alter joint mechanics. The imbalance in the adaptation of the cartilage and bone disrupts the physiological relationship between these tissues and further contributes to OA pathology. This review focuses on the specific articular cartilage and skeletal features of OA and the putative mechanisms involved in their pathogenesis.

PINK1 deficiency enhances autophagy and mitophagy induction.

PubMed

Gómez-Sánchez, Rubén; Yakhine-Diop, Sokhna M S; Bravo-San Pedro, José M; Pizarro-Estrella, Elisa; Rodríguez-Arribas, Mario; Climent, Vicente; Martin-Cano, Francisco E; González-Soltero, María E; Tandon, Anurag; Fuentes, José M; González-Polo, Rosa A

2016-03-01

Parkinson's disease (PD) is a neurodegenerative disorder with poorly understood etiology. Increasing evidence suggests that age-dependent compromise of the maintenance of mitochondrial function is a key risk factor. Several proteins encoded by PD-related genes are associated with mitochondria including PTEN-induced putative kinase 1 (PINK1), which was first identified as a gene that is upregulated by PTEN. Loss-of-function PINK1 mutations induce mitochondrial dysfunction and, ultimately, neuronal cell death. To mitigate the negative effects of altered cellular functions cells possess a degradation mechanism called autophagy for recycling damaged components; selective elimination of dysfunctional mitochondria by autophagy is termed mitophagy. Our study indicates that autophagy and mitophagy are upregulated in PINK1-deficient cells, and is the first report to demonstrate efficient fluxes by one-step analysis. We propose that autophagy is induced to maintain cellular homeostasis under conditions of non-regulated mitochondrial quality control.

PINK1 deficiency enhances autophagy and mitophagy induction

PubMed Central

Gómez-Sánchez, Rubén; Yakhine-Diop, Sokhna M S; Bravo-San Pedro, José M; Pizarro-Estrella, Elisa; Rodríguez-Arribas, Mario; Climent, Vicente; Martin-Cano, Francisco E; González-Soltero, María E; Tandon, Anurag; Fuentes, José M; González-Polo, Rosa A

2016-01-01

Parkinson's disease (PD) is a neurodegenerative disorder with poorly understood etiology. Increasing evidence suggests that age-dependent compromise of the maintenance of mitochondrial function is a key risk factor. Several proteins encoded by PD-related genes are associated with mitochondria including PTEN-induced putative kinase 1 (PINK1), which was first identified as a gene that is upregulated by PTEN. Loss-of-function PINK1 mutations induce mitochondrial dysfunction and, ultimately, neuronal cell death. To mitigate the negative effects of altered cellular functions cells possess a degradation mechanism called autophagy for recycling damaged components; selective elimination of dysfunctional mitochondria by autophagy is termed mitophagy. Our study indicates that autophagy and mitophagy are upregulated in PINK1-deficient cells, and is the first report to demonstrate efficient fluxes by one-step analysis. We propose that autophagy is induced to maintain cellular homeostasis under conditions of non-regulated mitochondrial quality control. PMID:27308585

Creativity and bipolar disorder: Touched by fire or burning with questions?☆

PubMed Central

Johnson, Sheri L.; Murray, Greg; Fredrickson, Barbara; Youngstrom, Eric A.; Hinshaw, Stephen; Bass, Julie Malbrancq; Deckersbach, Thilo; Schooler, Jonathan; Salloum, Ihsan

2012-01-01

Substantial literature has linked bipolar disorder with creative accomplishment. Much of the thinking in this area has been inspired by biographical accounts of poets, musicians, and other highly accomplished groups, which frequently document signs of bipolar disorder in these samples. A smaller literature has examined quantitative measures of creativity among people with bipolar disorder or at risk for the disorder. In this paper, we provide a critical review of such evidence. We then consider putative mechanisms related to the link of bipolar disorder with creativity, by drawing on literature outside of bipolar disorder on personality, motivational, and affective predictors of creativity. Because so little research has directly evaluated whether these factors could help explain the elevations of creativity in bipolar disorder, we conclude with an agenda for future research on the theoretically and clinically compelling topic of creativity in bipolar disorder. PMID:22088366

Castleman's Disease: From Basic Mechanisms to Molecular Therapeutics

PubMed Central

El-Osta, Hazem E.

2011-01-01

Castleman's disease is a rare lymphoproliferative disorder in which there has been recent progress in elucidating underlying mechanisms with potential therapeutic implications. Unicentric Castleman's disease is an indolent condition that is often treated with local approaches. In contrast, patients with multicentric Castleman's disease (MCD) have a less favorable prognosis and require systemic treatment. Cytotoxic chemotherapy, with its attendant risk for toxicity, has been widely used to treat MCD, with variable efficacy. The discovery of putative etiologic factors and targets in MCD, particularly human herpes virus 8, CD20, and interleukin (IL)-6, has been translated into the use of rituximab and anti–IL-6-based therapy, as well as antiviral agents. In this article, we review the current state of the art of our understanding of Castleman's disease and its treatment and we provide insight into future treatment strategies based on disease biology. PMID:21441298

Behavioral Addictions as Mental Disorders: To Be or Not To Be?

PubMed

Petry, Nancy M; Zajac, Kristyn; Ginley, Meredith K

2018-05-07

Should excessive and problematic engagement in nonsubstance use behaviors be mental disorders? The fifth edition of the Diagnostic and Statistical Manual of Mental Disorders (DSM-5) repositioned gambling disorder in the substance use disorders section and introduced Internet gaming disorder in the research appendix; the International Classification of Diseases (ICD-11) is also considering it. This article outlines pros and cons of considering behavioral addictions as mental disorders and also reviews the DSM-5 decision-making processes. It focuses on three conditions: gambling disorder, Internet gaming disorder (IGD), and Internet addiction (IA). We detail assessment methods and prevalence rates for these conditions and outline psychiatric comorbidities, demographic and biological risk factors, and promising treatment approaches. We also briefly discuss other putative behavioral addictions: eating/food, sex, exercise, shopping, and tanning "addictions." Overall, data are inconclusive, and consistent terminology and methodology are needed to define and evaluate these conditions more fully prior to considering them mental disorders.

Insulin resistance syndrome in children : pathophysiology and potential management strategies.

PubMed

Decsi, Tamás; Molnár, Dénes

2003-01-01

The simultaneous presence of various cardiovascular risk factors in the same individual is not rare, even in the pediatric age group. The clustering of risk factors can be termed insulin resistance syndrome (IRS) because of the putative central role of tissue insulin insensitivity in the background of the inter-related metabolic disturbances. Fasting hyperinsulinemia, impaired glucose tolerance, dyslipidemia, and hypertension are considered to represent the basic abnormalities of IRS. The most prevalent related disturbances are increased plasma levels of plasminogen activator inhibitor-1, fibrinogen, uric acid, homocysteine, and C-reactive protein, as well as visceral adiposity, microalbuminuria, disturbed essential fatty acid metabolism, low availability of lipid-soluble antioxidant vitamins, and enhanced expression of tumor necrosis factor-alpha in adipose tissues. Certain genetic abnormalities have been associated with IRS, but explain only a small part of the variability in insulin resistance. The exact prevalence of IRS in children remains to be defined; it was found to be 9% in one survey among children with obesity seeking medical attention. Modification of lifestyle, i.e. reduction of energy intake and enhancement of physical activity, are unquestionable prerequisites for long-term success in the management of IRS. In at least two randomized controlled studies, metformin proved to be clinically effective in increasing insulin sensitivity in hyperinsulinemic, nondiabetic adolescents. Thiazolidinediones have been successfully tested for the treatment of insulin resistance in adults, but not in children as yet. Prevention of the development of IRS in children is obviously of great significance for the health status of the community. However, the efficacy of various preventive approaches should be investigated further in carefully designed controlled trials.

Correlates of virulence in a frog-killing fungal pathogen: evidence from a California amphibian decline

Treesearch

Jonah Piovia-Scott; Karen Pope; S. Joy Worth; Erica Bree Rosenblum; Dean Simon; Gordon Warburton; Louise A. Rollins-Smith; Laura K. Reinert; Heather L. Wells; Dan Rejmanek; Sharon Lawler; Janet Foley

2015-01-01

The fungal pathogen Batrachochytrium dendrobatidis (Bd) has caused declines and extinctions in amphibians worldwide, and there is increasing evidence that some strains of this pathogen are more virulent than others. While a number of putative virulence factors have been identified, few studies link these factors to specific epizootic events. We...

Community Violence, School-Related Protective Factors, and Psychosocial Outcomes in Urban Youth

ERIC Educational Resources Information Center

Ludwig, Kristy A.; Warren, Jared S.

2009-01-01

This study examined the relationship of two putative school-based protective factors--student identification with school and perceived teacher support--to psychosocial outcomes in a sample of urban youth exposed to community violence. Participants were 175 high school students ages 14-19 in grades 9-12 from a large urban school district. Results…

Acrolein-induced arrhythmias and autonomic imbalance due to early life persistent vitamin D deficiency in mice is mediated by the putative anti-aging factor klotho.

EPA Science Inventory

Although epidemiological, human and animal data have conclusively linked air pollution exposure to adverse cardiovascular outcomes, the severity of responses depends on a number of intrinsic (diet, underlying disease, etc) and extrinsic (e.g. co-stressors) factors. As such, cardi...

Does Low Birth Weight Share Common Genetic or Environmental Risk with Childhood Disruptive Disorders?

PubMed Central

Ficks, Courtney A.; Lahey, Benjamin B.; Waldman, Irwin D.

2015-01-01

Although advances in neonatal care over the past century have resulted in increased rates of survival among at-risk births, including infants with low birth weight, we have much to learn about the psychological outcomes in this population. In particular, although it appears that there is growing evidence that low birth weight may be associated with an increased risk for Attention-Deficit/Hyperactive Disorder (ADHD) symptoms in childhood, few studies have examined birth weight as a risk factor for disruptive disorders that commonly co-occur with ADHD [e.g. Oppositional Defiant Disorder (ODD) or Conduct Disorder (CD)]. In addition, the etiology of the relation between birth weight and these disorders is unknown. The current investigation aimed to better understand the putative role of birth weight in disruptive behavior disorders in the context of potentially confounding genetic and environmental influences by examining phenotypic associations between birth weight and disruptive disorder symptoms across families (using generalized linear models with generalized estimating equations) as well as within families (using linear regression) in two independent twin samples (Sample 1: N = 1676 individuals; Sample 2: N = 4038 individuals). We found negative associations between birth weight and several childhood disruptive disorder symptom dimensions, including inattentive, hyperactive-impulsive, and broad externalizing symptoms in both samples. Nonetheless, the overall magnitude of these associations was very small, contributing to less than 1% of the variance in these symptom dimensions. Within-family associations between birth weight and disruptive disorder symptoms did not differ for monozygotic and dizygotic twin pairs, suggesting that nonshared environmental influences rather than common genetic influences are responsible for these associations. These consistent albeit weak associations between birth weight and disruptive disorder symptoms suggest that, at least in the general population, low birth weight does not represent a major risk factor in the development of these symptoms. PMID:23834065

Contamination of Canadian private drinking water sources with antimicrobial resistant Escherichia coli.

PubMed

Coleman, Brenda L; Louie, Marie; Salvadori, Marina I; McEwen, Scott A; Neumann, Norman; Sibley, Kristen; Irwin, Rebecca J; Jamieson, Frances B; Daignault, Danielle; Majury, Anna; Braithwaite, Shannon; Crago, Bryanne; McGeer, Allison J

2013-06-01

Surface and ground water across the world, including North America, is contaminated with bacteria resistant to antibiotics. The consumption of water contaminated with antimicrobial resistant Escherichia coli (E. coli) has been associated with the carriage of resistant E. coli in people who drink it. To describe the proportion of drinking water samples submitted from private sources for bacteriological testing that were contaminated with E. coli resistant to antibiotics and to determine risk factors for the contamination of these water sources with resistant and multi-class resistant E. coli. Water samples submitted for bacteriological testing in Ontario and Alberta Canada were tested for E. coli contamination, with a portion of the positive isolates tested for antimicrobial resistance. Households were invited to complete questionnaires to determine putative risk factors for well contamination. Using multinomial logistic regression, the risk of contamination with E. coli resistant to one or two classes of antibiotics compared to susceptible E. coli was higher for shore wells than drilled wells (odds ratio [OR] 2.8) and higher for farms housing chickens or turkeys (OR 3.0) than properties without poultry. The risk of contamination with multi-class resistant E. coli (3 or more classes) was higher if the properties housed swine (OR 5.5) or cattle (OR 2.2) than properties without these livestock and higher if the wells were located in gravel (OR 2.4) or clay (OR 2.1) than in loam. Housing livestock on the property, using a shore well, and having a well located in gravel or clay soil increases the risk of having antimicrobial resistant E. coli in E. coli contaminated wells. To reduce the incidence of water borne disease and the transmission of antimicrobial resistant bacteria, owners of private wells need to take measures to prevent contamination of their drinking water, routinely test their wells for contamination, and use treatments that eliminate bacteria. Copyright © 2013 Elsevier Ltd. All rights reserved.

School hygiene and deworming are key protective factors for reduced transmission of soil-transmitted helminths among schoolchildren in Honduras.

PubMed

Gabrie, José Antonio; Rueda, María Mercedes; Canales, Maritza; Gyorkos, Theresa W; Sanchez, Ana Lourdes

2014-08-04

Among many neglected tropical diseases endemic in Honduras, soil-transmitted helminth (STH) infections are of particular importance. However, knowledge gaps remain in terms of risk factors involved in infection transmission. The aim of this study was to investigate risk factors associated with STH infections in schoolchildren living in rural Honduras. A cross-sectional study was conducted among Honduran rural schoolchildren in 2011. Demographic, socio-economic, and epidemiological data were obtained through a standardized questionnaire and STH infections were determined by the Kato-Katz method. Logistic regression models accounting for school clustering were used to assess putative risk factors for infection. A total of 320 children completed the study. Prevalences for any STH and for Ascaris lumbricoides, Trichuris trichiura and hookworms were: 72.5%, 30.3%, 66.9% and 15.9%, respectively. A number of risk factors were identified at the individual, household, and school level. Boys were at increased odds of infection with hookworms (OR 2.33, 95% CI = 1.23-4.42). Higher socio-economic status in the family had a protective effect against infections by A. lumbricoides (OR 0.80, 95% CI = 0.65-0.99) and T. trichiura (OR 0.77, 95% CI = 0.63-0.94).Low school hygiene conditions significantly increased the odds for ascariasis (OR 14.85, 95% CI = 7.29-30.24), trichuriasis (OR 7.32, 95% CI = 3.71-14.45), mixed infections (OR 9.02, 95% CI = 4.66-17.46), and ascariasis intensity of infection (OR 3.32, 95% CI = 1.05 -10.52).Children attending schools not providing deworming treatment or that had provided it only once a year were at increased odds of ascariasis (OR 10.40, 95% CI = 4.39-24.65), hookworm (OR 2.92, 95% CI = 1.09-7.85) and mixed infections (OR 10.57, 95% CI = 4.53-24.66). Poverty-reduction strategies will ultimately lead to sustainable control of STH infections in Honduras, but as shorter-term measures, uninterrupted bi-annual deworming treatment paired with improvements in school sanitary conditions may result in significant reductions of STH prevalence among Honduran schoolchildren.

In Silico Assigned Resistance Genes Confer Bifidobacterium with Partial Resistance to Aminoglycosides but Not to Β-Lactams

PubMed Central

Fouhy, Fiona; O’Connell Motherway, Mary; Fitzgerald, Gerald F.; Ross, R. Paul; Stanton, Catherine; van Sinderen, Douwe; Cotter, Paul D.

2013-01-01

Bifidobacteria have received significant attention due to their contribution to human gut health and the use of specific strains as probiotics. It is thus not surprising that there has also been significant interest with respect to their antibiotic resistance profile. Numerous culture-based studies have demonstrated that bifidobacteria are resistant to the majority of aminoglycosides, but are sensitive to β-lactams. However, limited research exists with respect to the genetic basis for the resistance of bifidobacteria to aminoglycosides. Here we performed an in-depth in silico analysis of putative Bifidobacterium-encoded aminoglycoside resistance proteins and β-lactamases and assess the contribution of these proteins to antibiotic resistance. The in silico-based screen detected putative aminoglycoside and β-lactam resistance proteins across the Bifidobacterium genus. Laboratory-based investigations of a number of representative bifidobacteria strains confirmed that despite containing putative β-lactamases, these strains were sensitive to β-lactams. In contrast, all strains were resistant to the aminoglycosides tested. To assess the contribution of genes encoding putative aminoglycoside resistance proteins in Bifidobacterium sp. two genes, namely Bbr_0651 and Bbr_1586, were targeted for insertional inactivation in B. breve UCC2003. As compared to the wild-type, the UCC2003 insertion mutant strains exhibited decreased resistance to gentamycin, kanamycin and streptomycin. This study highlights the associated risks of relying on the in silico assignment of gene function. Although several putative β-lactam resistance proteins are located in bifidobacteria, their presence does not coincide with resistance to these antibiotics. In contrast however, this approach has resulted in the identification of two loci that contribute to the aminoglycoside resistance of B. breve UCC2003 and, potentially, many other bifidobacteria. PMID:24324818

Analyzing multiple data sets by interconnecting RSAT programs via SOAP Web services: an example with ChIP-chip data.

PubMed

Sand, Olivier; Thomas-Chollier, Morgane; Vervisch, Eric; van Helden, Jacques

2008-01-01

This protocol shows how to access the Regulatory Sequence Analysis Tools (RSAT) via a programmatic interface in order to automate the analysis of multiple data sets. We describe the steps for writing a Perl client that connects to the RSAT Web services and implements a workflow to discover putative cis-acting elements in promoters of gene clusters. In the presented example, we apply this workflow to lists of transcription factor target genes resulting from ChIP-chip experiments. For each factor, the protocol predicts the binding motifs by detecting significantly overrepresented hexanucleotides in the target promoters and generates a feature map that displays the positions of putative binding sites along the promoter sequences. This protocol is addressed to bioinformaticians and biologists with programming skills (notions of Perl). Running time is approximately 6 min on the example data set.

NAC transcription factor genes: genome-wide identification, phylogenetic, motif and cis-regulatory element analysis in pigeonpea (Cajanus cajan (L.) Millsp.).

PubMed

Satheesh, Viswanathan; Jagannadham, P Tej Kumar; Chidambaranathan, Parameswaran; Jain, P K; Srinivasan, R

2014-12-01

The NAC (NAM, ATAF and CUC) proteins are plant-specific transcription factors implicated in development and stress responses. In the present study 88 pigeonpea NAC genes were identified from the recently published draft genome of pigeonpea by using homology based and de novo prediction programmes. These sequences were further subjected to phylogenetic, motif and promoter analyses. In motif analysis, highly conserved motifs were identified in the NAC domain and also in the C-terminal region of the NAC proteins. A phylogenetic reconstruction using pigeonpea, Arabidopsis and soybean NAC genes revealed 33 putative stress-responsive pigeonpea NAC genes. Several stress-responsive cis-elements were identified through in silico analysis of the promoters of these putative stress-responsive genes. This analysis is the first report of NAC gene family in pigeonpea and will be useful for the identification and selection of candidate genes associated with stress tolerance.

Gastrokines: stomach-specific proteins with putative homeostatic and tumor suppressor roles.

PubMed

Menheniott, Trevelyan R; Kurklu, Bayzar; Giraud, Andrew S

2013-01-15

During the past decade, a new family of stomach-specific proteins has been recognized. Known as "gastrokines" (GKNs), these secreted proteins are products of gastric mucus-producing cell lineages. GKNs are highly conserved in physical structure, and emerging data point to convergent functions in the modulation of gastric mucosal homeostasis and inflammation. While GKNs are highly prevalent in the normal stomach, frequent loss of GKN expression in gastric cancers, coupled with established antiproliferative activity, suggests putative tumor suppressor roles. Conversely, ectopic expression of GKNs in reparative lesions of Crohn's disease alludes to additional activity in epithelial wound healing and/or repair. Modes of action remain unsolved, but the recent demonstration of a GKN2-trefoil factor 1 heterodimer implicates functional interplay with trefoil factors. This review aims to provide a historical account of GKN biology and encapsulate the rapidly accumulating evidence supporting roles in gastric epithelial homeostasis and tumor suppression.

Review and perspective on the composition and safety of green tea extracts

USDA-ARS?s Scientific Manuscript database

The growing body of evidence regarding the putative health benefits of green tea (Camellia sinensis), including reduced risk of cancer and cardiovascular disease, has led to an increase in the consumption of brewed green tea and the formulation of green tea extracts (GTE) into a variety of food and ...

Dietary fruits and vegetables and cardiovascular diseases risk.

PubMed

Alissa, Eman M; Ferns, Gordon A

2017-06-13

Diet is likely to be an important determinant of cardiovascular disease (CVD) risk. In this article, we will review the evidence linking the consumption of fruit and vegetables and CVD risk. The initial evidence that fruit and vegetable consumption has a protective effect against CVD came from observational studies. However, uncertainty remains about the magnitude of the benefit of fruit and vegetable intake on the occurrence of CVD and whether the optimal intake is five portions or greater. Results from randomized controlled trials do not show conclusively that fruit and vegetable intake protects against CVD, in part because the dietary interventions have been of limited intensity to enable optimal analysis of their putative effects. The protective mechanisms of fruit and vegetables may not only include some of the known bioactive nutrient effects dependent on their antioxidant, anti-inflammatory, and electrolyte properties, but also include their functional properties, such as low glycemic load and energy density. Taken together, the totality of the evidence accumulated so far does appear to support the notion that increased intake of fruits and vegetables may reduce cardiovascular risk. It is clear that fruit and vegetables should be eaten as part of a balanced diet, as a source of vitamins, fiber, minerals, and phytochemicals. The evidence now suggests that a complicated set of several nutrients may interact with genetic factors to influence CVD risk. Therefore, it may be more important to focus on whole foods and dietary patterns rather than individual nutrients to successfully impact on CVD risk reduction. A clearer understanding of the relationship between fruit and vegetable intake and cardiovascular risk would provide health professionals with significant information in terms of public health and clinical practice.

Latent profiles of early developmental vulnerabilities in a New South Wales child population at age 5 years.

PubMed

Green, Melissa J; Tzoumakis, Stacy; Laurens, Kristin R; Dean, Kimberlie; Kariuki, Maina; Harris, Felicity; O'Reilly, Nicole; Chilvers, Marilyn; Brinkman, Sally A; Carr, Vaughan J

2018-06-01

Detecting the early emergence of childhood risk for adult mental disorders may lead to interventions for reducing subsequent burden of these disorders. We set out to determine classes of children who may be at risk for later mental disorder on the basis of early patterns of development in a population cohort, and associated exposures gleaned from linked administrative records obtained within the New South Wales Child Development Study. Intergenerational records from government departments of health, education, justice and child protection were linked with the Australian Early Development Census for a state population cohort of 67,353 children approximately 5 years of age. We used binary data from 16 subdomains of the Australian Early Development Census to determine classes of children with shared patterns of Australian Early Development Census-defined vulnerability using latent class analysis. Covariates, which included demographic features (sex, socioeconomic status) and exposure to child maltreatment, parental mental illness, parental criminal offending and perinatal adversities (i.e. birth complications, smoking during pregnancy, low birth weight), were examined hierarchically within latent class analysis models. Four classes were identified, reflecting putative risk states for mental disorders: (1) disrespectful and aggressive/hyperactive behaviour, labelled 'misconduct risk' ( N = 4368; 6.5%); (2) 'pervasive risk' ( N = 2668; 4.0%); (3) 'mild generalised risk' ( N = 7822; 11.6%); and (4) 'no risk' ( N = 52,495; 77.9%). The odds of membership in putative risk groups (relative to the no risk group) were greater among children from backgrounds of child maltreatment, parental history of mental illness, parental history of criminal offending, socioeconomic disadvantage and perinatal adversities, with distinguishable patterns of association for some covariates. Patterns of early childhood developmental vulnerabilities may provide useful indicators for particular mental disorder outcomes in later life, although their predictive utility in this respect remains to be established in longitudinal follow-up of the cohort.

HLA-DQA1 and PLA2R1 Polymorphisms and Risk of Idiopathic Membranous Nephropathy

PubMed Central

Bullich, Gemma; Ballarín, José; Oliver, Artur; Ayasreh, Nadia; Silva, Irene; Santín, Sheila; Díaz-Encarnación, Montserrat M.; Torra, Roser

2014-01-01

Summary Background and objectives Single nucleotide polymorphisms (SNPs) within HLA complex class II HLA-DQ α-chain 1 (HLA-DQA1) and M-type phospholipase A2 receptor (PLA2R1) genes were identified as strong risk factors for idiopathic membranous nephropathy (IMN) development in a recent genome-wide association study. Copy number variants (CNVs) within the Fc gamma receptor III (FCGR3) locus have been associated with several autoimmune diseases, but their role in IMN has not been studied. This study aimed to validate the association of HLA-DQA1 and PLA2R1 risk alleles with IMN in a Spanish cohort, test the putative association of FCGR3A and FCGR3B CNVs with IMN, and assess the use of these genetic factors to predict the clinical outcome of the disease. Design, settings, participants, & measurements A Spanish cohort of 89 IMN patients and 286 matched controls without nephropathy was recruited between October of 2009 and July of 2012. Case-control studies for SNPs within HLA-DQA1 (rs2187668) and PLA2R1 (rs4664308) genes and CNVs for FCGR3A and FCGR3B genes were performed. The contribution of these polymorphisms to predict clinical outcome and renal function decline was analyzed. Results This study validated the association of these HLA-DQA1 and PLA2R1 SNPs with IMN in a Spanish cohort and its increased risk when combining both risk genotypes. No significant association was found between FCGR3 CNVs and IMN. These results revealed that HLA-DQA1 and PLA2R1 genotype combination adjusted for baseline proteinuria strongly predicted response to immunosuppressive therapy. HLA-DQA1 genotype adjusted for proteinuria was also linked with renal function decline. Conclusion This study confirms that HLA-DQA1 and PLA2R1 genotypes are risk factors for IMN, whereas no association was identified for FCGR3 CNVs. This study provides, for the first time, evidence of the contribution of these HLA-DQA1 and PLA2R1 polymorphisms in predicting IMN response to immunosuppressors and disease progression. Future studies are needed to validate and identify prognostic markers. PMID:24262501

Early Inherited Risk for Anxiety Moderates the Association between Fathers’ Child-Centered Parenting and Early Social Inhibition

PubMed Central

Brooker, Rebecca J.; Alto, Kathleen M.; Marceau, Kristine; Najjar, Reema; Leve, Leslie D.; Ganiban, Jody M.; Shaw, Daniel S.; Reiss, David; Neiderhiser, Jenae M.

2016-01-01

Studies of the role of the early environment in shaping children’s risk for anxiety problems have produced mixed results. It is possible that inconsistencies in previous findings result from a lack of consideration of a putative role for inherited influences moderators on the impact of early experiences. Early inherited influences not only contribute to vulnerabilities for anxiety problems throughout the lifespan, but can also modulate the ways that the early environment impacts child outcomes. In the current study, we tested the effects of child-centered parenting behaviors on putative anxiety risk in young children who differed in levels of inherited vulnerability. We tested this using a parent-offspring adoption design and a sample in which risk for anxiety problems and parenting behaviors were assessed in both mothers and fathers. Inherited influences on anxiety problems were assessed as anxiety symptoms in biological parents. Child-centered parenting was observed in adoptive mothers and fathers when children were 9 months old. Social inhibition, an early temperament marker of anxiety risk, was observed at child ages 9 and 18 months. Inherited influences on anxiety problems moderated the link between paternal child-centered parenting during infancy and social inhibition in toddlerhood. For children whose birth parents reported high levels of anxiety symptoms, greater child-centered parenting in adoptive fathers was related to greater social inhibition 9 months later. For children whose birth parents reported low levels of anxiety symptoms, greater child-centered parenting in adoptive fathers was related to less social inhibition across the same period. PMID:27572913

Early inherited risk for anxiety moderates the association between fathers' child-centered parenting and early social inhibition.

PubMed

Brooker, R J; Alto, K M; Marceau, K; Najjar, R; Leve, L D; Ganiban, J M; Shaw, D S; Reiss, D; Neiderhiser, J M

2016-12-01

Studies of the role of the early environment in shaping children's risk for anxiety problems have produced mixed results. It is possible that inconsistencies in previous findings result from a lack of consideration of a putative role for inherited influences moderators on the impact of early experiences. Early inherited influences not only contribute to vulnerabilities for anxiety problems throughout the lifespan, but can also modulate the ways that the early environment impacts child outcomes. In the current study, we tested the effects of child-centered parenting behaviors on putative anxiety risk in young children who differed in levels of inherited vulnerability. We tested this using a parent-offspring adoption design and a sample in which risk for anxiety problems and parenting behaviors were assessed in both mothers and fathers. Inherited influences on anxiety problems were assessed as anxiety symptoms in biological parents. Child-centered parenting was observed in adoptive mothers and fathers when children were 9 months old. Social inhibition, an early temperament marker of anxiety risk, was observed at child ages 9 and 18 months. Inherited influences on anxiety problems moderated the link between paternal child-centered parenting during infancy and social inhibition in toddlerhood. For children whose birth parents reported high levels of anxiety symptoms, greater child-centered parenting in adoptive fathers was related to greater social inhibition 9 months later. For children whose birth parents reported low levels of anxiety symptoms, greater child-centered parenting in adoptive fathers was related to less social inhibition across the same period.

Environmental factors affecting inflammatory bowel disease: have we made progress?

PubMed

Lakatos, Peter Laszlo

2009-01-01

The pathogenesis of inflammatory bowel disease (IBD) is only partially understood; various environmental and host (e.g. genetic, epithelial, immune, and nonimmune) factors are involved. The critical role for environmental factors is strongly supported by recent worldwide trends in IBD epidemiology. One important environmental factor is smoking. A meta-analysis partially confirms previous findings that smoking was found to be protective against ulcerative colitis and, after the onset of the disease, might improve its course, decreasing the need for colectomy. In contrast, smoking increases the risk of developing Crohn's disease and aggravates its course. The history of IBD is dotted by cyclic reports on the isolation of specific infectious agents responsible for Crohn's disease or ulcerative colitis. The more recently published cold chain hypothesis is providing an even broader platform by linking dietary factors and microbial agents. An additional, recent theory has suggested a breakdown in the balance between putative species of 'protective' versus 'harmful' intestinal bacteria - this concept has been termed dysbiosis resulting in decreased bacterial diversity. Other factors such as oral contraceptive use, appendectomy, dietary factors (e.g. refined sugar, fat, and fast food), perinatal events, and childhood infections have also been associated with both diseases, but their role is more controversial. Nonetheless, there is no doubt that economic development, leading to improved hygiene and other changes in lifestyle ('westernized lifestyle') may play a role in the increase in IBD. This review article focuses on the role of environmental factors in the pathogenesis and progression of IBDs. Copyright 2009 S. Karger AG, Basel.

Serratia marcescens Cyclic AMP Receptor Protein Controls Transcription of EepR, a Novel Regulator of Antimicrobial Secondary Metabolites.

PubMed

Stella, Nicholas A; Lahr, Roni M; Brothers, Kimberly M; Kalivoda, Eric J; Hunt, Kristin M; Kwak, Daniel H; Liu, Xinyu; Shanks, Robert M Q

2015-08-01

Serratia marcescens generates secondary metabolites and secreted enzymes, and it causes hospital infections and community-acquired ocular infections. Previous studies identified cyclic AMP (cAMP) receptor protein (CRP) as an indirect inhibitor of antimicrobial secondary metabolites. Here, we identified a putative two-component regulator that suppressed crp mutant phenotypes. Evidence supports that the putative response regulator eepR was directly transcriptionally inhibited by cAMP-CRP. EepR and the putative sensor kinase EepS were necessary for the biosynthesis of secondary metabolites, including prodigiosin- and serratamolide-dependent phenotypes, swarming motility, and hemolysis. Recombinant EepR bound to the prodigiosin and serratamolide promoters in vitro. Together, these data introduce a novel regulator of secondary metabolites that directly connects the broadly conserved metabolism regulator CRP with biosynthetic genes that may contribute to competition with other microbes. This study identifies a new transcription factor that is directly controlled by a broadly conserved transcription factor, CRP. CRP is well studied in its role to help bacteria respond to the amount of nutrients in their environment. The new transcription factor EepR is essential for the bacterium Serratia marcescens to produce two biologically active compounds, prodigiosin and serratamolide. These two compounds are antimicrobial and may allow S. marcescens to compete for limited nutrients with other microorganisms. Results from this study tie together the CRP environmental nutrient sensor with a new regulator of antimicrobial compounds. Beyond microbial ecology, prodigiosin and serratamolide have therapeutic potential; therefore, understanding their regulation is important for both applied and basic science. Copyright © 2015, American Society for Microbiology. All Rights Reserved.

Transcriptional regulators transforming growth factor-beta 1 and estrogen-related receptor-alpha identified as putative mediators of calf rumen epithelial tissue development and function during weaning

USDA-ARS?s Scientific Manuscript database

Molecular mechanisms controlling rumen epithelial development at weaning remain largely unknown. To identify gene networks and regulatory factors responsive to concentrate versus forage feeding at weaning, Holstein bull calves (n = 18) were fed commercial milk replacer only (MRO) until 42 d of age. ...

The Serum Response Factor and a Putative Novel Transcription Factor Regulate Expression of the Immediate-Early Gene Arc/Arg3.1 in Cultured Cortical Neurons

PubMed Central

Pintchovski, Sean A.; Peebles, Carol L.; Kim, Hong Joo; Verdin, Eric; Finkbeiner, Steven

2010-01-01

The immediate-early effector gene Arc/Arg3.1 is robustly upregulated by synaptic activity associated with learning and memory. Here we show in primary cortical neuron culture that diverse stimuli induce Arc expression through new transcription. Searching for regulatory regions important for Arc transcription, we found nine DNaseI-sensitive nucleosome-depleted sites at this genomic locus. A reporter gene encompassing these sites responded to synaptic activity in an NMDA receptor–dependent manner, consistent with endogenous Arc mRNA. Responsiveness mapped to two enhancer regions ∼6.5 kb and ∼1.4 kb upstream of Arc. We dissected these regions further and found that the proximal enhancer contains a functional and conserved “Zeste-like” response element that binds a putative novel nuclear protein in neurons. Therefore, activity regulates Arc transcription partly by a novel signaling pathway. We also found that the distal enhancer has a functional and highly conserved serum response element. This element binds serum response factor, which is recruited by synaptic activity to regulate Arc. Thus, Arc is the first target of serum response factor that functions at synapses to mediate plasticity. PMID:19193899

Histone H1 functions as a stimulatory factor in backup pathways of NHEJ

PubMed Central

Rosidi, Bustanur; Wang, Minli; Wu, Wenqi; Sharma, Aparna; Wang, Huichen; Iliakis, George

2008-01-01

DNA double-strand breaks (DSBs) induced in the genome of higher eukaryotes by ionizing radiation (IR) are predominantly removed by two pathways of non-homologous end-joining (NHEJ) termed D-NHEJ and B-NHEJ. While D-NHEJ depends on the activities of the DNA-dependent protein kinase (DNA-PK) and DNA ligase IV/XRCC4/XLF, B-NHEJ utilizes, at least partly, DNA ligase III/XRCC1 and PARP-1. Using in vitro end-joining assays and protein fractionation protocols similar to those previously applied for the characterization of DNA ligase III as an end-joining factor, we identify here histone H1 as an additional putative NHEJ factor. H1 strongly enhances DNA-end joining and shifts the product spectrum from circles to multimers. While H1 enhances the DNA-end-joining activities of both DNA Ligase IV and DNA Ligase III, the effect on ligase III is significantly stronger. Histone H1 also enhances the activity of PARP-1. Since histone H1 has been shown to counteract D-NHEJ, these observations and the known functions of the protein identify it as a putative alignment factor operating preferentially within B-NHEJ. PMID:18250087

Cloning and characterization of largemouth bass ( Micropterus salmoides) myostatin encoding gene and its promoter

NASA Astrophysics Data System (ADS)

Li, Shengjie; Bai, Junjie; Wang, Lin

2008-08-01

Myostatin or GDF-8, a member of the transforming growth factor-β (TGF-β) superfamily, has been demonstrated to be a negative regulator of skeletal muscle mass in mammals. In the present study, we obtained a 5.64 kb sequence of myostatin encoding gene and its promoter from largemouth bass ( Micropterus salmoides). The myostatin encoding gene consisted of three exons (488 bp, 371 bp and 1779 bp, respectively) and two introns (390 bp and 855 bp, respectively). The intron-exon boundaries were conservative in comparison with those of mammalian myostatin encoding genes, whereas the size of introns was smaller than that of mammals. Sequence analysis of 1.569 kb of the largemouth bass myostatin gene promoter region revealed that it contained two TATA boxes, one CAAT box and nine putative E-boxes. Putative muscle growth response elements for myocyte enhancer factor 2 (MEF2), serum response factor (SRF), activator protein 1 (AP1), etc., and muscle-specific Mt binding site (MTBF) were also detected. Some of the transcription factor binding sites were conserved among five teleost species. This information will be useful for studying the transcriptional regulation of myostatin in fish.

A comparative genomics perspective on the genetic content of the alkaliphilic haloarchaeon Natrialba magadii ATCC 43099T

PubMed Central

2012-01-01

Background Natrialba magadii is an aerobic chemoorganotrophic member of the Euryarchaeota and is a dual extremophile requiring alkaline conditions and hypersalinity for optimal growth. The genome sequence of Nab. magadii type strain ATCC 43099 was deciphered to obtain a comprehensive insight into the genetic content of this haloarchaeon and to understand the basis of some of the cellular functions necessary for its survival. Results The genome of Nab. magadii consists of four replicons with a total sequence of 4,443,643 bp and encodes 4,212 putative proteins, some of which contain peptide repeats of various lengths. Comparative genome analyses facilitated the identification of genes encoding putative proteins involved in adaptation to hypersalinity, stress response, glycosylation, and polysaccharide biosynthesis. A proton-driven ATP synthase and a variety of putative cytochromes and other proteins supporting aerobic respiration and electron transfer were encoded by one or more of Nab. magadii replicons. The genome encodes a number of putative proteases/peptidases as well as protein secretion functions. Genes encoding putative transcriptional regulators, basal transcription factors, signal perception/transduction proteins, and chemotaxis/phototaxis proteins were abundant in the genome. Pathways for the biosynthesis of thiamine, riboflavin, heme, cobalamin, coenzyme F420 and other essential co-factors were deduced by in depth sequence analyses. However, approximately 36% of Nab. magadii protein coding genes could not be assigned a function based on Blast analysis and have been annotated as encoding hypothetical or conserved hypothetical proteins. Furthermore, despite extensive comparative genomic analyses, genes necessary for survival in alkaline conditions could not be identified in Nab. magadii. Conclusions Based on genomic analyses, Nab. magadii is predicted to be metabolically versatile and it could use different carbon and energy sources to sustain growth. Nab. magadii has the genetic potential to adapt to its milieu by intracellular accumulation of inorganic cations and/or neutral organic compounds. The identification of Nab. magadii genes involved in coenzyme biosynthesis is a necessary step toward further reconstruction of the metabolic pathways in halophilic archaea and other extremophiles. The knowledge gained from the genome sequence of this haloalkaliphilic archaeon is highly valuable in advancing the applications of extremophiles and their enzymes. PMID:22559199

Genome-wide association study identifies multiple loci associated with both mammographic density and breast cancer risk

PubMed Central

Lindström, Sara; Thompson, Deborah J.; Paterson, Andrew D.; Li, Jingmei; Gierach, Gretchen L.; Scott, Christopher; Stone, Jennifer; Douglas, Julie A.; dos-Santos-Silva, Isabel; Fernandez-Navarro, Pablo; Verghase, Jajini; Smith, Paula; Brown, Judith; Luben, Robert; Wareham, Nicholas J.; Loos, Ruth J.F.; Heit, John A.; Pankratz, V. Shane; Norman, Aaron; Goode, Ellen L.; Cunningham, Julie M.; deAndrade, Mariza; Vierkant, Robert A.; Czene, Kamila; Fasching, Peter A.; Baglietto, Laura; Southey, Melissa C.; Giles, Graham G.; Shah, Kaanan P.; Chan, Heang-Ping; Helvie, Mark A.; Beck, Andrew H.; Knoblauch, Nicholas W.; Hazra, Aditi; Hunter, David J.; Kraft, Peter; Pollan, Marina; Figueroa, Jonine D.; Couch, Fergus J.; Hopper, John L.; Hall, Per; Easton, Douglas F.; Boyd, Norman F.; Vachon, Celine M.; Tamimi, Rulla M.

2015-01-01

Mammographic density reflects the amount of stromal and epithelial tissues in relation to adipose tissue in the breast and is a strong risk factor for breast cancer. Here we report the results from meta-analysis of genome-wide association studies (GWAS) of three mammographic density phenotypes: dense area, non-dense area and percent density in up to 7,916 women in stage 1 and an additional 10,379 women in stage 2. We identify genome-wide significant (P<5×10−8) loci for dense area (AREG, ESR1, ZNF365, LSP1/TNNT3, IGF1, TMEM184B, SGSM3/MKL1), non-dense area (8p11.23) and percent density (PRDM6, 8p11.23, TMEM184B). Four of these regions are known breast cancer susceptibility loci, and four additional regions were found to be associated with breast cancer (P<0.05) in a large meta-analysis. These results provide further evidence of a shared genetic basis between mammographic density and breast cancer and illustrate the power of studying intermediate quantitative phenotypes to identify putative disease susceptibility loci. PMID:25342443

CHICKEN COOPS, Triatoma dimidiata INFESTATION AND ITS INFECTION WITH Trypanosoma cruzi IN A RURAL VILLAGE OF YUCATAN, MEXICO.

PubMed

Koyoc-Cardeña, Edgar; Medina-Barreiro, Anuar; Escobedo-Ortegón, Francisco Javier; Rodríguez-Buenfil, Jorge Carlos; Barrera-Pérez, Mario; Reyes-Novelo, Enrique; Chablé-Santos, Juan; Selem-Salas, Celia; Vazquez-Prokopec, Gonzalo; Manrique-Saide, Pablo

2015-01-01

This study longitudinally investigated the association between Triatoma dimidiata infestation, triatomine infection with Trypanosoma cruzi and household/backyard environmental characteristics in 101 homesteads in Molas and Yucatan, Mexico, between November 2009 (rainy season) and May 2010 (dry season). Logistic regression models tested the associations between insect infestation/infection and potential household-level risk factors. A total of 200 T. dimidiata were collected from 35.6% of the homesteads, mostly (73%) from the peridomicile. Of all the insects collected, 48% were infected with T. cruzi. Infected insects were collected in 31.6% of the homesteads (54.1% and 45.9% intra- and peridomiciliary, respectively). Approximately 30% of all triatomines collected were found in chicken coops. The presence of a chicken coop in the backyard of a homestead was significantly associated with both the odds of finding T. dimidiata (OR = 4.10, CI 95% = 1.61-10.43, p = 0.003) and the presence of triatomines infected with T. cruzi (OR = 3.37, CI 95% = 1.36-8.33, p = 0.006). The results of this study emphasize the relevance of chicken coops as a putative source of T. dimidiata populations and a potential risk for T. cruzi transmission.

Breaking cycles of risk: The mitigating role of maternal working memory in associations among socioeconomic status, early caregiving, and children's working memory.

PubMed

Suor, Jennifer H; Sturge-Apple, Melissa L; Skibo, Michael A

2017-10-01

Previous research has documented socioeconomic-related disparities in children's working memory; however, the putative proximal caregiving mechanisms that underlie these effects are less known. The present study sought to examine whether the effects of early family socioeconomic status on children's working memory were mediated through experiences of caregiving, specifically maternal harsh discipline and responsiveness. Utilizing a psychobiological framework of parenting, the present study also tested whether maternal working memory moderated the initial paths between the family socioeconomic context and maternal harsh discipline and responsiveness in the mediation model. The sample included 185 socioeconomically diverse mother-child dyads assessed when children were 3.5 and 5 years old. Results demonstrated that maternal harsh discipline was a unique mediator of the relation between early experiences of family socioeconomic adversity and lower working memory outcomes in children. Individual differences in maternal working memory emerged as a potent individual difference factor that specifically moderated the mediating influence of harsh discipline within low socioeconomic contexts. The findings have implications for early risk processes underlying deficits in child working memory outcomes and potential targets for parent-child interventions.

Exome sequencing in an admixed isolated population indicates NFXL1 variants confer a risk for specific language impairment.

PubMed

Villanueva, Pía; Nudel, Ron; Hoischen, Alexander; Fernández, María Angélica; Simpson, Nuala H; Gilissen, Christian; Reader, Rose H; Jara, Lillian; Echeverry, María Magdalena; Echeverry, Maria Magdalena; Francks, Clyde; Baird, Gillian; Conti-Ramsden, Gina; O'Hare, Anne; Bolton, Patrick F; Hennessy, Elizabeth R; Palomino, Hernán; Carvajal-Carmona, Luis; Veltman, Joris A; Cazier, Jean-Baptiste; De Barbieri, Zulema; Fisher, Simon E; Newbury, Dianne F

2015-03-01

Children affected by Specific Language Impairment (SLI) fail to acquire age appropriate language skills despite adequate intelligence and opportunity. SLI is highly heritable, but the understanding of underlying genetic mechanisms has proved challenging. In this study, we use molecular genetic techniques to investigate an admixed isolated founder population from the Robinson Crusoe Island (Chile), who are affected by a high incidence of SLI, increasing the power to discover contributory genetic factors. We utilize exome sequencing in selected individuals from this population to identify eight coding variants that are of putative significance. We then apply association analyses across the wider population to highlight a single rare coding variant (rs144169475, Minor Allele Frequency of 4.1% in admixed South American populations) in the NFXL1 gene that confers a nonsynonymous change (N150K) and is significantly associated with language impairment in the Robinson Crusoe population (p = 2.04 × 10-4, 8 variants tested). Subsequent sequencing of NFXL1 in 117 UK SLI cases identified four individuals with heterozygous variants predicted to be of functional consequence. We conclude that coding variants within NFXL1 confer an increased risk of SLI within a complex genetic model.

Mismatch negativity (MMN) and sensory auditory processing in children aged 9-12 years presenting with putative antecedents of schizophrenia.

PubMed

Bruggemann, Jason M; Stockill, Helen V; Lenroot, Rhoshel K; Laurens, Kristin R

2013-09-01

Identification of markers of abnormal brain function in children at-risk of schizophrenia may inform early intervention and prevention programs. Individuals with schizophrenia are characterised by attenuation of MMN amplitude, which indexes automatic auditory sensory processing. The current aim was to examine whether children who may be at increased risk of schizophrenia due to their presenting multiple putative antecedents of schizophrenia (ASz) are similarly characterised by MMN amplitude reductions, relative to typically developing (TD) children. EEG was recorded from 22 ASz and 24 TD children aged 9 to 12 years (matched on age, sex, and IQ) during a passive auditory oddball task (15% duration deviant). ASz children were those presenting: (1) speech and/or motor development lags/problems; (2) social, emotional, or behavioural problems in the clinical range; and (3) psychotic-like experiences. TD children presented no antecedents, and had no family history of a schizophrenia spectrum disorder. MMN amplitude, but not latency, was significantly greater at frontal sites in the ASz group than in the TD group. Although the MMN exhibited by the children at risk of schizophrenia was unlike that of their typically developing peers, it also differed from the reduced MMN amplitude observed in adults with schizophrenia. This may reflect developmental and disease effects in a pre-prodromal phase of psychosis onset. Longitudinal follow-up is necessary to establish the developmental trajectory of MMN in at-risk children. Copyright © 2013 The Authors. Published by Elsevier B.V. All rights reserved.

Chancroid: from clinical practice to basic science.

PubMed

Lewis, D A

2000-01-01

Chancroid is a sexually transmitted disease caused by the bacterium Haemophilus ducreyi. It usually presents as a genital ulcer and may be associated with regional lymphadenopathy and bubo formation. H. ducreyi infection is predominantly seen in tropical resource-poor regions of the world where it is frequently the most common etiological cause of genital ulceration. Genital ulcer disease has been shown to be an extremely important co-factor in HIV transmission. With the advent of the AIDS epidemic, there has been increased research effort to elucidate those factors involved in the pathogenesis of chancroid. Several putative virulence factors have now been identified and isogenic H. ducreyi mutants constructed by mutagenesis of their encoding genes. This approach has facilitated investigations into the role each of these putative virulence factors may play in H. ducreyi pathogenesis through the use of in vitro and in vivo model systems. One major goal of current chancroid research is to identify antigens which are immunogenic and could form the basis of a vaccine against H. ducreyi infection. Such a vaccine, if shown to be effective in decreasing the prevalence of chancroid, could have the added benefit of slowing down the HIV incidence rates in those populations where chancroid is a major co-factor for HIV transmission.

De novo transcriptome sequence assembly and identification of AP2/ERF transcription factor related to abiotic stress in parsley (Petroselinum crispum).

PubMed

Li, Meng-Yao; Tan, Hua-Wei; Wang, Feng; Jiang, Qian; Xu, Zhi-Sheng; Tian, Chang; Xiong, Ai-Sheng

2014-01-01

Parsley is an important biennial Apiaceae species that is widely cultivated as herb, spice, and vegetable. Previous studies on parsley principally focused on its physiological and biochemical properties, including phenolic compound and volatile oil contents. However, little is known about the molecular and genetic properties of parsley. In this study, 23,686,707 high-quality reads were obtained and assembled into 81,852 transcripts and 50,161 unigenes for the first time. Functional annotation showed that 30,516 unigenes had sequence similarity to known genes. In addition, 3,244 putative simple sequence repeats were detected in curly parsley. Finally, 1,569 of the identified unigenes belonged to 58 transcription factor families. Various abiotic stresses have a strong detrimental effect on the yield and quality of parsley. AP2/ERF transcription factors have important functions in plant development, hormonal regulation, and abiotic response. A total of 88 putative AP2/ERF factors were identified from the transcriptome sequence of parsley. Seven AP2/ERF transcription factors were selected in this study to analyze the expression profiles of parsley under different abiotic stresses. Our data provide a potentially valuable resource that can be used for intensive parsley research.

De Novo Transcriptome Sequence Assembly and Identification of AP2/ERF Transcription Factor Related to Abiotic Stress in Parsley (Petroselinum crispum)

PubMed Central

Wang, Feng; Jiang, Qian; Xu, Zhi-Sheng; Tian, Chang; Xiong, Ai-Sheng

2014-01-01

Parsley is an important biennial Apiaceae species that is widely cultivated as herb, spice, and vegetable. Previous studies on parsley principally focused on its physiological and biochemical properties, including phenolic compound and volatile oil contents. However, little is known about the molecular and genetic properties of parsley. In this study, 23,686,707 high-quality reads were obtained and assembled into 81,852 transcripts and 50,161 unigenes for the first time. Functional annotation showed that 30,516 unigenes had sequence similarity to known genes. In addition, 3,244 putative simple sequence repeats were detected in curly parsley. Finally, 1,569 of the identified unigenes belonged to 58 transcription factor families. Various abiotic stresses have a strong detrimental effect on the yield and quality of parsley. AP2/ERF transcription factors have important functions in plant development, hormonal regulation, and abiotic response. A total of 88 putative AP2/ERF factors were identified from the transcriptome sequence of parsley. Seven AP2/ERF transcription factors were selected in this study to analyze the expression profiles of parsley under different abiotic stresses. Our data provide a potentially valuable resource that can be used for intensive parsley research. PMID:25268141

Recent progress in carcinogenesis, progression and therapy of breast cancer: the 20th Hiroshima Cancer Seminar--the 4th Three Universities' Consortium International Symposium, October 2010: 31 October 2010, International Conference Center Hiroshima.

PubMed

Toi, Masakazu; Yasui, Wataru; Ito, Hisao; Tahara, Eiichi

2011-07-01

The 20th Hiroshima Cancer seminar focused upon breast cancer research and treatment particularly on the mechanism of tumorigenesis and drug resistance and development of novel therapeutics. Several molecules such as retinoblastoma and p16 were raised as key factors in tumorigenesis and invasiveness. Estrogen-related pathways seem to be closely involved in the process. For the tumor lacking hormone receptor and human epidermal growth factor 2, some other mechanisms could be responsible. It seems that MicroRNA 22 directing some putative targets such as SIRT1, Sp1 and CDK6 plays a crucial role in breast tumor growth and metastasis. In addition, ribophorin and the associated molecules might be engaged in breast cancer stemness. Obviously, these molecules provide potential for therapeutic targets. It was also discussed about new drug development such as anti-human epidermal growth factor 2 therapy, anti-angiogenesis, pro-tumor aspects of anti-cancer therapy and application of circulating markers for monitoring, imaging and health-care system. Furthermore, we discussed risk factors, prevention and screening to reduce invasive cancers as well. Throughout the conference, panelists and attendee indicated the importance of translational research and biomarker exploration in order to realize efficient and individualized therapy for breast cancer.

Examination of the association between male gender and preterm delivery.

PubMed

Brettell, Rachel; Yeh, Peter S; Impey, Lawrence W M

2008-12-01

To examine possible reasons why a male fetus constitutes a risk factor for preterm delivery. Retrospective study of deliveries from hospital database in a UK teaching hospital. The population comprised all deliveries >23 weeks over an 11-year period, excluding multiples, terminations and pregnancies with major abnormalities including indeterminate gender. Obstetric variables and outcomes were initially compared in male and female babies for preterm births in different gestation bands, extreme (<28 weeks), severe (29-32 weeks) and moderate (33-36 weeks). For each, the odds ratios with 95% confidence intervals for preterm delivery were calculated. Then, using binary logistic regression with adjusted odds ratios with 95% confidence intervals, putative causal pathways that might explain the male excess were tested. 75,725 deliveries occurred, of which 4003 (5.3%) were preterm. Males delivered preterm more frequently (OR 1.13, 95% CI 1.06-1.20). This was due to spontaneous (OR 1.30, 95% CI 1.19-1.42) but not iatrogenic (OR 0.96, 95% CI 0.87-1.05) preterm birth. There was an increased risk of pre eclampsia among preterm females. Although males were larger, and male pregnancies were more frequently nulliparous and affected by some other obstetric complications (abruption, urinary tract infection), these did not account for their increased risk. Any effect of growth restriction could not be properly determined. Being male carries an increased risk of spontaneous but not iatrogenic preterm birth. The reasons behind this remain obscure.

Acute acalculous cholecystitis: A new safety risk for patients with MS treated with alemtuzumab.

PubMed

Croteau, David; Flowers, Charlene; Kulick, Corrinne G; Brinker, Allen; Kortepeter, Cindy M

2018-05-01

To evaluate acute acalculous cholecystitis (AAC) as a potential safety risk for patients treated with alemtuzumab. The Food and Drug Administration Adverse Event Reporting System and the medical literature were searched for cases of AAC in conjunction with alemtuzumab for all clinical indications. Eight spontaneously reported cases meeting the case definition of AAC in close temporal association with alemtuzumab use were identified. Based on established criteria within the Food and Drug Administration Division of Pharmacovigilance for causality assessment, 4 cases were assessed as probable while 4 were possible. All cases occurred in patients with relapsing-remitting multiple sclerosis. Seven of the 8 cases presented with AAC during or shortly after alemtuzumab treatment, thereby suggesting an acute cytokine release syndrome as a putative pathogenic mechanism. The cases identified in this review differ from the typical AAC cases described in the medical literature based on female preponderance, lack of concurrent critical illnesses, inconsistent presence of other risk factors, and resolution with conservative treatment in the majority of cases. AAC represents a new and potentially life-threatening adverse event associated with alemtuzumab use in relapsing-remitting multiple sclerosis. In cases seen to date, early and conservative treatment resulted in good clinical outcome, although the natural history of AAC in this population without critical illness is not well defined. Awareness of this safety risk by general and specialty neurologists is important for prompt recognition and optimal management. © 2018 American Academy of Neurology.

A structural equation modelling approach to explore the role of B vitamins and immune markers in lung cancer risk.

PubMed

Baltar, Valéria Troncoso; Xun, Wei W; Johansson, Mattias; Ferrari, Pietro; Chuang, Shu-Chun; Relton, Caroline; Ueland, Per Magne; Midttun, Øivind; Slimani, Nadia; Jenab, Mazda; Clavel-Chapelon, Françoise; Boutron-Ruault, Marie-Christine; Fagherazzi, Guy; Kaaks, Rudolf; Rohrmann, Sabine; Boeing, Heiner; Weikert, Cornelia; Bueno-de-Mesquita, Bas; Boshuizen, Hendriek; van Gils, Carla H; Onland-Moret, N Charlotte; Agudo, Antonio; Barricarte, Aurelio; Navarro, Carmen; Rodríguez, Laudina; Castaño, José Maria Huerta; Larrañaga, Nerea; Khaw, Kay-Tee; Wareham, Nick; Allen, Naomi E; Crowe, Francesca; Gallo, Valentina; Norat, Teresa; Krogh, Vittorio; Masala, Giovanna; Panico, Salvatore; Sacerdote, Carlotta; Tumino, Rosario; Trichopoulou, Antonia; Lagiou, Pagona; Trichopoulos, Dimitrios; Rasmuson, Torgny; Hallmans, Göran; Roswall, Nina; Tjønneland, Anne; Riboli, Elio; Brennan, Paul; Vineis, Paolo

2013-08-01

The one-carbon metabolism (OCM) is considered key in maintaining DNA integrity and regulating gene expression, and may be involved in the process of carcinogenesis. Several B-vitamins and amino acids have been implicated in lung cancer risk, via the OCM directly as well as immune system activation. However it is unclear whether these factors act independently or through complex mechanisms. The current study applies structural equations modelling (SEM) to further disentangle the mechanisms involved in lung carcinogenesis. SEM allows simultaneous estimation of linear relations where a variable can be the outcome in one equation and the predictor in another, as well as allowing estimation using latent variables (factors estimated by correlation matrix). A large number of biomarkers have been analysed from 891 lung cancer cases and 1,747 controls nested within the European Prospective Investigation into Cancer and Nutrition (EPIC) cohort. Four putative mechanisms in the OCM and immunity were investigated in relation to lung cancer risk: methionine-homocysteine metabolism, folate cycle, transsulfuration, and mechanisms involved in inflammation and immune activation, all adjusted for tobacco exposure. The hypothesized SEM model confirmed a direct and protective effect for factors representing methionine-homocysteine metabolism (p = 0.020) and immune activation (p = 0.021), and an indirect protective effect of folate cycle (p = 0.019), after adjustment for tobacco smoking. In conclusion, our results show that in the investigation of the involvement of the OCM, the folate cycle and immune system in lung carcinogenesis, it is important to consider complex pathways (by applying SEM) rather than the effects of single vitamins or nutrients (e.g. using traditional multiple regression). In our study SEM were able to suggest a greater role of the methionine-homocysteine metabolism and immune activation over other potential mechanisms.

Elevated Plasma C-Terminal Endothelin-1 Precursor Fragment Concentrations Are Associated with Less Anxiety in Patients with Cardiovascular Risk Factors. Results from the Observational DIAST-CHF Study.

PubMed

Meyer, Thomas; Chavanon, Mira-Lynn; Herrrmann-Lingen, Christoph; Roggenthien, Maren; Nolte, Kathleen; Pieske, Burkert; Wachter, Rolf; Edelmann, Frank

2015-01-01

The role of endothelin-1 (ET-1) in the neurobiology of anxiety is unknown, therefore, we assessed in the observational multicenter DIAST-CHF study whether the C-terminal ET-1 precursor fragment (CT-proET-1) is linked to anxiety. Plasma concentrations of CT-proET-1 were measured in a total of 1,410 patients presenting with cardiovascular risk factors (mean age 66.91±8.2 years, 49.3% males, mean left ventricular ejection fraction 60.0±8.2%) who had completed the Hospital Anxiety and Depression Scale (HADS) questionnaire. Among the total study cohort (n = 1,410), there were 118 subjects (8.4%) with an HADS anxiety score above the cut-off level of 11 suggestive of clinically relevant anxiety. Plasma CT-proET-1 levels were significantly lower in the group of anxious patients as compared to non-anxious patients (p = 0.013). In regression models adjusted for sex, age, systolic blood pressure, and diameters of left atrium and ventricle, plasma CT-proET-1 was again linked to anxiety (Exp(β) = 0.247, 95%-confidence interval [95%-CI] = 0.067-0.914, p = 0.036). Given the high prevalence of depressive disorders in anxious patients, we additionally included the HADS depression score as an independent variable in the models and found that CT-proET-1 remained a significant predictor of anxiety, independent of comorbid depression (Exp(β) = 0.114, 95%-CI = 0.023-0.566, p = 0.008). Our data from a population-based study in outpatients with cardiovascular risk factors revealed that circulating CT-proET-1 levels are negatively associated with anxiety. Further investigations are required to clarify the putative anxiolytic effect of ET-1 or its precursor molecules in humans and to decipher its mechanistic pathways.

Two pheromone precursor genes are transcriptionally expressed in the homothallic ascomycete Sordaria macrospora.

PubMed

Pöggeler, S

2000-06-01

In order to analyze the involvement of pheromones in cell recognition and mating in a homothallic fungus, two putative pheromone precursor genes, named ppg1 and ppg2, were isolated from a genomic library of Sordaria macrospora. The ppg1 gene is predicted to encode a precursor pheromone that is processed by a Kex2-like protease to yield a pheromone that is structurally similar to the alpha-factor of the yeast Saccharomyces cerevisiae. The ppg2 gene encodes a 24-amino-acid polypeptide that contains a putative farnesylated and carboxy methylated C-terminal cysteine residue. The sequences of the predicted pheromones display strong structural similarity to those encoded by putative pheromones of heterothallic filamentous ascomycetes. Both genes are expressed during the life cycle of S. macrospora. This is the first description of pheromone precursor genes encoded by a homothallic fungus. Southern-hybridization experiments indicated that ppg1 and ppg2 homologues are also present in other homothallic ascomycetes.

Innovative biomarkers for predicting type 2 diabetes mellitus: relevance to dietary management of frailty in older adults.

PubMed

Ikwuobe, John; Bellary, Srikanth; Griffiths, Helen R

2016-06-01

Type 2 diabetes mellitus (T2DM) increases in prevalence in the elderly. There is evidence for significant muscle loss and accelerated cognitive impairment in older adults with T2DM; these comorbidities are critical features of frailty. In the early stages of T2DM, insulin sensitivity can be improved by a "healthy" diet. Management of insulin resistance by diet in people over 65 years of age should be carefully re-evaluated because of the risk for falling due to hypoglycaemia. To date, an optimal dietary programme for older adults with insulin resistance and T2DM has not been described. The use of biomarkers to identify those at risk for T2DM will enable clinicians to offer early dietary advice that will delay onset of disease and of frailty. Here we have used an in silico literature search for putative novel biomarkers of T2DM risk and frailty. We suggest that plasma bilirubin, plasma, urinary DPP4-positive microparticles and plasma pigment epithelium-derived factor merit further investigation as predictive biomarkers for T2DM and frailty risk in older adults. Bilirubin is screened routinely in clinical practice. Measurement of specific microparticle frequency in urine is less invasive than a blood sample so is a good choice for biomonitoring. Future studies should investigate whether early dietary changes, such as increased intake of whey protein and micronutrients that improve muscle function and insulin sensitivity, affect biomarkers and can reduce the longer term complication of frailty in people at risk for T2DM.

Aberrant Methylation-Mediated Suppression of APAF1 in Myelodysplastic Syndrome.

PubMed

Zaker, Farhad; Nasiri, Nahid; Amirizadeh, Naser; Razavi, Seyed Mohsen; Yaghmaie, Marjan; Teimoori-Toolabi, Ladan; Maleki, Ali; Bakhshayesh, Masoumeh

2017-04-01

Background: Myelodysplastic syndromes (MDSs) include a diverse group of clonal bone marrow disorders characterized by ineffective hematopoiesis and pancytopenia. It was found that down regulation of APAF1, a putative tumor suppressor gene (TSG), leads to resistance to chemotherapy and disease development in some cancers. In this study, we investigated the relation of APAF1 methylation status with its expression and clinicopathological factors in myelodysplastic syndrome (MDS) patients. Materials and Methods: Methylation Sensitive-High Resolution Melting Curve Analysis (MS-HRM) was employed in studying the methylation of CpG islands in the APAF1promoter region in MDS. Gene expression was analyzed by using real time RT-PCR. Results: 42.6% of patient samples were methylated in promoter region of APAF1analyzed, while methylation of the gene was not seen in controls (P<0.05). Methylation of APAF1was significantly associated with the suppression of its mRNA expression (P=0.00). The methylation status of APAF1in advanced-stage MDS patients (80%) was significantly higher than that of the early-stage MDS patients (28.2%) (P=0.001). The difference in frequency of hypermethylatedAPAF1 gene was significant between good (37.5%) and poor (85.71%) cytogenetic risk groups (P=0.043). In addition, a higher frequency of APAF1hypermethylation was observed in higher-risk MDS group (69.2%) compared to lower-risk MDS group (34.14%) (P=0.026). Conclusion: Our study indicated that APAF1hypermethylation in MDS was associated to high-risk disease classified according to the IPSS, WHO and cytogenetic risk.

High risk for obstructive sleep apnea and other sleep disorders among overweight and obese pregnant women.

PubMed

Rice, Jayne R; Larrabure-Torrealva, Gloria T; Luque Fernandez, Miguel Angel; Grande, Mirtha; Motta, Vicky; Barrios, Yasmin V; Sanchez, Sixto; Gelaye, Bizu; Williams, Michelle A

2015-09-02

Obstructive sleep apnea (OSA), a common and serious disorder in which breathing repeatedly stops during sleep, is associated with excess weight and obesity. Little is known about the co-occurrence of OSA among pregnant women from low and middle-income countries. We examined the extent to which maternal pre-pregnancy overweight or obesity status are associated with high risk for OSA, poor sleep quality, and excessive daytime sleepiness in 1032 pregnant women in Lima, Peru. The Berlin questionnaire was used to identify women at high risk for OSA. The Pittsburgh Sleep Quality Index (PSQI) and Epworth Sleepiness Scale (ESS) were used to examine sleep quality and excessive daytime sleepiness, respectively. Multinomial logistic regression procedures were employed to estimate odds ratios (aOR) and 95% confidence intervals (CI) adjusted for putative confounding factors. Compared with lean women (<25 kg/m(2)), overweight women (25-29.9 kg/m(2)) had 3.69-fold higher odds of high risk for OSA (95% CI 1.82-7.50). The corresponding aOR for obese women (≥30 kg/m(2)) was 13.23 (95% CI: 6.25-28.01). Obese women, as compared with their lean counterparts had a 1.61-fold higher odds of poor sleep quality (95% CI: 1.00-2.63). Overweight or obese pregnant women have increased odds of sleep disorders, particularly OSA. OSA screening and risk management may be indicated among pregnant women in low and middle income countries, particularly those undergoing rapid epidemiologic transitions characterized by increased prevalence of excessive adult weight gain.

Childhood maltreatment is associated with a sex-dependent functional reorganization of a brain inhibitory control network.

PubMed

Elton, Amanda; Tripathi, Shanti P; Mletzko, Tanja; Young, Jonathan; Cisler, Josh M; James, G Andrew; Kilts, Clinton D

2014-04-01

Childhood adversity represents a major risk factor for drug addiction and other mental disorders. However, the specific mechanisms by which childhood adversity impacts human brain organization to confer greater vulnerability for negative outcomes in adulthood is largely unknown. As an impaired process in drug addiction, inhibitory control of behavior was investigated as a target of childhood maltreatment (abuse and neglect). Forty adults without Axis-I psychiatric disorders (21 females) completed a Childhood Trauma Questionnaire (CTQ) and underwent functional MRI (fMRI) while performing a stop-signal task. A group independent component analysis identified a putative brain inhibitory control network. Graph theoretical analyses and structural equation modeling investigated the impact of childhood maltreatment on the functional organization of this neural processing network. Graph theory outcomes revealed sex differences in the relationship between network functional connectivity and inhibitory control which were dependent on the severity of childhood maltreatment exposure. A network effective connectivity analysis indicated that a maltreatment dose-related negative modulation of dorsal anterior cingulate (dACC) activity by the left inferior frontal cortex (IFC) predicted better response inhibition and lesser attention deficit hyperactivity disorder (ADHD) symptoms in females, but poorer response inhibition and greater ADHD symptoms in males. Less inhibition of the right IFC by dACC in males with higher CTQ scores improved inhibitory control ability. The childhood maltreatment-related reorganization of a brain inhibitory control network provides sex-dependent mechanisms by which childhood adversity may confer greater risk for drug use and related disorders and by which adaptive brain responses protect individuals from this risk factor. Copyright © 2013 Wiley Periodicals, Inc.

E-cadherin breast tumor expression, risk factors and survival: Pooled analysis of 5,933 cases from 12 studies in the Breast Cancer Association Consortium.

PubMed

Horne, Hisani N; Oh, Hannah; Sherman, Mark E; Palakal, Maya; Hewitt, Stephen M; Schmidt, Marjanka K; Milne, Roger L; Hardisson, David; Benitez, Javier; Blomqvist, Carl; Bolla, Manjeet K; Brenner, Hermann; Chang-Claude, Jenny; Cora, Renata; Couch, Fergus J; Cuk, Katarina; Devilee, Peter; Easton, Douglas F; Eccles, Diana M; Eilber, Ursula; Hartikainen, Jaana M; Heikkilä, Päivi; Holleczek, Bernd; Hooning, Maartje J; Jones, Michael; Keeman, Renske; Mannermaa, Arto; Martens, John W M; Muranen, Taru A; Nevanlinna, Heli; Olson, Janet E; Orr, Nick; Perez, Jose I A; Pharoah, Paul D P; Ruddy, Kathryn J; Saum, Kai-Uwe; Schoemaker, Minouk J; Seynaeve, Caroline; Sironen, Reijo; Smit, Vincent T H B M; Swerdlow, Anthony J; Tengström, Maria; Thomas, Abigail S; Timmermans, A Mieke; Tollenaar, Rob A E M; Troester, Melissa A; van Asperen, Christi J; van Deurzen, Carolien H M; Van Leeuwen, Flora F; Van't Veer, Laura J; García-Closas, Montserrat; Figueroa, Jonine D

2018-04-26

E-cadherin (CDH1) is a putative tumor suppressor gene implicated in breast carcinogenesis. Yet, whether risk factors or survival differ by E-cadherin tumor expression is unclear. We evaluated E-cadherin tumor immunohistochemistry expression using tissue microarrays of 5,933 female invasive breast cancers from 12 studies from the Breast Cancer Consortium. H-scores were calculated and case-case odds ratios (OR) and 95% confidence intervals (CIs) were estimated using logistic regression. Survival analyses were performed using Cox regression models. All analyses were stratified by estrogen receptor (ER) status and histologic subtype. E-cadherin low cases (N = 1191, 20%) were more frequently of lobular histology, low grade, >2 cm, and HER2-negative. Loss of E-cadherin expression (score < 100) was associated with menopausal hormone use among ER-positive tumors (ever compared to never users, OR = 1.24, 95% CI = 0.97-1.59), which was stronger when we evaluated complete loss of E-cadherin (i.e. H-score = 0), OR = 1.57, 95% CI = 1.06-2.33. Breast cancer specific mortality was unrelated to E-cadherin expression in multivariable models. E-cadherin low expression is associated with lobular histology, tumor characteristics and menopausal hormone use, with no evidence of an association with breast cancer specific survival. These data support loss of E-cadherin expression as an important marker of tumor subtypes.

Social anxiety, reasons for drinking, and college students.

PubMed

Norberg, Melissa M; Norton, Alice R; Olivier, Jake; Zvolensky, Michael J

2010-12-01

Recent research suggests that social anxiety may be associated with higher rates of alcohol problems in women, yet may be associated with lower levels of drinking in men. The current study investigated putative mechanisms that may underlie potential gender differences in the social anxiety-alcohol relationship. One hundred and eighteen college students (61.0% women) completed an interview assessing drinking behaviors and questionnaires measuring social anxiety, drinking motives, and drinking situations. Although college men and women both reported similar frequencies of drinking in positive situations and to enhance positive emotions, women reported drinking more often in negative situations and to cope with aversive emotions than men. Mediated moderation analyses suggested that women with social anxiety may be at greater risk of encountering adverse consequences because of their likelihood to drink to conform or to cope with the aversive affect they experience in negative situations. Conversely, when men experience high rates of adverse consequences, it may be due to drinking greater quantities of alcohol in positive situations. Highly socially anxious college men may drink less alcohol and experience fewer adverse consequences than their nonanxious or mildly anxious counterparts because they may find themselves in positive situations and drinking to enhance positive feelings less often, potentially due to avoidant behavior. These findings may help to explain why social anxiety serves as a potential risk factor for alcohol-related problems for college women, but a protective factor for college men. Copyright © 2010. Published by Elsevier Ltd.

Anticholinergic load negatively correlates with recovery of cognitive activities of daily living for geriatric patients after stroke in the convalescent stage.

PubMed

Kose, E; Hirai, T; Seki, T; Hidaka, S; Hamamoto, T

2018-05-16

Anticholinergic drugs are associated with risks of falls, confusion and cognitive dysfunction. However, the effect of anticholinergic drug use on rehabilitation outcomes after a stroke is poorly documented. We therefore aimed to establish whether the anticholinergic load was associated with functional recovery among geriatric patients convalescing after stroke. Consecutive geriatric stroke patients admitted and discharged from a convalescence rehabilitation ward between 2010 and 2016 were included in this retrospective cohort study. Anticholinergic load was assessed by the Anticholinergic Risk Scale (ARS), and functional recovery was assessed by the Functional Independence Measure (FIM). The primary outcome was cognitive FIM (FIM-C) gain, but we also assessed the interaction of other putative factors identified from univariate analysis. Multivariate analyses were performed, adjusting for confounding factors. We included 418 participants (171 males, 247 females) with a median age of 78 years (interquartile range, 72-84 years). Multiple regression analysis revealed that ARS change, length of stay, and epilepsy were independently and negatively correlated with cognitive FIM gain. Multiple logistic regression analysis indicated that the "Comprehension" and "Memory" items of the cognitive FIM gain were independently and negatively associated with anticholinergic load. A causal relationship cannot be established, but increased ARS scores during hospitalization may predict limited cognitive functional improvement in geriatric patients after stroke. Alternatively, cognitive impairment may lead to increased use of anticholinergic drugs. © 2018 John Wiley & Sons Ltd.

Is the Prevalence of Gallbladder Polyp Different between Vegetarians and General Population?

PubMed

Jo, Hee Bum; Lee, Jun Kyu; Choi, Min Young; Han, In Woong; Choi, Han Seok; Kang, Hyoun Woo; Kim, Jae Hak; Lim, Yun Jeong; Koh, Moon Soo; Lee, Jin Ho

2015-11-01

Gallbladder polyps (GBP) are a common clinical finding that can express malignant potential. The aim of this study was to evaluate whether vegetarianism protects against GBP, together with other putative risk factors. A retrospective, cross-sectional study was conducted with subjects who received a health check-up from July 2005 to December 2011. Korean Buddhist priests, who are obligatory vegetarians by religious belief, were identified as vegetarians (vegetarian group) and compared with a non-vegetarian control group sampled from those coming for health check-ups at the same institution. Out of 18,483 subjects, GBP were found in 810 (4.4%). Al though GBP tended to be less common in the vegetarian group (23 [3.5%] out of 666) than in control group (787 [4.4%] out of 17,817), the difference was insignificant statistically (p=0.233). By logistic regression, old age (OR=1.61, 95% CI=1.1 9-2.26 for 30-39 years; OR=1.47, 95% CI=1.08-1.98 for 40-49 years), male gender (OR=1.51, 95% CI=1.31-1.75), high BMI (OR=1.18, 95% CI=1.00-1.39 for ≥ 23.0 kg/m(2) and < 25.0 kg/m(2) ) and HBsAg positivity (OR=1.53, 95% CI=1.19-1.98) were independent risk factors of GBP. GBP was significantly associated with old age, male gender , high BMI and HBsAg positivity, but not with vegetarianism.

Characterization of the colorectal cancer-associated enhancer MYC-335 at 8q24: the role of rs67491583.

PubMed

Tuupanen, Sari; Yan, Jian; Turunen, Mikko; Gylfe, Alexandra E; Kaasinen, Eevi; Li, Li; Eng, Charis; Culver, Daniel A; Kalady, Matthew F; Pennison, Michael J; Pasche, Boris; Manne, Upender; de la Chapelle, Albert; Hampel, Heather; Henderson, Brian E; Marchand, Loic Le; Hautaniemi, Sampsa; Askhtorab, Hassan; Smoot, Duane; Sandler, Robert S; Keku, Temitope; Kupfer, Sonia S; Ellis, Nathan A; Haiman, Christopher A; Taipale, Jussi; Aaltonen, Lauri A

2012-01-01

Recent genome-wide association studies have identified multiple regions at 8q24 that confer susceptibility to many cancers. In our previous work, we showed that the colorectal cancer (CRC) risk variant rs6983267 at 8q24 resides within a TCF4 binding site at the MYC-335 enhancer, with the risk allele G having a stronger binding capacity and Wnt responsiveness. Here, we searched for other potential functional variants within MYC-335. Genetic variation within MYC-335 was determined in samples from individuals of European, African, and Asian descent, with emphasis on variants in putative transcription factor binding sites. A 2-bp GA deletion rs67491583 was found to affect a growth factor independent (GFI) binding site and was present only in individuals with African ancestry. Chromatin immunoprecipitation performed in heterozygous cells showed that the GA deletion had an ability to reduce binding of the transcriptional repressors GFI1 and GFI1b. Screening of 1,027 African American colorectal cancer cases and 1,773 healthy controls did not reveal evidence for association (odds ratio: 1.17, 95% confidence interval: 0.97-1.41, P = 0.095). In this study, rs67491583 was identified as another functional variant in the CRC-associated enhancer MYC-335, but further studies are needed to establish the role of rs67491583 in the colorectal cancer predisposition of African Americans. Copyright © 2012 Elsevier Inc. All rights reserved.

MONKEY: Identifying conserved transcription-factor binding sitesin multiple alignments using a binding site-specific evolutionarymodel

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

Moses, Alan M.; Chiang, Derek Y.; Pollard, Daniel A.

2004-10-28

We introduce a method (MONKEY) to identify conserved transcription-factor binding sites in multispecies alignments. MONKEY employs probabilistic models of factor specificity and binding site evolution, on which basis we compute the likelihood that putative sites are conserved and assign statistical significance to each hit. Using genomes from the genus Saccharomyces, we illustrate how the significance of real sites increases with evolutionary distance and explore the relationship between conservation and function.

Identification of InuR, a new Zn(II)2Cys6 transcriptional activator involved in the regulation of inulinolytic genes in Aspergillus niger.

PubMed

Yuan, Xiao-Lian; Roubos, Johannes A; van den Hondel, Cees A M J J; Ram, Arthur F J

2008-01-01

The expression of inulinolytic genes in Aspergillus niger is co-regulated and induced by inulin and sucrose. We have identified a positive acting transcription factor InuR, which is required for the induced expression of inulinolytic genes. InuR is a member of the fungal specific class of transcription factors of the Zn(II)2Cys6 type. Involvement of InuR in inulin and sucrose metabolism was suspected because of the clustering of inuR gene with sucB, which encodes an intracellular invertase with transfructosylation activity and a putative sugar transporter encoding gene (An15g00310). Deletion of the inuR gene resulted in a strain displaying a severe reduction in growth on inulin and sucrose medium. Northern analysis revealed that expression of inulinolytic and sucrolytic genes, e.g., inuE, inuA, sucA, as well as the putative sugar transporter gene (An15g00310) is dependent on InuR. Genome-wide expression analysis revealed, three additional putative sugar transporters encoding genes (An15g04060, An15g03940 and An17g01710), which were strongly induced by sucrose in an InuR dependent way. In silico analysis of the promoter sequences of strongly InuR regulated genes suggests that InuR might bind as dimer to two CGG triplets, which are separated by eight nucleotides.

Regulation of insulin-like growth factor binding proteins in young growing animals by alteration of energy status.

PubMed

Dauncey, M J; Rudd, B T; White, D A; Shakespear, R A

1993-09-01

The regulation of plasma insulin-like growth factor binding proteins (IGFBPs) by energy status has been assessed in 2-month-old pigs. Energy balance was modified by altering thermoregulatory demand and energy intake, with litter-mates being kept for several weeks at either 35 or 10 degrees C on a high (H) or low (L) level of food intake (where H = 2L); plasma samples were taken 20-24 h after the last meal. The two major forms of circulating IGFBP, as estimated by Western blot analysis, were identified putatively as IGFBP-2 and IGFBP-3 (relative molecular weights of 34 and 40-45 kDa respectively). There were significant differences in IGFBP profiles between the four treatment groups of 35H, 35L, 10H and 10L: the 40-45 kDa IGFBP (putative IGFBP-3) was elevated both in the warm and on a high food intake (P < 0.001), and there was a marked reciprocal relation between the 40-45 and 34 kDa IGFBPs. The relative concentration of the 34 kDa IGFBP (putative IGFBP-2) was greatest in the 10L and least in the 35H group. It is concluded that long-term alterations in energy balance, induced by changes in either intake or thermoregulatory demand, can significantly affect the plasma profile of IGFBPs during the first two months of life.

Spatial Distribution of Taenia solium Porcine Cysticercosis within a Rural Area of Mexico

PubMed Central

Morales, Julio; Martínez, José Juan; Rosetti, Marcos; Fleury, Agnes; Maza, Victor; Hernandez, Marisela; Villalobos, Nelly; Fragoso, Gladis; de Aluja, Aline S.; Larralde, Carlos; Sciutto, Edda

2008-01-01

Cysticercosis is caused by Taenia solium, a parasitic disease that affects humans and rurally bred pigs in developing countries. The cysticercus may localize in the central nervous system of the human, causing neurocysticercosis, the most severe and frequent form of the disease. There appears to be an association between the prevalence of porcine cysticercosis and domestic pigs that wander freely and have access to human feces. In order to assess whether the risk of cysticercosis infection is clustered or widely dispersed in a limited rural area, a spatial analysis of rural porcine cysticercosis was applied to 13 villages of the Sierra de Huautla in Central Mexico. Clustering of cases in specific households would indicate tapeworm carriers in the vicinity, whereas their dispersal would suggest that the ambulatory habits of both humans and pigs contribute to the spread of cysticercosis. A total of 562 pigs were included in this study (August–December 2003). A global positioning system was employed in order to plot the geographic distribution of both cysticercotic pigs and risk factors for infection within the villages. Prevalence of pig tongue cysticercosis varied significantly in sampled villages (p = 0.003), ranging from 0% to 33.3% and averaging 13.3%. Pigs were clustered in households, but no differences in the clustering of cysticercotic and healthy pigs were found. In contrast, the presence of pigs roaming freely and drinking stagnant water correlated significantly with porcine cysticercosis (p = 0.07), as did the absence of latrines (p = 0.0008). High prevalence of porcine cysticercosis proves that transmission is still quite common in rural Mexico. The lack of significant differentiation in the geographical clustering of healthy and cysticercotic pigs weakens the argument that focal factors (e.g., household location of putative tapeworm carriers) play an important role in increasing the risk of cysticercosis transmission in pigs. Instead, it would appear that other wide-ranging biological, physical, and cultural factors determine the geographic spread of the disease. Extensive geographic dispersal of the risk of cysticercosis makes it imperative that control measures be applied indiscriminately to all pigs and humans living in this endemic area. PMID:18846230

Language Switching--but Not Foreign Language Use Per Se--Reduces the Framing Effect

ERIC Educational Resources Information Center

Oganian, Y.; Korn, C. W.; Heekeren, H. R.

2016-01-01

Recent studies reported reductions of well-established biases in decision making under risk, such as the framing effect, during foreign language (FL) use. These modulations were attributed to the use of FL itself, which putatively entails an increase in emotional distance. A reduced framing effect in this setting, however, might also result from…

Thought Disorder and Communication Deviance as Predictors of Outcome in Youth at Clinical High Risk for Psychosis

ERIC Educational Resources Information Center

Bearden, Carrie E.; Wu, Keng Nei; Caplan, Rochelle; Cannon, Tyrone D.

2011-01-01

Objective: Given the fundamental role of thought disorder in schizophrenia, subtle communication disturbance may be a valuable predictor of subsequent development of psychosis. Here we examined the contribution of thought and communication disturbance to the prediction of outcome in adolescents identified as putatively prodromal for psychosis.…

Genetic polymorphisms associated with increased risk of developing chronic myelogenous leukemia

PubMed Central

Bruzzoni-Giovanelli, Heriberto; González, Juan R.; Sigaux, François; Villoutreix, Bruno O.; Cayuela, Jean Michel; Guilhot, Joëlle; Preudhomme, Claude; Guilhot, François; Poyet, Jean-Luc; Rousselot, Philippe

2015-01-01

Little is known about inherited factors associated with the risk of developing chronic myelogenous leukemia (CML). We used a dedicated DNA chip containing 16 561 single nucleotide polymorphisms (SNPs) covering 1 916 candidate genes to analyze 437 CML patients and 1 144 healthy control individuals. Single SNP association analysis identified 139 SNPs that passed multiple comparisons (1% false discovery rate). The HDAC9, AVEN, SEMA3C, IKBKB, GSTA3, RIPK1 and FGF2 genes were each represented by three SNPs, the PSM family by four SNPs and the SLC15A1 gene by six. Haplotype analysis showed that certain combinations of rare alleles of these genes increased the risk of developing CML by more than two or three-fold. A classification tree model identified five SNPs belonging to the genes PSMB10, TNFRSF10D, PSMB2, PPARD and CYP26B1, which were associated with CML predisposition. A CML-risk-allele score was created using these five SNPs. This score was accurate for discriminating CML status (AUC: 0.61, 95%CI: 0.58–0.64). Interestingly, the score was associated with age at diagnosis and the average number of risk alleles was significantly higher in younger patients. The risk-allele score showed the same distribution in the general population (HapMap CEU samples) as in our control individuals and was associated with differential gene expression patterns of two genes (VAPA and TDRKH). In conclusion, we describe haplotypes and a genetic score that are significantly associated with a predisposition to develop CML. The SNPs identified will also serve to drive fundamental research on the putative role of these genes in CML development. PMID:26474455

Network-Based Integration of GWAS and Gene Expression Identifies a HOX-Centric Network Associated with Serous Ovarian Cancer Risk.

PubMed

Kar, Siddhartha P; Tyrer, Jonathan P; Li, Qiyuan; Lawrenson, Kate; Aben, Katja K H; Anton-Culver, Hoda; Antonenkova, Natalia; Chenevix-Trench, Georgia; Baker, Helen; Bandera, Elisa V; Bean, Yukie T; Beckmann, Matthias W; Berchuck, Andrew; Bisogna, Maria; Bjørge, Line; Bogdanova, Natalia; Brinton, Louise; Brooks-Wilson, Angela; Butzow, Ralf; Campbell, Ian; Carty, Karen; Chang-Claude, Jenny; Chen, Yian Ann; Chen, Zhihua; Cook, Linda S; Cramer, Daniel; Cunningham, Julie M; Cybulski, Cezary; Dansonka-Mieszkowska, Agnieszka; Dennis, Joe; Dicks, Ed; Doherty, Jennifer A; Dörk, Thilo; du Bois, Andreas; Dürst, Matthias; Eccles, Diana; Easton, Douglas F; Edwards, Robert P; Ekici, Arif B; Fasching, Peter A; Fridley, Brooke L; Gao, Yu-Tang; Gentry-Maharaj, Aleksandra; Giles, Graham G; Glasspool, Rosalind; Goode, Ellen L; Goodman, Marc T; Grownwald, Jacek; Harrington, Patricia; Harter, Philipp; Hein, Alexander; Heitz, Florian; Hildebrandt, Michelle A T; Hillemanns, Peter; Hogdall, Estrid; Hogdall, Claus K; Hosono, Satoyo; Iversen, Edwin S; Jakubowska, Anna; Paul, James; Jensen, Allan; Ji, Bu-Tian; Karlan, Beth Y; Kjaer, Susanne K; Kelemen, Linda E; Kellar, Melissa; Kelley, Joseph; Kiemeney, Lambertus A; Krakstad, Camilla; Kupryjanczyk, Jolanta; Lambrechts, Diether; Lambrechts, Sandrina; Le, Nhu D; Lee, Alice W; Lele, Shashi; Leminen, Arto; Lester, Jenny; Levine, Douglas A; Liang, Dong; Lissowska, Jolanta; Lu, Karen; Lubinski, Jan; Lundvall, Lene; Massuger, Leon; Matsuo, Keitaro; McGuire, Valerie; McLaughlin, John R; McNeish, Iain A; Menon, Usha; Modugno, Francesmary; Moysich, Kirsten B; Narod, Steven A; Nedergaard, Lotte; Ness, Roberta B; Nevanlinna, Heli; Odunsi, Kunle; Olson, Sara H; Orlow, Irene; Orsulic, Sandra; Weber, Rachel Palmieri; Pearce, Celeste Leigh; Pejovic, Tanja; Pelttari, Liisa M; Permuth-Wey, Jennifer; Phelan, Catherine M; Pike, Malcolm C; Poole, Elizabeth M; Ramus, Susan J; Risch, Harvey A; Rosen, Barry; Rossing, Mary Anne; Rothstein, Joseph H; Rudolph, Anja; Runnebaum, Ingo B; Rzepecka, Iwona K; Salvesen, Helga B; Schildkraut, Joellen M; Schwaab, Ira; Shu, Xiao-Ou; Shvetsov, Yurii B; Siddiqui, Nadeem; Sieh, Weiva; Song, Honglin; Southey, Melissa C; Sucheston-Campbell, Lara E; Tangen, Ingvild L; Teo, Soo-Hwang; Terry, Kathryn L; Thompson, Pamela J; Timorek, Agnieszka; Tsai, Ya-Yu; Tworoger, Shelley S; van Altena, Anne M; Van Nieuwenhuysen, Els; Vergote, Ignace; Vierkant, Robert A; Wang-Gohrke, Shan; Walsh, Christine; Wentzensen, Nicolas; Whittemore, Alice S; Wicklund, Kristine G; Wilkens, Lynne R; Woo, Yin-Ling; Wu, Xifeng; Wu, Anna; Yang, Hannah; Zheng, Wei; Ziogas, Argyrios; Sellers, Thomas A; Monteiro, Alvaro N A; Freedman, Matthew L; Gayther, Simon A; Pharoah, Paul D P

2015-10-01

Genome-wide association studies (GWAS) have so far reported 12 loci associated with serous epithelial ovarian cancer (EOC) risk. We hypothesized that some of these loci function through nearby transcription factor (TF) genes and that putative target genes of these TFs as identified by coexpression may also be enriched for additional EOC risk associations. We selected TF genes within 1 Mb of the top signal at the 12 genome-wide significant risk loci. Mutual information, a form of correlation, was used to build networks of genes strongly coexpressed with each selected TF gene in the unified microarray dataset of 489 serous EOC tumors from The Cancer Genome Atlas. Genes represented in this dataset were subsequently ranked using a gene-level test based on results for germline SNPs from a serous EOC GWAS meta-analysis (2,196 cases/4,396 controls). Gene set enrichment analysis identified six networks centered on TF genes (HOXB2, HOXB5, HOXB6, HOXB7 at 17q21.32 and HOXD1, HOXD3 at 2q31) that were significantly enriched for genes from the risk-associated end of the ranked list (P < 0.05 and FDR < 0.05). These results were replicated (P < 0.05) using an independent association study (7,035 cases/21,693 controls). Genes underlying enrichment in the six networks were pooled into a combined network. We identified a HOX-centric network associated with serous EOC risk containing several genes with known or emerging roles in serous EOC development. Network analysis integrating large, context-specific datasets has the potential to offer mechanistic insights into cancer susceptibility and prioritize genes for experimental characterization. ©2015 American Association for Cancer Research.

Network-based integration of GWAS and gene expression identifies a HOX-centric network associated with serous ovarian cancer risk

PubMed Central

Kar, Siddhartha P.; Tyrer, Jonathan P.; Li, Qiyuan; Lawrenson, Kate; Aben, Katja K.H.; Anton-Culver, Hoda; Antonenkova, Natalia; Chenevix-Trench, Georgia; Baker, Helen; Bandera, Elisa V.; Bean, Yukie T.; Beckmann, Matthias W.; Berchuck, Andrew; Bisogna, Maria; Bjørge, Line; Bogdanova, Natalia; Brinton, Louise; Brooks-Wilson, Angela; Butzow, Ralf; Campbell, Ian; Carty, Karen; Chang-Claude, Jenny; Chen, Yian Ann; Chen, Zhihua; Cook, Linda S.; Cramer, Daniel; Cunningham, Julie M.; Cybulski, Cezary; Dansonka-Mieszkowska, Agnieszka; Dennis, Joe; Dicks, Ed; Doherty, Jennifer A.; Dörk, Thilo; du Bois, Andreas; Dürst, Matthias; Eccles, Diana; Easton, Douglas F.; Edwards, Robert P.; Ekici, Arif B.; Fasching, Peter A.; Fridley, Brooke L.; Gao, Yu-Tang; Gentry-Maharaj, Aleksandra; Giles, Graham G.; Glasspool, Rosalind; Goode, Ellen L.; Goodman, Marc T.; Grownwald, Jacek; Harrington, Patricia; Harter, Philipp; Hein, Alexander; Heitz, Florian; Hildebrandt, Michelle A.T.; Hillemanns, Peter; Hogdall, Estrid; Hogdall, Claus K.; Hosono, Satoyo; Iversen, Edwin S.; Jakubowska, Anna; Paul, James; Jensen, Allan; Ji, Bu-Tian; Karlan, Beth Y; Kjaer, Susanne K.; Kelemen, Linda E.; Kellar, Melissa; Kelley, Joseph; Kiemeney, Lambertus A.; Krakstad, Camilla; Kupryjanczyk, Jolanta; Lambrechts, Diether; Lambrechts, Sandrina; Le, Nhu D.; Lee, Alice W.; Lele, Shashi; Leminen, Arto; Lester, Jenny; Levine, Douglas A.; Liang, Dong; Lissowska, Jolanta; Lu, Karen; Lubinski, Jan; Lundvall, Lene; Massuger, Leon; Matsuo, Keitaro; McGuire, Valerie; McLaughlin, John R.; McNeish, Iain A.; Menon, Usha; Modugno, Francesmary; Moysich, Kirsten B.; Narod, Steven A.; Nedergaard, Lotte; Ness, Roberta B.; Nevanlinna, Heli; Odunsi, Kunle; Olson, Sara H.; Orlow, Irene; Orsulic, Sandra; Weber, Rachel Palmieri; Pearce, Celeste Leigh; Pejovic, Tanja; Pelttari, Liisa M.; Permuth-Wey, Jennifer; Phelan, Catherine M.; Pike, Malcolm C.; Poole, Elizabeth M.; Ramus, Susan J.; Risch, Harvey A.; Rosen, Barry; Rossing, Mary Anne; Rothstein, Joseph H.; Rudolph, Anja; Runnebaum, Ingo B.; Rzepecka, Iwona K.; Salvesen, Helga B.; Schildkraut, Joellen M.; Schwaab, Ira; Shu, Xiao-Ou; Shvetsov, Yurii B; Siddiqui, Nadeem; Sieh, Weiva; Song, Honglin; Southey, Melissa C.; Sucheston-Campbell, Lara E.; Tangen, Ingvild L.; Teo, Soo-Hwang; Terry, Kathryn L.; Thompson, Pamela J; Timorek, Agnieszka; Tsai, Ya-Yu; Tworoger, Shelley S.; van Altena, Anne M.; Van Nieuwenhuysen, Els; Vergote, Ignace; Vierkant, Robert A.; Wang-Gohrke, Shan; Walsh, Christine; Wentzensen, Nicolas; Whittemore, Alice S.; Wicklund, Kristine G.; Wilkens, Lynne R.; Woo, Yin-Ling; Wu, Xifeng; Wu, Anna; Yang, Hannah; Zheng, Wei; Ziogas, Argyrios; Sellers, Thomas A.; Monteiro, Alvaro N. A.; Freedman, Matthew L.; Gayther, Simon A.; Pharoah, Paul D. P.

2015-01-01

Background Genome-wide association studies (GWAS) have so far reported 12 loci associated with serous epithelial ovarian cancer (EOC) risk. We hypothesized that some of these loci function through nearby transcription factor (TF) genes and that putative target genes of these TFs as identified by co-expression may also be enriched for additional EOC risk associations. Methods We selected TF genes within 1 Mb of the top signal at the 12 genome-wide significant risk loci. Mutual information, a form of correlation, was used to build networks of genes strongly co-expressed with each selected TF gene in the unified microarray data set of 489 serous EOC tumors from The Cancer Genome Atlas. Genes represented in this data set were subsequently ranked using a gene-level test based on results for germline SNPs from a serous EOC GWAS meta-analysis (2,196 cases/4,396 controls). Results Gene set enrichment analysis identified six networks centered on TF genes (HOXB2, HOXB5, HOXB6, HOXB7 at 17q21.32 and HOXD1, HOXD3 at 2q31) that were significantly enriched for genes from the risk-associated end of the ranked list (P<0.05 and FDR<0.05). These results were replicated (P<0.05) using an independent association study (7,035 cases/21,693 controls). Genes underlying enrichment in the six networks were pooled into a combined network. Conclusion We identified a HOX-centric network associated with serous EOC risk containing several genes with known or emerging roles in serous EOC development. Impact Network analysis integrating large, context-specific data sets has the potential to offer mechanistic insights into cancer susceptibility and prioritize genes for experimental characterization. PMID:26209509

Loss-of-function of neuroplasticity-related genes confers risk for human neurodevelopmental disorders.

PubMed

Smith, Milo R; Glicksberg, Benjamin S; Li, Li; Chen, Rong; Morishita, Hirofumi; Dudley, Joel T

2018-01-01

High and increasing prevalence of neurodevelopmental disorders place enormous personal and economic burdens on society. Given the growing realization that the roots of neurodevelopmental disorders often lie in early childhood, there is an urgent need to identify childhood risk factors. Neurodevelopment is marked by periods of heightened experience-dependent neuroplasticity wherein neural circuitry is optimized by the environment. If these critical periods are disrupted, development of normal brain function can be permanently altered, leading to neurodevelopmental disorders. Here, we aim to systematically identify human variants in neuroplasticity-related genes that confer risk for neurodevelopmental disorders. Historically, this knowledge has been limited by a lack of techniques to identify genes related to neurodevelopmental plasticity in a high-throughput manner and a lack of methods to systematically identify mutations in these genes that confer risk for neurodevelopmental disorders. Using an integrative genomics approach, we determined loss-of-function (LOF) variants in putative plasticity genes, identified from transcriptional profiles of brain from mice with elevated plasticity, that were associated with neurodevelopmental disorders. From five shared differentially expressed genes found in two mouse models of juvenile-like elevated plasticity (juvenile wild-type or adult Lynx1-/- relative to adult wild-type) that were also genotyped in the Mount Sinai BioMe Biobank we identified multiple associations between LOF genes and increased risk for neurodevelopmental disorders across 10,510 patients linked to the Mount Sinai Electronic Medical Records (EMR), including epilepsy and schizophrenia. This work demonstrates a novel approach to identify neurodevelopmental risk genes and points toward a promising avenue to discover new drug targets to address the unmet therapeutic needs of neurodevelopmental disease.

Increased anaesthesia duration increases venous thromboembolism risk in plastic surgery: A 6-year analysis of over 19,000 cases using the NSQIP dataset.

PubMed

Mlodinow, Alexei S; Khavanin, Nima; Ver Halen, Jon P; Rambachan, Aksharananda; Gutowski, Karol A; Kim, John Y S

2015-01-01

Venous thromboembolism (VTE) is a significant cause of morbidity and mortality, particularly in the postoperative setting. Various risk stratification schema exist in the plastic surgery literature, but do not take into account variations in procedure length. The putative risk of VTE conferred by increased length of time under anaesthesia has never been rigorously explored. The goal of this study is to assess this relationship and to benchmark VTE rates in plastic surgery. A large, multi-institutional quality-improvement database was queried for plastic and reconstructive surgery procedures performed under general anaesthesia between 2005-2011. In total, 19,276 cases were abstracted from the database. Z-scores were calculated based on procedure-specific mean surgical durations, to assess each case's length in comparison to the mean for that procedure. A total of 70 patients (0.36%) experienced a post-operative VTE. Patients with and without post-operative VTE were compared with respect to a variety of demographics, comorbidities, and intraoperative characteristics. Potential confounders for VTE were included in a regression model, along with the Z-scores. VTE occurred in both cosmetic and reconstructive procedures. Longer surgery time, relative to procedural means, was associated with increased VTE rates. Further, regression analysis showed increase in Z-score to be an independent risk factor for post-operative VTE (Odds Ratio of 1.772 per unit, p-value < 0.001). Subgroup analyses corroborated these findings. This study validates the long-held view that increased surgical duration confers risk of VTE, as well as benchmarks VTE rates in plastic surgery procedures. While this in itself does not suggest an intervention, surgical time under general anaesthesia would be a useful addition to existing risk models in plastic surgery.

Autonomic nervous system dysfunction in psychiatric disorders and the impact of psychotropic medications: a systematic review and meta-analysis

PubMed Central

Alvares, Gail A.; Quintana, Daniel S.; Hickie, Ian B.; Guastella, Adam J.

2016-01-01

Background Autonomic nervous system (ANS) dysfunction is a putative underlying mechanism for increased cardiovascular disease risk in individuals with psychiatric disorders. Previous studies suggest that this risk may be related to psychotropic medication use. In the present study we systematically reviewed and analyzed published studies of heart rate variability (HRV), measuring ANS output, to determine the effect of psychiatric illness and medication use. Methods We searched for studies comparing HRV in physically healthy adults with a diagnosed psychiatric disorder to controls and comparing HRV pre- and post-treatment with a psychotropic medication. Results In total, 140 case–control (mood, anxiety, psychosis, dependent disorders, k = 151) and 30 treatment (antidepressants, antipsychotics; k = 43) studies were included. We found that HRV was reduced in all patient groups compared to controls (Hedges g = −0.583) with a large effect for psychotic disorders (Hedges g = −0.948). Effect sizes remained highly significant for medication-free patients compared to controls across all disorders. Smaller and significant reductions in HRV were observed for specific antidepressants and antipsychotics. Limitations Study quality significantly moderated effect sizes in case–control analyses, underscoring the importance of assessing methodological quality when interpreting HRV findings. Conclusion Combined findings confirm substantial reductions in HRV across psychiatric disorders, and these effects remained significant even in medication-free individuals. Reductions in HRV may therefore represent a significant mechanism contributing to elevated cardiovascular risk in individuals with psychiatric disorders. The negative impact of specific medications on HRV suggest increased risk for cardiovascular disease in these groups, highlighting a need for treatment providers to consider modifiable cardiovascular risk factors to attenuate this risk. PMID:26447819

Prediction of incidence and stability of alcohol use disorders by latent internalizing psychopathology risk profiles in adolescence and young adulthood.

PubMed

Behrendt, Silke; Bühringer, Gerhard; Höfler, Michael; Lieb, Roselind; Beesdo-Baum, Katja

2017-10-01

Comorbid internalizing mental disorders in alcohol use disorders (AUD) can be understood as putative independent risk factors for AUD or as expressions of underlying shared psychopathology vulnerabilities. However, it remains unclear whether: 1) specific latent internalizing psychopathology risk-profiles predict AUD-incidence and 2) specific latent internalizing comorbidity-profiles in AUD predict AUD-stability. To investigate baseline latent internalizing psychopathology risk profiles as predictors of subsequent AUD-incidence and -stability in adolescents and young adults. Data from the prospective-longitudinal EDSP study (baseline age 14-24 years) were used. The study-design included up to three follow-up assessments in up to ten years. DSM-IV mental disorders were assessed with the DIA-X/M-CIDI. To investigate risk-profiles and their associations with AUD-outcomes, latent class analysis with auxiliary outcome variables was applied. AUD-incidence: a 4-class model (N=1683) was identified (classes: normative-male [45.9%], normative-female [44.2%], internalizing [5.3%], nicotine dependence [4.5%]). Compared to the normative-female class, all other classes were associated with a higher risk of subsequent incident alcohol dependence (p<0.05). AUD-stability: a 3-class model (N=1940) was identified with only one class (11.6%) with high probabilities for baseline AUD. This class was further characterized by elevated substance use disorder (SUD) probabilities and predicted any subsequent AUD (OR 8.5, 95% CI 5.4-13.3). An internalizing vulnerability may constitute a pathway to AUD incidence in adolescence and young adulthood. In contrast, no indication for a role of internalizing comorbidity profiles in AUD-stability was found, which may indicate a limited importance of such profiles - in contrast to SUD-related profiles - in AUD stability. Copyright © 2017 Elsevier B.V. All rights reserved.

Cocoa, blood pressure, and cardiovascular health.

PubMed

Ferri, Claudio; Desideri, Giovambattista; Ferri, Livia; Proietti, Ilenia; Di Agostino, Stefania; Martella, Letizia; Mai, Francesca; Di Giosia, Paolo; Grassi, Davide

2015-11-18

High blood pressure is an important risk factor for cardiovascular disease and cardiovascular events worldwide. Clinical and epidemiological studies suggest that cocoa-rich products reduce the risk of cardiovascular disease. According to this, cocoa has a high content in polyphenols, especially flavanols. Flavanols have been described to exert favorable effects on endothelium-derived vasodilation via the stimulation of nitric oxide-synthase, the increased availability of l-arginine, and the decreased degradation of NO. Cocoa may also have a beneficial effect by protecting against oxidative stress alterations and via decreased platelet aggregation, decreased lipid oxidation, and insulin resistance. These effects are associated with a decrease of blood pressure and a favorable trend toward a reduction in cardiovascular events and strokes. Previous meta-analyses have shown that cocoa-rich foods may reduce blood pressure. Long-term trials investigating the effect of cocoa products are needed to determine whether or not blood pressure is reduced on a chronic basis by daily ingestion of cocoa. Furthermore, long-term trials investigating the effect of cocoa on clinical outcomes are also needed to assess whether cocoa has an effect on cardiovascular events. A 3 mmHg systolic blood pressure reduction has been estimated to decrease the risk of cardiovascular and all-cause mortality. This paper summarizes new findings concerning cocoa effects on blood pressure and cardiovascular health, focusing on putative mechanisms of action and "nutraceutical " viewpoints.

Bioavailable Insulin-Like Growth Factor-I Inversely Related to Weight Gain in Postmenopausal Women regardless of Exogenous Estrogen

PubMed Central

Jung, Su Yon; Hursting, Stephen D.; Guindani, Michele; Vitolins, Mara Z.; Paskett, Electra; Chang, Shine

2014-01-01

Background Weight gain, insulin-like growth factor-I (IGF-I) levels, and excess exogenous steroid hormone use are putative cancer risk factors, yet their interconnected pathways have not been fully characterized. This cross-sectional study investigated the relationship between plasma IGF-I levels and weight gain according to body mass index (BMI), leptin levels, and exogenous estrogen use among postmenopausal women. Methods This study included 794 postmenopausal women who enrolled in an ancillary study of the Women's Health Initiative Observational Study between February 1995 and July 1998. The relationship between IGF-I levels and weight gain was analyzed using ordinal logistic regression. We used the molar ratio of IGF-I to IGF binding protein-3 (IGF-I/IGFBP-3) or circulating IGF-I levels adjusting for IGFBP-3 as a proxy of bioavailable IGF-I. The plasma concentrations were expressed as quartiles. Results Among the obese group, women in the third quartile (Q3) of IGF-I and highest quartile of IGF-I/IGFBP-3 were less likely to gain weight (>3% from baseline) than were women in the first quartiles (Q1). Among the normal weight group, women in Q2 and Q3 of IGF-I/IGFBP-3 were 70% less likely than those in Q1 to gain weight. Among current estrogen users, Q3 of IGF-I/IGFBP-3 had 0.5 times the odds of gaining weight than Q1. Conclusions Bioavailable IGF-I levels were inversely related to weight gain overall. Impact Although weight gain was not consistent with increases in IGF-I levels among postmenopausal women in this report, avoidance of weight gain as a strategy to reduce cancer risk may be recommend. PMID:24363252

Anxiety and depression with neurogenesis defects in exchange protein directly activated by cAMP 2-deficient mice are ameliorated by a selective serotonin reuptake inhibitor, Prozac

PubMed Central

Zhou, L; Ma, S L; Yeung, P K K; Wong, Y H; Tsim, K W K; So, K F; Lam, L C W; Chung, S K

2016-01-01

Intracellular cAMP and serotonin are important modulators of anxiety and depression. Fluoxetine, a selective serotonin reuptake inhibitor (SSRI) also known as Prozac, is widely used against depression, potentially by activating cAMP response element-binding protein (CREB) and increasing brain-derived neurotrophic factor (BDNF) through protein kinase A (PKA). However, the role of Epac1 and Epac2 (Rap guanine nucleotide exchange factors, RAPGEF3 and RAPGEF4, respectively) as potential downstream targets of SSRI/cAMP in mood regulations is not yet clear. Here, we investigated the phenotypes of Epac1 (Epac1−/−) or Epac2 (Epac2−/−) knockout mice by comparing them with their wild-type counterparts. Surprisingly, Epac2−/− mice exhibited a wide range of mood disorders, including anxiety and depression with learning and memory deficits in contextual and cued fear-conditioning tests without affecting Epac1 expression or PKA activity. Interestingly, rs17746510, one of the three single-nucleotide polymorphisms (SNPs) in RAPGEF4 associated with cognitive decline in Chinese Alzheimer's disease (AD) patients, was significantly correlated with apathy and mood disturbance, whereas no significant association was observed between RAPGEF3 SNPs and the risk of AD or neuropsychiatric inventory scores. To further determine the detailed role of Epac2 in SSRI/serotonin/cAMP-involved mood disorders, we treated Epac2−/− mice with a SSRI, Prozac. The alteration in open field behavior and impaired hippocampal cell proliferation in Epac2−/− mice were alleviated by Prozac. Taken together, Epac2 gene polymorphism is a putative risk factor for mood disorders in AD patients in part by affecting the hippocampal neurogenesis. PMID:27598965

Distribution and factors associated with Salmonella enterica genotypes in a diverse population of humans and animals in Qatar using multi-locus sequence typing (MLST).

PubMed

Chang, Yu C; Scaria, Joy; Ibraham, Mariamma; Doiphode, Sanjay; Chang, Yung-Fu; Sultan, Ali; Mohammed, Hussni O

2016-01-01

Salmonella enterica is one of the most commonly reported causes of bacterial foodborne illness around the world. Understanding the sources of this pathogen and the associated factors that exacerbate its risk to humans will help in developing risk mitigation strategies. The genetic relatedness among Salmonella isolates recovered from human gastroenteritis cases and food animals in Qatar were investigated in the hope of shedding light on these sources, their possible transmission routes, and any associated factors. A repeat cross-sectional study was conducted in which the samples and associated data were collected from both populations (gastroenteritis cases and animals). Salmonella isolates were initially analyzed using multi-locus sequence typing (MLST) to investigate the genetic diversity and clonality. The relatedness among the isolates was assessed using the minimum spanning tree (MST). Twenty-seven different sequence types (STs) were identified in this study; among them, seven were novel, including ST1695, ST1696, ST1697, ST1698, ST1699, ST1702, and ST1703. The pattern of overall ST distribution was diverse; in particular, it was revealed that ST11 and ST19 were the most common sequence types, presenting 29.5% and 11.5% within the whole population. In addition, 20 eBurst Groups (eBGs) were identified in our data, which indicates that ST11 and ST19 belonged to eBG4 and eBG1, respectively. In addition, the potential association between the putative risk factors and eBGs were evaluated. There was no significant clustering of these eBGs by season; however, a significant association was identified in terms of nationality in that Qataris were six times more likely to present with eBG1 compared to non-Qataris. In the MST analysis, four major clusters were presented, namely, ST11, ST19, ST16, and ST31. The linkages between the clusters alluded to a possible transmission route. The results of the study have provided insight into the ST distributions of S. enterica and their possible zoonotic associations in Qatar. Published by Elsevier Ltd.

Linking brain imaging and genomics in the study of Alzheimer's disease and aging.

PubMed

Reiman, Eric M

2007-02-01

My colleagues and I have been using positron emission tomography (PET) and magnetic resonance imaging (MRI) to detect and track the brain changes associated with Alzheimer's disease (AD) and normal brain aging in cognitively normal persons with two copies, one copy, and no copies of the apolipoprotein E (APOE) epsilon4 allele, a common AD susceptibility gene. In this review article, I consider how brain imaging techniques could be used to evaluate putative AD prevention therapies in cognitively normal APOE epsilon4 carriers and putative age-modifying therapies in cognitively normal APOE epsilon4 noncarriers, how they could help investigate the individual and aggregate effects of putative AD risk modifiers, and how they could help guide the investigation of a molecular mechanism associated with AD vulnerability and normal neurological aging. I suggest how high-resolution genome-wide genetic and transcriptomic studies could further help in the scientific understanding of AD, aging, and other common and genetically complex phenotypes, such as variation in normal human memory performance, and in the discovery and evaluation of promising treatments for these phenotypes. Finally, I illustrate the push-pull relationship between brain imaging, genomics research, and other neuroscientific research in the study of AD and aging.

Illness Progression as a Function of Independent and Accumulating Poor Prognosis Factors in Outpatients With Bipolar Disorder in the United States

PubMed Central

Altshuler, Lori L.; Leverich, Gabriele S.; Nolen, Willem A.; Kupka, Ralph; Grunze, Heinz; Frye, Mark A.; Suppes, Trisha; McElroy, Susan L.; Keck, Paul E.; Rowe, Mike

2014-01-01

Objective: Many patients with bipolar disorder in the United States experience a deteriorating course of illness despite naturalistic treatment in the community. We examined a variety of factors associated with this pattern of illness progression. Method: From 1995 to 2002, we studied 634 adult outpatients with bipolar disorder (mean age of 40 years) emanating from 4 sites in the United States. Patients gave informed consent and completed a detailed questionnaire about demographic, vulnerability, and course-of-illness factors and indicated whether their illness had shown a pattern of increasing frequency or severity of manic or depressive episodes. Fifteen factors previously linked in the literature to a poor outcome were examined for their relationship to illness progression using Kruskal-Wallis test, followed by a 2-sample Wilcoxon rank sum (Mann-Whitney) test, χ2, and logistical regression. Results: All of the putative poor prognosis factors occurred with a high incidence, and, with the exception of obesity, were significantly (P < .05) associated with illness progression. These factors included indicators of genetic and psychosocial risk and loss of social support, early onset, long delay to first treatment, anxiety and substance abuse comorbidity, rapid cycling in any year, and the occurrence of more than 20 prior episodes prior to entering the network. A greater number of factors were linearly associated with the likelihood of a progressively worsening course. Conclusions: Multiple genetic, psychosocial, and illness factors were associated with a deteriorating course of bipolar disorder from onset to study entry in adulthood. The identification of these factors provides important targets for earlier and more effective therapeutic intervention in the hope of achieving a more benign course of bipolar disorder. PMID:25834764

Transcriptional regulation of the operon encoding stress-responsive ECF sigma factor SigH and its anti-sigma factor RshA, and control of its regulatory network in Corynebacterium glutamicum

PubMed Central

2012-01-01

Background The expression of genes in Corynebacterium glutamicum, a Gram-positive non-pathogenic bacterium used mainly for the industrial production of amino acids, is regulated by seven different sigma factors of RNA polymerase, including the stress-responsive ECF-sigma factor SigH. The sigH gene is located in a gene cluster together with the rshA gene, putatively encoding an anti-sigma factor. The aim of this study was to analyze the transcriptional regulation of the sigH and rshA gene cluster and the effects of RshA on the SigH regulon, in order to refine the model describing the role of SigH and RshA during stress response. Results Transcription analyses revealed that the sigH gene and rshA gene are cotranscribed from four sigH housekeeping promoters in C. glutamicum. In addition, a SigH-controlled rshA promoter was found to only drive the transcription of the rshA gene. To test the role of the putative anti-sigma factor gene rshA under normal growth conditions, a C. glutamicum rshA deletion strain was constructed and used for genome-wide transcription profiling with DNA microarrays. In total, 83 genes organized in 61 putative transcriptional units, including those previously detected using sigH mutant strains, exhibited increased transcript levels in the rshA deletion mutant compared to its parental strain. The genes encoding proteins related to disulphide stress response, heat stress proteins, components of the SOS-response to DNA damage and proteasome components were the most markedly upregulated gene groups. Altogether six SigH-dependent promoters upstream of the identified genes were determined by primer extension and a refined consensus promoter consisting of 45 original promoter sequences was constructed. Conclusions The rshA gene codes for an anti-sigma factor controlling the function of the stress-responsive sigma factor SigH in C. glutamicum. Transcription of rshA from a SigH-dependent promoter may serve to quickly shutdown the SigH-dependent stress response after the cells have overcome the stress condition. Here we propose a model of the regulation of oxidative and heat stress response including redox homeostasis by SigH, RshA and the thioredoxin system. PMID:22943411

Transcriptional regulation of the operon encoding stress-responsive ECF sigma factor SigH and its anti-sigma factor RshA, and control of its regulatory network in Corynebacterium glutamicum.

PubMed

Busche, Tobias; Silar, Radoslav; Pičmanová, Martina; Pátek, Miroslav; Kalinowski, Jörn

2012-09-03

The expression of genes in Corynebacterium glutamicum, a Gram-positive non-pathogenic bacterium used mainly for the industrial production of amino acids, is regulated by seven different sigma factors of RNA polymerase, including the stress-responsive ECF-sigma factor SigH. The sigH gene is located in a gene cluster together with the rshA gene, putatively encoding an anti-sigma factor. The aim of this study was to analyze the transcriptional regulation of the sigH and rshA gene cluster and the effects of RshA on the SigH regulon, in order to refine the model describing the role of SigH and RshA during stress response. Transcription analyses revealed that the sigH gene and rshA gene are cotranscribed from four sigH housekeeping promoters in C. glutamicum. In addition, a SigH-controlled rshA promoter was found to only drive the transcription of the rshA gene. To test the role of the putative anti-sigma factor gene rshA under normal growth conditions, a C. glutamicum rshA deletion strain was constructed and used for genome-wide transcription profiling with DNA microarrays. In total, 83 genes organized in 61 putative transcriptional units, including those previously detected using sigH mutant strains, exhibited increased transcript levels in the rshA deletion mutant compared to its parental strain. The genes encoding proteins related to disulphide stress response, heat stress proteins, components of the SOS-response to DNA damage and proteasome components were the most markedly upregulated gene groups. Altogether six SigH-dependent promoters upstream of the identified genes were determined by primer extension and a refined consensus promoter consisting of 45 original promoter sequences was constructed. The rshA gene codes for an anti-sigma factor controlling the function of the stress-responsive sigma factor SigH in C. glutamicum. Transcription of rshA from a SigH-dependent promoter may serve to quickly shutdown the SigH-dependent stress response after the cells have overcome the stress condition. Here we propose a model of the regulation of oxidative and heat stress response including redox homeostasis by SigH, RshA and the thioredoxin system.

Postoperative Surgical Infection After Spinal Surgery in Rheumatoid Arthritis.

PubMed

Koyama, Kensuke; Ohba, Tetsuro; Ebata, Shigeto; Haro, Hirotaka

2016-05-01

Individuals with rheumatoid arthritis are at higher risk for infection than the general population, and surgical site infection after spinal surgery in this population can result in clinically significant complications. The goal of this study was to identify risk factors for acute surgical site infection after spinal surgery in patients with rheumatoid arthritis who were treated with nonbiologic (conventional) disease-modifying antirheumatic drugs (DMARDs) alone or with biologic DMARDs. All patients treated with biologic agents were treated with nonbiologic agents as well. The authors performed a retrospective, single-center review of 47 consecutive patients with rheumatoid arthritis who underwent spinal surgery and had follow-up of 3 months or longer. The incidence of surgical site infection was examined, and multivariate logistic regression analysis was performed to test the association of surgical site infection with putative risk factors, including the use of biologic agents, methotrexate, and prednisolone, as well as the duration of rheumatoid arthritis, the presence of diabetes, patient age, length of surgery, and number of operative levels. After spinal surgery, 14.89% (7 of 47) of patients had surgical site infection. Use of methotrexate and/or prednisolone, patient age, diabetes, duration of rheumatoid arthritis, length of surgery, number of operative levels, and use of biologic DMARDs did not significantly increase the risk of infection associated with spinal surgery. All patients who had surgical site infection had undergone spinal surgery with instrumentation. The findings show that greater attention to preventing surgical site infection may be needed in patients with rheumatoid arthritis who undergo spinal surgery with instrumentation. To the authors' knowledge, this is the first study to show that the use of biologic agents did not increase the incidence of surgical site infection after spinal surgery in patients with rheumatoid arthritis. [Orthopedics. 2016; 39(3):e430-e433.]. Copyright 2016, SLACK Incorporated.

Molecular epidemiology of MRSA in 13 ICUs from eight European countries.

PubMed

Hetem, D J; Derde, L P G; Empel, J; Mroczkowska, A; Orczykowska-Kotyna, M; Kozińska, A; Hryniewicz, W; Goossens, H; Bonten, M J M

2016-01-01

The European epidemiology of MRSA is changing with the emergence of community-associated MRSA (CA-MRSA) and livestock-associated MRSA (LA-MRSA). In this study, we investigated the molecular epidemiology of MRSA during 2 years in 13 ICUs in France, Greece, Italy, Latvia, Luxemburg, Portugal, Slovenia and Spain. Surveillance cultures for MRSA from nose and wounds were obtained on admission and twice weekly from all patients admitted to an ICU for ≥3 days. The first MRSA isolate per patient was genotyped in a central laboratory by MLST, spa typing, agr typing and SCCmec (sub)typing. Risk factors for patients with an unknown history of MRSA colonization were identified. Overall, 14 390 ICU patients were screened, of whom 8519 stayed in an ICU for ≥3 days. Overall MRSA admission prevalence was 3.9% and ranged from 1.0% to 7.0% for individual ICUs. Overall MRSA acquisition rate was 2.5/1000 patient days at risk and ranged from 0.2 to 8/1000 patient days at risk per ICU. In total, 557 putative MRSA isolates were submitted to the central laboratory for typing, of which 511 (92%) were confirmed as MRSA. Each country had a distinct epidemiology, with ST8-IVc (UK-EMRSA-2/-6, USA500) being most prevalent, especially in France and Spain, and detected in ICUs in five of eight countries. Seventeen (3%) and three (<1%) isolates were categorized as CA-MRSA and LA-MRSA, respectively. Risk factors for MRSA carriage on ICU admission were age >70 years and hospitalization within 1 year prior to ICU admission. The molecular epidemiology of MRSA in 13 European ICUs in eight countries was homogeneous within, but heterogeneous between, countries. CA-MRSA and LA-MRSA genotypes and Panton-Valentine leucocidin-producing isolates were detected sporadically. © The Author 2015. Published by Oxford University Press on behalf of the British Society for Antimicrobial Chemotherapy. All rights reserved. For Permissions, please e-mail: journals.permissions@oup.com.

Characterization of breast density in Vietnam and its association with demographic, reproductive and lifestyle factors

NASA Astrophysics Data System (ADS)

Trieu, Phuong Dung (Yun); Mello-Thoms, Claudia; Peat, Jenny; Do, Thuan Doan; Brennan, Patrick C.

2017-03-01

This study aims to investigate patterns of breast density among women in Vietnam and their association with demographic, reproductive and lifestyle features. Mammographic densities of 1,651 women were collected from the two largest breast cancer screening and treatment centers in Ha Noi and Ho Chi Minh city. Putative factors associated with breast density were obtained from self-administered questionnaires which considered demographic, reproductive and lifestyle elements and were provided by women who attended mammography examinations. Results show that a large proportion of Vietnamese women (78.4%) had a high breast density. With multivariable logistic regression, significant associations of high breast density were evident with women with less than 55 years old (OR=3.0), having BMI less than 23 (OR=2.2), experiencing pre-menopausal status (OR=2.9), having less than three children (OR=1.7), and being less than 32 years old when having their last child (OR=1.8). Participants who consumed more than two vegetable servings per day also had an increased risk of higher density (OR=2.6). The findings suggest some unique features regarding mammographic density amongst Vietnamese compared with westernized women.

Innate lymphoid cells at the interface between obesity and asthma.

PubMed

Everaere, Laetitia; Ait Yahia, Saliha; Bouté, Mélodie; Audousset, Camille; Chenivesse, Cécile; Tsicopoulos, Anne

2018-01-01

Obesity and asthma prevalence has dramatically and concomitantly increased over the last 25 years, and many epidemiological studies have highlighted obesity as an important risk factor for asthma. Although many studies have been performed, the underlying mechanisms remain poorly understood. Innate mechanisms have been involved in both diseases, in particular through the recently described innate lymphoid cells (ILCs). ILCs are subdivided into three groups that are defined by their cytokine production and by their master transcription factor expression, in sharp correlation with their T helper counterparts. However, unlike T helper cells, ILCs do not express antigen-specific receptors, but respond to damage-induced signals. ILCs have been found in target tissues of both diseases, and data have implicated these cells in the pathogenesis of both diseases. In particular group 2 ILCs (ILC2) are activated in both the adipose and lung tissues under the effect of interleukin-33 and interleukin-25 expression. However, counter-intuitively to the well-known association between obesity and asthma, ILC2 are beneficial for obesity but deleterious for asthma. This review will examine the roles of ILCs in each disease and recent data highlighting ILCs as a putative link between obesity and asthma. © 2017 John Wiley & Sons Ltd.

CRISPR-Cas9 Mediated Telomere Removal Leads to Mitochondrial Stress and Protein Aggregation.

PubMed

Kim, Hyojung; Ham, Sangwoo; Jo, Minkyung; Lee, Gum Hwa; Lee, Yun-Song; Shin, Joo-Ho; Lee, Yunjong

2017-10-03

Aging is considered the major risk factor for neurodegenerative diseases including Parkinson's disease (PD). Telomere shortening is associated with cellular senescence. In this regard, pharmacological or genetic inhibition of telomerase activity has been used to model cellular aging. Here, we employed CRISPR-Cas9 technology to instantly remove the telomere to induce aging in a neuroblastoma cell line. Expression of both Cas9 and guide RNA targeting telomere repeats ablated the telomere, leading to retardation of cell proliferation. Instant deletion of telomere in SH-SY5Y cells impaired mitochondrial function with diminished mitochondrial respiration and cell viability. Supporting the pathological relevance of cell aging by CRISPR-Cas9 mediated telomere removal, alterations were observed in the levels of PD-associated proteins including PTEN-induced putative kinase 1, peroxisome proliferator-activated receptor γ coactivator 1-α, nuclear respiratory factor 1, parkin, and aminoacyl tRNA synthetase complex interacting multifunctional protein 2. Significantly, α-synuclein expression in the background of telomere removal led to the enhancement of protein aggregation, suggesting positive feed-forward interaction between aging and PD pathogenesis. Collectively, our results demonstrate that CRISPR-Cas9 can be used to efficiently model cellular aging and PD.

The Role of Leptin, Melanocortin, and Neurotrophin System Genes on Body Weight in Anorexia Nervosa and Bulimia Nervosa

PubMed Central

Yilmaz, Zeynep; Kaplan, Allan S.; Tiwari, Arun K.; Levitan, Robert D.; Piran, Sara; Bergen, Andrew W.; Kaye, Walter H.; Hakonarson, Hakon; Wang, Kai; Berrettini, Wade H.; Brandt, Harry A.; Bulik, Cynthia M.; Crawford, Steve; Crow, Scott; Fichter, Manfred M.; Halmi, Katherine A.; Johnson, Craig L.; Keel, Pamela K.; Klump, Kelly L.; Magistretti, Pierre; Mitchell, James E.; Strober, Michael; Thornton, Laura M.; Treasure, Janet; Woodside, D. Blake; Knight, Joanne; Kennedy, James L.

2014-01-01

Objective Although low weight is a key factor contributing to the high mortality in anorexia nervosa (AN), it is unclear how AN patients sustain low weight compared with bulimia nervosa (BN) patients with similar psychopathology. Studies of genes involved in appetite and weight regulation in eating disorders have yielded variable findings in part due to small sample size and clinical heterogeneity. This study: (1) assessed the role of leptin, melanocortin, and neurotrophin genetic variants in conferring risk for AN and BN and (2) explored the involvement of these genes in body mass index (BMI) variations within AN and BN. Method Our sample consisted of 745 individuals with AN without a history of BN, 245 with BN without a history of AN, and 321 controls. We genotyped 20 markers with known or putative function among genes selected from leptin, melanocortin, and neurotrophin systems. Results There were no significant differences in allele frequencies among individuals with AN, BN, and controls. AGRP rs13338499 polymorphism was associated with lowest illness-related BMI in those with AN (p=0.0013), and NTRK2 rs1042571 was associated with highest BMI in those with BN (p=0.0018). Discussion To our knowledge, this is the first study to address the issue of clinical heterogeneity in eating disorder genetics and to explore the role of known or putatively functional markers in genes regulating appetite and weight in individuals with AN and BN. If replicated, our results may serve as an important first step toward gaining a better understanding of weight regulation in eating disorders. PMID:24831852

Decoding the network of Trypanosoma brucei proteins that determines sensitivity to apolipoprotein-L1

PubMed Central

MacLeod, Annette

2018-01-01

In contrast to Trypanosoma brucei gambiense and T. b. rhodesiense (the causative agents of human African trypanosomiasis), T. b. brucei is lysed by apolipoprotein-L1 (apoL1)-containing human serum trypanolytic factors (TLF), rendering it non-infectious to humans. While the mechanisms of TLF1 uptake, apoL1 membrane integration, and T. b. gambiense and T. b. rhodesiense apoL1-resistance have been extensively characterised, our understanding of the range of factors that drive apoL1 action in T. b. brucei is limited. Selecting our bloodstream-form T. b. brucei RNAi library with recombinant apoL1 identified an array of factors that supports the trypanocidal action of apoL1, including six putative ubiquitin modifiers and several proteins putatively involved in membrane trafficking; we also identified the known apoL1 sensitivity determinants, TbKIFC1 and the V-ATPase. Most prominent amongst the novel apoL1 sensitivity determinants was a putative ubiquitin ligase. Intriguingly, while loss of this ubiquitin ligase reduces parasite sensitivity to apoL1, its loss enhances parasite sensitivity to TLF1-dominated normal human serum, indicating that free and TLF1-bound apoL1 have contrasting modes-of-action. Indeed, loss of the known human serum sensitivity determinants, p67 (lysosomal associated membrane protein) and the cathepsin-L regulator, ‘inhibitor of cysteine peptidase’, had no effect on sensitivity to free apoL1. Our findings highlight a complex network of proteins that influences apoL1 action, with implications for our understanding of the anti-trypanosomal action of human serum. PMID:29346416

A Putative Nononcogene Addiction Gene Target and Marker for Radiosensitivity in High-Risk Prostate Cancer

DTIC Science & Technology

2014-12-01

transduction with viral particles containing RNASEH2A driven by a CMV promoter in the pG3.3 vector and selected for with blasticidin along with...and repair. Genes Cells. 2000 Oct;5(10):789-802. PubMed PMID: 11029655. Epub 2000 /10/13. eng. 3. Aguilera A, Garcia-Muse T. R loops: from

Antepartum and Postpartum Exposure to Maternal Depression: Different Effects on Different Adolescent Outcomes

ERIC Educational Resources Information Center

Hay, Dale F.; Pawlby, Susan; Waters, Cerith S.; Sharp, Deborah

2008-01-01

Background: Postpartum depression (PPD) is considered a major public health problem that conveys risk to mothers and offspring. Yet PPD typically occurs in the context of a lifelong episodic illness, and its putative effects might derive from the child's exposure to other episodes, in pregnancy or later childhood. The aim of the study is to test…

The omega-3 fatty acid DHA dose-dependently reduces atherosclerosis: a putative role for F4-neuroprostanes a specific class of peroxidized metabolites

USDA-ARS?s Scientific Manuscript database

Objective. Consumption of long chain omega-3 polyunsaturated fatty acids is associated with reduced risks of cardiovascular disease but the role of their oxygenated metabolites remains unclear. We hypothesized that peroxidized metabolites of docosahexaenoic acid (DHA, 22:6 n-3) could play a role in ...

Predicting Social Impairment and ASD Diagnosis in Younger Siblings of Children with Autism Spectrum Disorder

ERIC Educational Resources Information Center

Yoder, Paul; Stone, Wendy L.; Walden, Tedra; Malesa, Elizabeth

2009-01-01

Later-born siblings of children with autism spectrum disorder (Sibs-ASD) are at elevated risk for social impairments. Two putative predictors of later social impairment--measures of responding to joint attention and weighted triadic communication--were examined in a sample of 43 Sibs-ASD who were followed from 15 to 34 months of age. Results…

Investigation of a Putative Estrogen-Imprinting Gene, Phosphodiesterase Type IV Variant (PDE4D4), in Determining Prostate Cancer Risk

DTIC Science & Technology

2007-04-01

ductal prostate adenocarcinomas in NBL / Cr and Sprague-Dawley Hsd:SD rats treated with a combination of testosterone and estradiol-17h or...Androl 1981;2(6):293–9. 80] Bosland MC, Ford H, Horton L. Induction at high incidence of ductal prostate adenocarcinomas in NBL /Cr and Sprague–Dawley

Mental Health and Substance Use Disorders among Latino and Asian American Lesbian, Gay, and Bisexual Adults

ERIC Educational Resources Information Center

Cochran, Susan D.; Mays, Vickie M.; Alegria, Margarita; Ortega, Alexander N.; Takeuchi, David

2007-01-01

Growing evidence suggests that lesbian, gay, and bisexual adults may be at elevated risk for mental health and substance use disorders, possibly due to anti-gay stigma. Little of this work has examined putative excess morbidity among ethnic/racial minorities resulting from the experience of multiple sources of discrimination. The authors report…

Are MAO-A deficiency states in the general population and in putative high-risk populations highly uncommon?

PubMed

Murphy, D L; Sims, K; Eisenhofer, G; Greenberg, B D; George, T; Berlin, F; Zametkin, A; Ernst, M; Breakefield, X O

1998-01-01

Lack of monoamine oxidase A (MAO-A) due to either Xp chromosomal deletions or alterations in the coding sequence of the gene for this enzyme are associated with marked changes in monoamine metabolism and appear to be associated with variable cognitive deficits and behavioral changes in humans and in transgenic mice. In mice, some of the most marked behavioral changes are ameliorated by pharmacologically-induced reductions in serotonin synthesis during early development, raising the question of possible therapeutic interventions in humans with MAO deficiency states. At the present time, only one multi-generational family and a few other individuals with marked MAO-A deficiency states have been identified and studied in detail. Although MAO deficiency states associated with Xp chromosomal deletions were identified by distinct symptoms (including blindness in infancy) produced by the contiguous Norrie disease gene, the primarily behavioral phenotype of individuals with the MAO mutation is less obvious. This paper reports a sequential research design and preliminary results from screening several hundred volunteers in the general population and from putative high-risk groups for possible MAO deficiency states. These preliminary results suggest that marked MAO deficiency states are very rare.

Novel Burkholderia mallei Virulence Factors Linked to Specific Host-Pathogen Protein Interactions

DTIC Science & Technology

2013-06-23

Wallqvist‡ Burkholderia mallei is an infectious intracellular pathogen whose virulence and resistance to antibiotics makes it a potential bioterrorism agent ...experimental Burkholderia data to ini- tially select a small number of proteins as putative viru- lence factors. We then used yeast two-hybrid assays...causative agent of glan- ders, a disease primarily affecting horses but transmittable to humans; and Burkholderia pseudomallei, which is responsible for

Repression of YdaS Toxin Is Mediated by Transcriptional Repressor RacR in the Cryptic rac Prophage of Escherichia coli K-12.

PubMed

Krishnamurthi, Revathy; Ghosh, Swagatha; Khedkar, Supriya; Seshasayee, Aswin Sai Narain

2017-01-01

Horizontal gene transfer is a major driving force behind the genomic diversity seen in prokaryotes. The cryptic rac prophage in Escherichia coli K-12 carries the gene for a putative transcription factor RacR, whose deletion is lethal. We have shown that the essentiality of racR in E. coli K-12 is attributed to its role in transcriptionally repressing toxin gene(s) called ydaS and ydaT , which are adjacent to and coded divergently to racR . IMPORTANCE Transcription factors in the bacterium E. coli are rarely essential, and when they are essential, they are largely toxin-antitoxin systems. While studying transcription factors encoded in horizontally acquired regions in E. coli , we realized that the protein RacR, a putative transcription factor encoded by a gene on the rac prophage, is an essential protein. Here, using genetics, biochemistry, and bioinformatics, we show that its essentiality derives from its role as a transcriptional repressor of the ydaS and ydaT genes, whose products are toxic to the cell. Unlike type II toxin-antitoxin systems in which transcriptional regulation involves complexes of the toxin and antitoxin, repression by RacR is sufficient to keep ydaS transcriptionally silent.

Expression of a maize Myb transcription factor driven by a putative silk-specific promoter significantly enhances resistance to Helicoverpa zea in transgenic maize.

PubMed

Johnson, Eric T; Berhow, Mark A; Dowd, Patrick F

2007-04-18

Hi II maize (Zea mays) plants were engineered to express maize p1 cDNA, a Myb transcription factor, controlled by a putative silk specific promoter, for secondary metabolite production and corn earworm resistance. Transgene expression did not enhance silk color, but about half of the transformed plant silks displayed browning when cut, which indicated the presence of p1-produced secondary metabolites. Levels of maysin, a secondary metabolite with insect toxicity, were highest in newly emerged browning silks. The insect resistance of transgenic silks was also highest at emergence, regardless of maysin levels, which suggests that other unidentified p1-induced molecules likely contributed to larval mortality. Mean survivor weights of corn earworm larvae fed mature browning transgenic silks were significantly lower than weights of those fed mature nonbrowning transgenic silks. Some transgenic pericarps browned with drying and contained similar molecules found in pericarps expressing a dominant p1 allele, suggesting that the promoter may not be silk-specific.

A MADS box protein interacts with a mating-type protein and is required for fruiting body development in the homothallic ascomycete Sordaria macrospora.

PubMed

Nolting, Nicole; Pöggeler, Stefanie

2006-07-01

MADS box transcription factors control diverse developmental processes in plants, metazoans, and fungi. To analyze the involvement of MADS box proteins in fruiting body development of filamentous ascomycetes, we isolated the mcm1 gene from the homothallic ascomycete Sordaria macrospora, which encodes a putative homologue of the Saccharomyces cerevisiae MADS box protein Mcm1p. Deletion of the S. macrospora mcm1 gene resulted in reduced biomass, increased hyphal branching, and reduced hyphal compartment length during vegetative growth. Furthermore, the S. macrospora Deltamcm1 strain was unable to produce fruiting bodies or ascospores during sexual development. A yeast two-hybrid analysis in conjugation with in vitro analyses demonstrated that the S. macrospora MCM1 protein can interact with the putative transcription factor SMTA-1, encoded by the S. macrospora mating-type locus. These results suggest that the S. macrospora MCM1 protein is involved in the transcriptional regulation of mating-type-specific genes as well as in fruiting body development.

Blood pressure and cardiovascular risk: what about cocoa and chocolate?

PubMed

Grassi, Davide; Desideri, Giovambattista; Ferri, Claudio

2010-09-01

Cocoa flavonoids are able to reduce cardiovascular risk by improving endothelial function and decreasing blood pressure (BP). Interest in the biological activities of cocoa is daily increasing. A recent meta-analysis shows flavanol-rich cocoa administration decreases mean systolic (-4.5mm Hg; p<0.001) and diastolic (-2.5mm Hg; p<0.001) BP. A 3-mm Hg systolic BP reduction has been estimated to decrease the risk of cardiovascular and all-cause mortality. This paper summarizes new findings concerning cocoa effects on cardiovascular health focusing on putative mechanisms of action and nutritional and "pharmacological" viewpoints. Cocoa consumption could play a pivotal role in human health. 2010 Elsevier Inc. All rights reserved.

Genome sequence and analysis of a broad-host range lytic bacteriophage that infects the Bacillus cereus group

PubMed Central

2013-01-01

Background Comparatively little information is available on members of the Myoviridae infecting low G+C content, Gram-positive host bacteria of the family Firmicutes. While numerous Bacillus phages have been isolated up till now only very few Bacillus cereus phages have been characterized in detail. Results Here we present data on the large, virulent, broad-host-range B. cereus phage vB_BceM_Bc431v3 (Bc431v3). Bc431v3 features a 158,618 bp dsDNA genome, encompassing 239 putative open reading frames (ORFs) and, 20 tRNA genes encoding 17 different amino acids. Since pulsed-field gel electrophoresis indicated that the genome of this phage has a mass of 155-158 kb Bc431v3 DNA appears not to contain long terminal repeats that are found in the genome of Bacillus phage SPO1. Conclusions Bc431v3 displays significant sequence similarity, at the protein level, to B. cereus phage BCP78, Listeria phage A511 and Enterococcus phage ØEF24C and other morphologically related phages infecting Firmicutes such as Staphylococcus phage K and Lactobacillus phage LP65. Based on these data we suggest that Bc431v3 should be included as a member of the Spounavirinae; however, because of all the diverse taxonomical information has been addressed recently, it is difficult to determine the genus. The Bc431v3 phage contains some highly unusual genes such as gp143 encoding putative tRNAHis guanylyltransferase. In addition, it carries some genes that appear to be related to the host sporulation regulators. These are: gp098, which encodes a putative segregation protein related to FstK/SpoIIIE DNA transporters; gp105, a putative segregation protein; gp108, RNA polymerase sigma factor F/B; and, gp109 encoding RNA polymerase sigma factor G. PMID:23388049

Comparative analysis of programmed cell death pathways in filamentous fungi.

PubMed

Fedorova, Natalie D; Badger, Jonathan H; Robson, Geoff D; Wortman, Jennifer R; Nierman, William C

2005-12-08

Fungi can undergo autophagic- or apoptotic-type programmed cell death (PCD) on exposure to antifungal agents, developmental signals, and stress factors. Filamentous fungi can also exhibit a form of cell death called heterokaryon incompatibility (HI) triggered by fusion between two genetically incompatible individuals. With the availability of recently sequenced genomes of Aspergillus fumigatus and several related species, we were able to define putative components of fungi-specific death pathways and the ancestral core apoptotic machinery shared by all fungi and metazoa. Phylogenetic profiling of HI-associated proteins from four Aspergilli and seven other fungal species revealed lineage-specific protein families, orphan genes, and core genes conserved across all fungi and metazoa. The Aspergilli-specific domain architectures include NACHT family NTPases, which may function as key integrators of stress and nutrient availability signals. They are often found fused to putative effector domains such as Pfs, SesB/LipA, and a newly identified domain, HET-s/LopB. Many putative HI inducers and mediators are specific to filamentous fungi and not found in unicellular yeasts. In addition to their role in HI, several of them appear to be involved in regulation of cell cycle, development and sexual differentiation. Finally, the Aspergilli possess many putative downstream components of the mammalian apoptotic machinery including several proteins not found in the model yeast, Saccharomyces cerevisiae. Our analysis identified more than 100 putative PCD associated genes in the Aspergilli, which may help expand the range of currently available treatments for aspergillosis and other invasive fungal diseases. The list includes species-specific protein families as well as conserved core components of the ancestral PCD machinery shared by fungi and metazoa.

Functional polymorphisms in NFκB1/IκBα predict risks of chronic obstructive pulmonary disease and lung cancer in Chinese.

PubMed

Huang, Dongsheng; Yang, Lei; Liu, Yehua; Zhou, Yumin; Guo, Yuan; Pan, Mingan; Wang, Yunnan; Tan, Yigang; Zhong, Haibo; Hu, Min; Lu, Wenju; Ji, Weidong; Wang, Jian; Ran, Pixin; Zhong, Nanshan; Zhou, Yifeng; Lu, Jiachun

2013-04-01

Lung inflammation is the major pathogenetic feature for both chronic obstructive pulmonary disease (COPD) and lung cancer. The nuclear factor-kappa B (NFκB) and its inhibitor (IκB) play crucial roles in inflammatory. Here, we tested the hypothesis that single nucleotide polymorphisms (SNPs) in NFκB/IκB confer consistent risks for COPD and lung cancer. Four putative functional SNPs (NFκB1: -94del>insATTG; NFκB2: -2966G>A; IκBα: -826C>T, 2758G>A) were analyzed in southern and validated in eastern Chineses to test their associations with COPD risk in 1,511 COPD patients and 1,677 normal lung function controls, as well as lung cancer risk in 1,559 lung cancer cases and 1,679 cancer-free controls. We found that the -94ins ATTG variants (ins/del + ins/ins) in NFκB1 conferred an increased risk of COPD (OR 1.27, 95% CI 1.06-1.52) and promoted COPD progression by accelerating annual FEV1 decline (P = 0.015). The 2758AA variant in IκBα had an increased risk of lung cancer (OR 1.53, 95% CI 1.30-1.80) by decreasing IκBα expression due to the modulation of microRNA hsa-miR-449a but not hsa-miR-34b. Furthermore, both adverse genotypes exerted effect on increasing lung cancer risk in individuals with pre-existing COPD, while the -94del>insATTG did not in those without pre-existing COPD. However, no significant association with COPD or lung cancer was observed for -2966G>A and -826C>T. Our data suggested a common susceptible mechanism of inflammation in lung induced by genetic variants in NFκB1 (-94del>ins ATTG) or IκBα (2758G>A) to predict risk of COPD or lung cancer.

Identification of EhTIF-IA: The putative E. histolytica orthologue of the human ribosomal RNA transcription initiation factor-IA.

PubMed

Srivastava, Ankita; Bhattacharya, Alok; Bhattacharya, Sudha; Jhingan, Gagan Deep

2016-03-01

Initiation of rDNA transcription requires the assembly of a specific multi-protein complex at the rDNA promoter containing the RNA Pol I with auxiliary factors. One of these factors is known as Rrn3P in yeast and Transcription Initiation Factor IA (TIF-IA) in mammals. Rrn3p/TIF-IA serves as a bridge between RNA Pol I and the pre-initiation complex at the promoter. It is phosphorylated at multiple sites and is involved in regulation of rDNA transcription in a growth-dependent manner. In the early branching parasitic protist Entamoeba histolytica, the rRNA genes are present exclusively on circular extra chromosomal plasmids. The protein factors involved in regulation of rDNA transcription in E. histolytica are not known. We have identified the E. histolytica equivalent of TIF-1A (EhTIF-IA) by homology search within the database and was further cloned and expressed. Immuno-localization studies showed that EhTIF-IA co-localized partially with fibrillarin in the peripherally localized nucleolus. EhTIF-IA was shown to interact with the RNA Pol I-specific subunit RPA12 both in vivo and in vitro. Mass spectroscopy data identified RNA Pol I-specific subunits and other nucleolar proteins to be the interacting partners of EhTIF-IA. Our study demonstrates for the first time a conserved putative RNA Pol I transcription factor TIF-IA in E. histolytica.

The protein network surrounding the human telomere repeat binding factors TRF1, TRF2, and POT1

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

Giannone, Richard J; McDonald, W Hayes; Hurst, Gregory

Telomere integrity (including telomere length and capping) is critical in overall genomic stability. Telomere repeat binding factors and their associated proteins play vital roles in telomere length regulation and end protection. In this study, we explore the protein network surrounding telomere repeat binding factors, TRF1, TRF2, and POT1 using dual-tag affinity purification in combination with multidimensional protein identification technology liquid chromatography - tandem mass spectrometry (MudPIT LC-MS/MS). After control subtraction and data filtering, we found that TRF2 and POT1 co-purified all six members of the telomere protein complex, while TRF1 identified five of six components at frequencies that lend evidencemore » towards the currently accepted telomere architecture. Many of the known TRF1 or TRF2 interacting proteins were also identified. Moreover, putative associating partners identified for each of the three core components fell into functional categories such as DNA damage repair, ubiquitination, chromosome cohesion, chromatin modification/remodeling, DNA replication, cell cycle and transcription regulation, nucleotide metabolism, RNA processing, and nuclear transport. These putative protein-protein associations may participate in different biological processes at telomeres or, intriguingly, outside telomeres.« less

Radiation, Inflammation, and Immune Responses in Cancer

PubMed Central

Multhoff, Gabriele; Radons, Jürgen

2012-01-01

Chronic inflammation has emerged as one of the hallmarks of cancer. Inflammation also plays a pivotal role in modulating radiation responsiveness of tumors. As discussed in this review, ionizing radiation (IR) leads to activation of several transcription factors modulating the expression of numerous mediators in tumor cells and cells of the microenvironment promoting cancer development. Novel therapeutic approaches thus aim to interfere with the activity or expression of these factors, either in single-agent or combinatorial treatment or as supplements of the existing therapeutic concepts. Among them, NF-κB, STAT-3, and HIF-1 play a crucial role in radiation-induced inflammatory responses embedded in a complex inflammatory network. A great variety of classical or novel drugs including nutraceuticals such as plant phytochemicals have the capacity to interfere with the inflammatory network in cancer and are considered as putative radiosensitizers. Thus, targeting the inflammatory signaling pathways induced by IR offers the opportunity to improve the clinical outcome of radiation therapy by enhancing radiosensitivity and decreasing putative metabolic effects. Since inflammation and sex steroids also impact tumorigenesis, a therapeutic approach targeting glucocorticoid receptors and radiation-induced production of tumorigenic factors might be effective in sensitizing certain tumors to IR. PMID:22675673

An epidemiological examination of the subluxation construct using Hill's criteria of causation.

PubMed

Mirtz, Timothy A; Morgan, Lon; Wyatt, Lawrence H; Greene, Leon

2009-12-02

Chiropractors claim to locate, analyze and diagnose a putative spinal lesion known as subluxation and apply the mode of spinal manipulation (adjustment) for the correction of this lesion. The purpose of this examination is to review the current evidence on the epidemiology of the subluxation construct and to evaluate the subluxation by applying epidemiologic criteria for it's significance as a causal factor. The databases of PubMed, Cinahl, and Mantis were searched for studies using the keywords subluxation, epidemiology, manipulation, dose-response, temporality, odds ratio, relative risk, biological plausibility, coherence, and analogy. The criteria for causation in epidemiology are strength (strength of association), consistency, specificity, temporality (temporal sequence), dose response, experimental evidence, biological plausibility, coherence, and analogy. Applied to the subluxation all of these criteria remain for the most part unfulfilled. There is a significant lack of evidence to fulfill the basic criteria of causation. This lack of crucial supportive epidemiologic evidence prohibits the accurate promulgation of the chiropractic subluxation.

An epidemiological examination of the subluxation construct using Hill's criteria of causation

PubMed Central

2009-01-01

Background Chiropractors claim to locate, analyze and diagnose a putative spinal lesion known as subluxation and apply the mode of spinal manipulation (adjustment) for the correction of this lesion. Aim The purpose of this examination is to review the current evidence on the epidemiology of the subluxation construct and to evaluate the subluxation by applying epidemiologic criteria for it's significance as a causal factor. Methods The databases of PubMed, Cinahl, and Mantis were searched for studies using the keywords subluxation, epidemiology, manipulation, dose-response, temporality, odds ratio, relative risk, biological plausibility, coherence, and analogy. Results The criteria for causation in epidemiology are strength (strength of association), consistency, specificity, temporality (temporal sequence), dose response, experimental evidence, biological plausibility, coherence, and analogy. Applied to the subluxation all of these criteria remain for the most part unfulfilled. Conclusion There is a significant lack of evidence to fulfill the basic criteria of causation. This lack of crucial supportive epidemiologic evidence prohibits the accurate promulgation of the chiropractic subluxation. PMID:19954544

Primary Biliary Cirrhosis Beyond Ursodeoxycholic Acid.

PubMed

Corpechot, Christophe

2016-02-01

Although ursodeoxycholic acid remains the only approved pharmacotherapy for patients with primary biliary cirrhosis, the better characterization of factors responsible for the poor response to this drug and the emergence of several new putative therapeutic targets now offer significant opportunities to improve the management of patients and our capacity to treat them more efficiently. The availability of novel treatment options, such as fibrates, budesonide, and obeticholic acid, all capable of improving prognostic markers, invites us to reconsider our management and treatment strategies. Early identification of high-risk patients should remain a priority to deliver adjunctive therapies to appropriately selected populations and increase their chances of success. Given the absence of comparative trials, the choice between second-line treatments should be dictated by the biochemical, histological, and expected tolerance profiles. Here the author presents a brief overview of what should be known in this field and proposes a practical approach to facilitate decision making. Thieme Medical Publishers 333 Seventh Avenue, New York, NY 10001, USA.

Is adenosine associated with sudden death in schizophrenia? A new framework linking the adenosine pathway to risk of sudden death.

PubMed

Gadelha, Ary; Zugman, André; Calzavara, Mariana Bendlin; de Mendonça Furtado, Remo Holanda; Scorza, Fulvio Alexandre; Bressan, Rodrigo Afonsecca

2018-01-01

Schizophrenia is associated with an increased mortality from cardiovascular disease. Relatively few studies have assessed the putative association of schizophrenia pathophysiology with sudden death. Low adenosine levels have been associated with schizophrenia. In cardiology, increased mortality among patients with congestive heart failure has been associated with genetic polymorphisms that potentially lead to lower adenosine levels. Thus, we hypothesize that adenosine could link schizophrenia and cardiovascular mortality, with decreased adenosine levels leading to increased vulnerability to hyperexcitability following hypoxic insults, increasing the odds of fatal arrhythmias. Low adenosine levels might also lead to a small increase in overall mortality rates and a major increase in the sudden death rate. This hypothesis paves the way for further investigation of the increased cardiac mortality associated with schizophrenia. Potentially, a better characterization of adenosine-related mechanisms of sudden death in schizophrenia could lead to new evidence of factors leading to sudden death in the general population. Copyright © 2017. Published by Elsevier Ltd.

Maternal Depression and Trait Anger as Risk Factors for Escalated Physical Discipline

PubMed Central

Shay, Nicole L.; Knutson, John F.

2008-01-01

To test the hypothesized anger-mediated relation between maternal depression and escalation of physical discipline, 122 economically disadvantaged mothers were assessed for current and lifetime diagnoses of depression using the Current Depressive Episode, Past Depression, and Dysthymia sections of the Structured Clinical Interview for DSM-IV (SCID) and a measure of current depressive symptoms, the Beck Depression Inventory–Second Edition (BDI-II). Escalation of physical discipline was assessed using a video analog parenting task; maternal anger not specific to discipline was assessed using the Spielberger Trait Anger Expression Inventory. Reports of anger were associated with the diagnosis of depression and depressive symptoms. Bootstrap analyses of indirect effects indicated that the link between depression and escalated discipline was mediated by anger. Parallel analyses based on BDI-II scores identified a marginally significant indirect effect of depression on discipline. Findings suggest that anger and irritability are central to the putative link between depression and harsh discipline. PMID:18174347

The role of central and peripheral hormones in sexual and violent recidivism in sex offenders.

PubMed

Kingston, Drew A; Seto, Michael C; Ahmed, Adekunle G; Fedoroff, Paul; Firestone, Philip; Bradford, John M

2012-01-01

Hormonal factors are important in multifactorial theories of sexual offending. The relationship between hormones and aggression in nonhumans is well established, but the putative effect in humans is more complex, and the direction of the effect is usually unclear. In this study, a large sample (N = 771) of adult male sex offenders was assessed between 1982 and 1996. Gonadotrophic (follicle-stimulating hormone and luteinizing hormone) and androgen hormone (total and free testosterone; T) levels were assessed at Time 1, along with indicators of sex drive and hostility. Individuals were observed up to 20 years in the community, with an average time at risk of 10.9 years (SD 4.6). Gonadotrophic hormones correlated positively with self-reported hostility and were better predictors of recidivism than was T (area under the curve (AUC), 0.58-0.63). Self-reported hostility emerged as a partial mediator of this relationship between gonadotrophic hormones and recidivism. These results point to a potentially new area of investigation for hormones and sexual aggression.

Effectiveness of multiple sclerosis treatment with current immunomodulatory drugs.

PubMed

Milo, Ron

2015-04-01

Multiple sclerosis (MS) is a chronic inflammatory disease of the CNS of a putative autoimmune origin characterized by neurologic dysfunction disseminated in space and time due to demyelination and axonal loss that results in progressive disability. Recent advances in understanding the immune pathogenesis of the disease resulted in the introduction of numerous effective immunomodulatoty drugs having diverse mechanisms of action, modes of administration and risk-benefit profiles. This results in more complex albeit more promising treatment selection and choices. The epidemiology, clinical features, pathogenesis and diagnosis of the disease are discussed. The mode of action and main characteristics of current immunomodulatory drugs for MS and their place in the therapeutic algorithm of the disease based on evidence from clinical trials are described. Speculation on new paradigms, treatment goals and outcome measures aimed at improving the landscape of MS treatment is presented. Multiple disease, drug and patient-related factors should be taken into consideration when selecting the appropriate drug and treatment strategy to the appropriate patient, thus paving the road for personalized medicine in MS.

Identification and Characterization of microRNA319a and Its Putative Target Gene, PvPCF5, in the Bioenergy Grass Switchgrass (Panicum virgatum).

PubMed

Xie, Qi; Liu, Xue; Zhang, Yinbing; Tang, Jinfu; Yin, Dedong; Fan, Bo; Zhu, Lihuang; Han, Liebao; Song, Guilong; Li, Dayong

2017-01-01

Due to its high biomass yield, low environmental impact, and widespread adaptability to poor soils and harsh conditions, switchgrass ( Panicum virgatum L.), a warm-region perennial herbaceous plant, has attracted much attention in recent years. However, little is known about microRNAs (miRNAs) and their functions in this bioenergy grass. Here, we identified and characterized a miRNA gene, Pvi-MIR319a , encoding microRNA319a in switchgrass. Transgenic rice lines generated by overexpressing the Pvi-MIR319a precursor gene exhibited broader leaves and delayed flowering compared with the control. Gene expression analysis indicated at least four putative target genes were downregulated. Additionally, we cloned a putative target gene ( PvPCF5 ) of Pvi-MIR319a from switchgrass. PvPCF5, a TCP transcription factor, is a nuclear-localized protein with transactivation activity and control the development of leaf. Our results suggest that Pvi-MIR319a and its target genes may be used as potential genetic regulators for future switchgrass genetic improvement.

Landscape genomics reveal signatures of local adaptation in barley (Hordeum vulgare L.)

PubMed Central

Abebe, Tiegist D.; Naz, Ali A.; Léon, Jens

2015-01-01

Land plants are sessile organisms that cannot escape the adverse climatic conditions of a given environment. Hence, adaptation is one of the solutions to surviving in a challenging environment. This study was aimed at detecting adaptive loci in barley landraces that are affected by selection. To that end, a diverse population of barley landraces was analyzed using the genotyping by sequencing approach. Climatic data for altitude, rainfall and temperature were collected from 61 weather sites near the origin of selected landraces across Ethiopia. Population structure analysis revealed three groups whereas spatial analysis accounted significant similarities at shorter geographic distances (< 40 Km) among barley landraces. Partitioning the variance between climate variables and geographic distances indicated that climate variables accounted for most of the explainable genetic variation. Markers by climatic variables association analysis resulted in altogether 18 and 62 putative adaptive loci using Bayenv and latent factor mixed model (LFMM), respectively. Subsequent analysis of the associated SNPs revealed putative candidate genes for plant adaptation. This study highlights the presence of putative adaptive loci among barley landraces representing original gene pool of the farming communities. PMID:26483825

The putative RNA helicase Dbp6p functionally interacts with Rpl3p, Nop8p and the novel trans-acting Factor Rsa3p during biogenesis of 60S ribosomal subunits in Saccharomyces cerevisiae.

PubMed Central

de la Cruz, Jesús; Lacombe, Thierry; Deloche, Olivier; Linder, Patrick; Kressler, Dieter

2004-01-01

Ribosome biogenesis requires at least 18 putative ATP-dependent RNA helicases in Saccharomyces cerevisiae. To explore the functional environment of one of these putative RNA helicases, Dbp6p, we have performed a synthetic lethal screen with dbp6 alleles. We have previously characterized the nonessential Rsa1p, whose null allele is synthetically lethal with dbp6 alleles. Here, we report on the characterization of the four remaining synthetic lethal mutants, which reveals that Dbp6p also functionally interacts with Rpl3p, Nop8p, and the so-far-uncharacterized Rsa3p (ribosome assembly 3). The nonessential Rsa3p is a predominantly nucleolar protein required for optimal biogenesis of 60S ribosomal subunits. Both Dbp6p and Rsa3p are associated with complexes that most likely correspond to early pre-60S ribosomal particles. Moreover, Rsa3p is co-immunoprecipitated with protA-tagged Dbp6p under low salt conditions. In addition, we have established a synthetic interaction network among factors involved in different aspects of 60S-ribosomal-subunit biogenesis. This extensive genetic analysis reveals that the rsa3 null mutant displays some specificity by being synthetically lethal with dbp6 alleles and by showing some synthetic enhancement with the nop8-101 and the rsa1 null allele. PMID:15126390

Identification of virulence determinants for endocarditis in Streptococcus sanguinis by signature-tagged mutagenesis.

PubMed

Paik, Sehmi; Senty, Lauren; Das, Sankar; Noe, Jody C; Munro, Cindy L; Kitten, Todd

2005-09-01

Streptococcus sanguinis is a gram-positive, facultative anaerobe and a normal inhabitant of the human oral cavity. It is also one of the most common agents of infective endocarditis, a serious endovascular infection. To identify virulence factors for infective endocarditis, signature-tagged mutagenesis (STM) was applied to the SK36 strain of S. sanguinis, whose genome is being sequenced. STM allows the large-scale creation, in vivo screening, and recovery of a series of mutants with altered virulence. Screening of 800 mutants by STM identified 38 putative avirulent and 5 putative hypervirulent mutants. Subsequent molecular analysis of a subset of these mutants identified genes encoding undecaprenol kinase, homoserine kinase, anaerobic ribonucleotide reductase, adenylosuccinate lyase, and a hypothetical protein. Virulence reductions ranging from 2-to 150-fold were confirmed by competitive index assays. One putatively hypervirulent strain with a transposon insertion in an intergenic region was identified, though increased virulence was not confirmed in competitive index assays. All mutants grew comparably to SK36 in aerobic broth culture except for the homoserine kinase mutant. Growth of this mutant was restored by the addition of threonine to the medium. Mutants containing an insertion or in-frame deletion in the anaerobic ribonucleotide reductase gene failed to grow under strictly anaerobic conditions. The results suggest that housekeeping functions such as cell wall synthesis, amino acid and nucleic acid synthesis, and the ability to survive under anaerobic conditions are important virulence factors in S. sanguinis endocarditis.

Identification of Virulence Determinants for Endocarditis in Streptococcus sanguinis by Signature-Tagged Mutagenesis†

PubMed Central

Paik, Sehmi; Senty, Lauren; Das, Sankar; Noe, Jody C.; Munro, Cindy L.; Kitten, Todd

2005-01-01

Streptococcus sanguinis is a gram-positive, facultative anaerobe and a normal inhabitant of the human oral cavity. It is also one of the most common agents of infective endocarditis, a serious endovascular infection. To identify virulence factors for infective endocarditis, signature-tagged mutagenesis (STM) was applied to the SK36 strain of S. sanguinis, whose genome is being sequenced. STM allows the large-scale creation, in vivo screening, and recovery of a series of mutants with altered virulence. Screening of 800 mutants by STM identified 38 putative avirulent and 5 putative hypervirulent mutants. Subsequent molecular analysis of a subset of these mutants identified genes encoding undecaprenol kinase, homoserine kinase, anaerobic ribonucleotide reductase, adenylosuccinate lyase, and a hypothetical protein. Virulence reductions ranging from 2-to 150-fold were confirmed by competitive index assays. One putatively hypervirulent strain with a transposon insertion in an intergenic region was identified, though increased virulence was not confirmed in competitive index assays. All mutants grew comparably to SK36 in aerobic broth culture except for the homoserine kinase mutant. Growth of this mutant was restored by the addition of threonine to the medium. Mutants containing an insertion or in-frame deletion in the anaerobic ribonucleotide reductase gene failed to grow under strictly anaerobic conditions. The results suggest that housekeeping functions such as cell wall synthesis, amino acid and nucleic acid synthesis, and the ability to survive under anaerobic conditions are important virulence factors in S. sanguinis endocarditis. PMID:16113327

PATHOGENICITY OF DRINKING WATER ISOLATES OF HETEROTROPHIC BACTERIA WITH PUTATIVE VIRULENCE FACTORS

EPA Science Inventory

Although the heterotrophic plate count (HPC) bacteria normally found in potable water are not a threat to the healthy population, some of them may be opportunistic pathogens that could cause adverse health effects in individuals with impaired immune systems. Earlier studies of t...

THE WIDESPREAD OCCURRENCE OF THE ENTEROHEMOLYSIN GENE EHLYA AMONG ENVIRONMENTAL STRAINS OF ESCHERICHIA COLI

EPA Science Inventory

The putative virulence factor enterohemolysin, encoded for by the ehlyA gene, has been closely associated with the pathogenic enterohemorrhagic Escherichia coli (EHEC) group. E. coli isolates from effluents from seven geographically dispersed municipal ...

Serum Uromodulin: A Biomarker of Long-Term Kidney Allograft Failure.

PubMed

Bostom, Andrew; Steubl, Dominik; Garimella, Pranav S; Franceschini, Nora; Roberts, Mary B; Pasch, Andreas; Ix, Joachim H; Tuttle, Katherine R; Ivanova, Anastasia; Shireman, Theresa; Kim, S Joseph; Gohh, Reginald; Weiner, Daniel E; Levey, Andrew S; Hsu, Chi-Yuan; Kusek, John W; Eaton, Charles B

2018-01-01

Uromodulin is a kidney-derived glycoprotein and putative tubular function index. Lower serum uromodulin was recently associated with increased risk for kidney allograft failure in a preliminary, longitudinal single-center -European study involving 91 kidney transplant recipients (KTRs). The Folic Acid for Vascular Outcome Reduction in Transplantation (FAVORIT) trial is a completed, large, multiethnic controlled clinical trial cohort, which studied chronic, stable KTRs. We conducted a case cohort analysis using a randomly selected subset of patients (random subcohort, n = 433), and all individuals who developed kidney allograft failure (cases, n = 226) during follow-up. Serum uromodulin was determined in this total of n = 613 FAVORIT trial participants at randomization. Death-censored kidney allograft failure was the study outcome. The 226 kidney allograft failures occurred during a median surveillance of 3.2 years. Unadjusted, weighted Cox proportional hazards modeling revealed that lower serum uromodulin, tertile 1 vs. tertile 3, was associated with a threefold greater risk for kidney allograft failure (hazards ratio [HR], 95% CI 3.20 [2.05-5.01]). This association was attenuated but persisted at twofold greater risk for allograft failure, after adjustment for age, sex, smoking, allograft type and vintage, prevalent diabetes mellitus and cardiovascular disease (CVD), total/high-density lipoprotein cholesterol ratio, systolic blood pressure, estimated glomerular filtration rate, and natural log urinary albumin/creatinine: HR 2.00, 95% CI (1.06-3.77). Lower serum uromodulin, a possible indicator of less well-preserved renal tubular function, remained associated with greater risk for kidney allograft failure, after adjustment for major, established clinical kidney allograft failure and CVD risk factors, in a large, multiethnic cohort of long-term, stable KTRs. © 2018 S. Karger AG, Basel.

Improving discrimination in antepartum depression screening using the Edinburgh Postnatal Depression Scale.

PubMed

Venkatesh, Kartik K; Kaimal, Anjali J; Castro, Victor M; Perlis, Roy H

2017-05-01

Universal screening of pregnant women for postpartum depression has recently been recommended; however, optimal application of depression screening tools in stratifying risk has not been defined. The current study examines new approaches to improve the ability of the Edinburgh Postnatal Depression Scale (EPDS) to stratify risk for postpartum depression, including alternate cut points, use of a continuous measure, and incorporation of other putative risk factors. An observational cohort study of 4939 women screened both antepartum and postpartum with a negative EPDS screen antepartum(i.e. EPDS<10). The primary outcome was a probable postpartum major depressive episode(EPDS cut-off ≥10). Area under the receiver operating characteristics curve(AUC), sensitivity, specificity, and predictive values were calculated. 287 women(5.8%) screened positive for postpartum depression. An antepartum EPDS cut-off<5 optimally identified women with a low risk of postpartum depression with a negative predictive value of 97.6%; however, overall discrimination was modest(AUC 0.66, 95%CI: 0.64-0.69); sensitivity was 78.7%, and specificity was 53.8%, and the positive predictive value was low at 9.5%. The negative predictive values were similar(>95%) at all antepartum EPDS cut-off values from 4 to 8. Discrimination was improved(AUC ranging from 0.70 to 0.73) when the antepartum EPDS was combined with a prior history of major depressive disorder before pregnancy. An inability to assess EPDS subscales and a relatively low prevalence of depression in this cohort. Though an antepartum EPDS cut-off score <5 yielded the greatest discrimination identifying women at low risk for postpartum depression, the negative predictive value was insufficient to substitute for postpartum screening. Copyright © 2017. Published by Elsevier B.V.

Environmental exposure to pesticides and cancer risk in multiple human organ systems.

PubMed

Parrón, Tesifón; Requena, Mar; Hernández, Antonio F; Alarcón, Raquel

2014-10-15

There is growing evidence on the association between long-term exposure to pesticides in occupational settings and an elevated rate of chronic diseases, including different types of cancer. However, data on non-occupational exposures are scarce to draw any conclusion. The objective of this study was to investigate the putative associations of environmental pesticide exposures in the general population with several cancer sites and to discuss potential carcinogenic mechanisms by which pesticides develop cancer. A population-based case-control study was conducted among people residing in 10 Health districts from Andalusia (South Spain) to estimate the risk of cancer at different sites. Health districts were categorized into areas of high and low environmental pesticide exposure based on two quantitative criteria: number of hectares devoted to intensive agriculture and pesticide sales per capita. The study population consisted of 34,205 cancer cases and 1,832,969 age and health district matched controls. Data were collected by computerized hospital records (minimum dataset) between 1998 and 2005. Prevalence rates and the risk of cancer at most organ sites were significantly higher in districts with greater pesticide use related to those with lower pesticide use. Conditional logistic regression analyses showed that the population living in areas with high pesticide use had an increased risk of cancer at all sites studied (odds ratios between 1.15 and 3.45) with the exception of Hodgkin's disease and non-Hodgkin lymphoma. The results of this study support and extend previous evidence from occupational studies indicating that environmental exposure to pesticides may be a risk factor for different types of cancer at the level of the general population. Copyright © 2013 Elsevier Ireland Ltd. All rights reserved.

Vitamin D, calcium, and breast cancer risk: a review.

PubMed

Cui, Yan; Rohan, Thomas E

2006-08-01

Vitamin D and calcium are metabolically interrelated and highly correlated dietary factors. Experimental studies have shown their anticarcinogenic effects due to their participation in regulating cell proliferation, differentiation, and apoptosis in normal and malignant breast cells. Given the emerging interest in their potential roles in the etiology of breast cancer, we review the current epidemiologic literature on dietary and/or supplemental intakes of vitamin D, endogenous circulating levels of vitamin D, and dietary and/or supplemental intakes of calcium in relation to breast cancer risk. To place these studies in context, we also provide a brief review of other supporting epidemiologic evidence. Despite inconsistent results from the epidemiologic studies, several lines of evidence suggest that vitamin D and calcium may be involved in the development of breast cancer. Specifically, (a) there is some epidemiologic evidence for inverse associations between vitamin D and calcium intakes and breast cancer; (b) serum, plasma, and/or blood levels of vitamin D metabolites have been inversely associated with breast cancer risk in some studies; (c) high sunlight exposure, presumably reflecting vitamin D synthesis in the skin, has been associated with a reduced risk of breast cancer; (d) vitamin D and calcium intakes have been inversely related to breast density, an intermediate end point for breast cancer; (e) calcium has been associated with a reduced risk of benign proliferative epithelial disorders of the breast, putative precursors of breast cancer; and (f) certain polymorphisms of the vitamin D receptor might modify breast cancer susceptibility. To further confirm the potential protective effects of calcium and vitamin D on breast cancer, well-designed cohort studies and clinical trials are warranted.

Impact of Public Safety Policies on Human Immunodeficiency Virus Transmission Dynamics in Tijuana, Mexico.

PubMed

Mehta, Sanjay R; Chaillon, Antoine; Gaines, Tommi L; Gonzalez-Zuniga, Patricia E; Stockman, Jamila K; Almanza-Reyes, Horatio; Chavez, Jose Roman; Vera, Alicia; Wagner, Karla D; Patterson, Thomas L; Scott, Brianna; Smith, Davey M; Strathdee, Steffanie A

2018-02-10

North Tijuana, Mexico is home to many individuals at high risk for transmitting and acquiring human immunodeficiency virus (HIV). Recently, policy shifts by local government impacted how these individuals were handled by authorities. Here we examined how this affected regional HIV transmission dynamics. HIV pol sequences and associated demographic information were collected from 8 research studies enrolling persons in Tijuana and were used to infer viral transmission patterns. To evaluate the impact of recent policy changes on HIV transmission dynamics, qualitative interviews were performed on a subset of recently infected individuals. Between 2004 and 2016, 288 unique HIV pol sequences were obtained from individuals in Tijuana, including 46.4% from men who have sex with men, 42.1% from individuals reporting transactional sex, and 27.8% from persons who inject drugs (some individuals had >1 risk factor). Forty-two percent of sequences linked to at least 1 other sequence, forming 37 transmission clusters. Thirty-two individuals seroconverted during the observation period, including 8 between April and July 2016. Three of these individuals were putatively linked together. Qualitative interviews suggested changes in policing led individuals to shift locations of residence and injection drug use, leading to increased risk taking (eg, sharing needles). Near real-time molecular epidemiologic analyses identified a cluster of linked transmissions temporally associated with policy shifts. Interviews suggested these shifts may have led to increased risk taking among individuals at high risk for HIV acquisition. With all public policy shifts, downstream impacts need to be carefully considered, as even well-intentioned policies can have major public health consequences. © The Author 2017. Published by Oxford University Press for the Infectious Diseases Society of America. All rights reserved. For permissions, e-mail: journals.permissions@oup.com.

Genetics of healthy aging and longevity.

PubMed

Brooks-Wilson, Angela R

2013-12-01

Longevity and healthy aging are among the most complex phenotypes studied to date. The heritability of age at death in adulthood is approximately 25 %. Studies of exceptionally long-lived individuals show that heritability is greatest at the oldest ages. Linkage studies of exceptionally long-lived families now support a longevity locus on chromosome 3; other putative longevity loci differ between studies. Candidate gene studies have identified variants at APOE and FOXO3A associated with longevity; other genes show inconsistent results. Genome-wide association scans (GWAS) of centenarians vs. younger controls reveal only APOE as achieving genome-wide significance (GWS); however, analyses of combinations of SNPs or genes represented among associations that do not reach GWS have identified pathways and signatures that converge upon genes and biological processes related to aging. The impact of these SNPs, which may exert joint effects, may be obscured by gene-environment interactions or inter-ethnic differences. GWAS and whole genome sequencing data both show that the risk alleles defined by GWAS of common complex diseases are, perhaps surprisingly, found in long-lived individuals, who may tolerate them by means of protective genetic factors. Such protective factors may 'buffer' the effects of specific risk alleles. Rare alleles are also likely to contribute to healthy aging and longevity. Epigenetics is quickly emerging as a critical aspect of aging and longevity. Centenarians delay age-related methylation changes, and they can pass this methylation preservation ability on to their offspring. Non-genetic factors, particularly lifestyle, clearly affect the development of age-related diseases and affect health and lifespan in the general population. To fully understand the desirable phenotypes of healthy aging and longevity, it will be necessary to examine whole genome data from large numbers of healthy long-lived individuals to look simultaneously at both common and rare alleles, with impeccable control for population stratification and consideration of non-genetic factors such as environment.

Integrating Survey and Molecular Approaches to Better Understand Wildlife Disease Ecology

PubMed Central

Cowled, Brendan D.; Ward, Michael P.; Laffan, Shawn W.; Galea, Francesca; Garner, M. Graeme; MacDonald, Anna J.; Marsh, Ian; Muellner, Petra; Negus, Katherine; Quasim, Sumaiya; Woolnough, Andrew P.; Sarre, Stephen D.

2012-01-01

Infectious wildlife diseases have enormous global impacts, leading to human pandemics, global biodiversity declines and socio-economic hardship. Understanding how infection persists and is transmitted in wildlife is critical for managing diseases, but our understanding is limited. Our study aim was to better understand how infectious disease persists in wildlife populations by integrating genetics, ecology and epidemiology approaches. Specifically, we aimed to determine whether environmental or host factors were stronger drivers of Salmonella persistence or transmission within a remote and isolated wild pig (Sus scrofa) population. We determined the Salmonella infection status of wild pigs. Salmonella isolates were genotyped and a range of data was collected on putative risk factors for Salmonella transmission. We a priori identified several plausible biological hypotheses for Salmonella prevalence (cross sectional study design) versus transmission (molecular case series study design) and fit the data to these models. There were 543 wild pig Salmonella observations, sampled at 93 unique locations. Salmonella prevalence was 41% (95% confidence interval [CI]: 37–45%). The median Salmonella DICE coefficient (or Salmonella genetic similarity) was 52% (interquartile range [IQR]: 42–62%). Using the traditional cross sectional prevalence study design, the only supported model was based on the hypothesis that abundance of available ecological resources determines Salmonella prevalence in wild pigs. In the molecular study design, spatial proximity and herd membership as well as some individual risk factors (sex, condition score and relative density) determined transmission between pigs. Traditional cross sectional surveys and molecular epidemiological approaches are complementary and together can enhance understanding of disease ecology: abundance of ecological resources critical for wildlife influences Salmonella prevalence, whereas Salmonella transmission is driven by local spatial, social, density and individual factors, rather than resources. This enhanced understanding has implications for the control of diseases in wildlife populations. Attempts to manage wildlife disease using simplistic density approaches do not acknowledge the complexity of disease ecology. PMID:23071552

Prospective Cohort Study of Enterotoxigenic Escherichia coli Infections in Argentinean Children

PubMed Central

Viboud, Gloria I.; Jouve, Mabel J.; Binsztein, Norma; Vergara, Marta; Rivas, Marta; Quiroga, Marina; Svennerholm, Ann-Mari

1999-01-01

In a follow-up study, enterotoxigenic Escherichia coli (ETEC) infections in 145 children from two communities located in northeastern Argentina were monitored for 2 years. The occurrence of diarrhea was monitored by weekly household visits. Of 730 fecal specimens collected, 137 (19%) corresponded to diarrheal episodes. ETEC was isolated from a significantly higher proportion of symptomatic (18.3%) than asymptomatic (13.3%) children (P = 0.04541). Individuals of up to 24 months of age were found to have a higher risk of developing ETEC diarrhea than older children (odds ratio [OR], 3.872; P = 0.00021). When the toxin profiles were considered, only heat stable enterotoxin (ST)-producing ETEC was directly associated with diarrhea (P = 0.00035). Fifty-five percent of the ETEC isolated from symptomatic children and 19% of the ETEC isolated from asymptomatic children expressed one of the colonization factors (CFs) investigated, i.e., CF antigen I (CFA/I), CFA/II, CFA/III, and CFA/IV; coli surface antigens CS7 and CS17; and putative CFs PCFO159, PCFO166, and PCFO20, indicating a clear association between diarrhea and ETEC strains that carry these factors (P = 0.0000034). The most frequently identified CFs were CFA/IV (16%), CFA/I (10%), and CS17 (9%). CFs were mostly associated with ETEC strains that produce ST and both heat-labile enterotoxin and ST. Logistic regression analysis, applied to remove confounding effects, revealed that the expression of CFs was associated with illness independently of the toxin type (OR, 4.81; P = 0.0003). When each CF was considered separately, CS17 was the only factor independently associated with illness (OR, 16.6; P = 0.0151). Most CFs (the exception was CFA/IV) fell within a limited array of serotypes, while the CF-negative isolates belonged to many different O:H types. These results demonstrate that some CFs are risk factors for the development of ETEC diarrhea. PMID:10449460

Quantitative genetics of circulating Hyaluronic Acid (HA) and its correlation with hand osteoarthritis and obesity-related phenotypes in a community-based sample.

PubMed

Prakash, Jai; Gabdulina, Gulzhan; Trofimov, Svetlana; Livshits, Gregory

2017-09-01

One of the potential molecular biomarkers of osteoarthritis (OA) is hyaluronic acid (HA). HA levels may be related to the severity and progression of OA. However, little is known about the contribution of major risk factors for osteoarthritis, e.g. obesity-related phenotypes and genetics to HA variation. To clarify the quantitative effect of these factors on HA. An ethnically homogeneous sample of 911 apparently healthy European-derived individuals, assessed for radiographic hand osteoarthritis (RHOA), HA, leptin, adiponectin, and several anthropometrical measures of obesity-related phenotypes was studied. Model-based quantitative genetic analysis was used to reveal genetic and shared environmental factors affecting the variation of the study's phenotypes. The HA levels significantly correlated with the age, RHOA, adiponectin, obesity-related phenotypes, and the waist-to-hip ratio. The putative genetic effects contributed significantly to the variation of HA (66.2 ± 9.3%) and they were also significant factors in the variations of all the other studied phenotypes, with the heritability estimate ranging between 0.122 ± 4.4% (WHR) and 45.7 ± 2.2% (joint space narrowing). This is the first study to report heritability estimates of HA variation and its correlation with obesity-related phenotypes, ADP and RHOA. However, the nature of genetic effects on HA and its correlation with other study phenotypes require further clarification.

Nutritional approaches in the risk reduction and management of Alzheimer's disease.

PubMed

Mi, Weiqian; van Wijk, Nick; Cansev, Mehmet; Sijben, John W C; Kamphuis, Patrick J G H

2013-09-01

Alzheimer's disease (AD) is a heterogeneous and devastating neurodegenerative disease with increasing socioeconomic burden for society. In the past 30 y, notwithstanding advances in the understanding of the pathogenesis of the disease and consequent development of therapeutic approaches to novel pathogenic targets, no cure has so far emerged. This contribution focuses on recent nutritional approaches in the risk reduction and management of AD with emphasis on factors providing a rationale for nutritional approaches in AD, including compromised nutritional status, altered nutrient uptake and metabolism, and nutrient requirements for synapse formation. Collectively these factors are believed to result in specific nutritional requirement in AD. The chapter also emphasizes investigated nutritional interventions in patients with AD, including studies with single nutrients and with the specific nutrient combination Fortasyn Connect and discusses the current shift of paradigm to intervene in earlier stages of AD, which offers opportunities for investigating nutritional strategies to reduce the risk for disease progression. Fortasyn Connect was designed to enhance synapse formation and function in AD by addressing the putative specific nutritional requirements and contains docosahexaenoic acid, eicosapentaenoic acid, uridine-5'-mono-phosphate, choline, phospholipids, antioxidants, and B vitamins. Two randomized controlled trials (RCTs) with the medical food Souvenaid, containing Fortasyn Connect, showed that this intervention improved memory performance in mild, drug-naïve patients with AD. Electroencephalography outcome in one of these clinical studies suggests that Souvenaid has an effect on brain functional connectivity, which is a derivative of changed synaptic activity. Thus, these studies suggest that nutritional requirements in AD can be successfully addressed and result in improvements in behavioral and neuro-physiological alterations that are characteristic to AD. The recent advance of methodologies and techniques for early diagnosis of AD facilitates the investigation of strategies to reduce the risk for AD progression in the earliest stages of the disease. Nutrition-based approaches deserve further investigation as an integral part of such strategies due to their low risk for side effects and their potential to affect pathological processes of very early AD. Copyright © 2013 Elsevier Inc. All rights reserved.

Age, gender and tumour size predict work capacity after surgical treatment of vestibular schwannomas.

PubMed

Al-Shudifat, Abdul Rahman; Kahlon, Babar; Höglund, Peter; Soliman, Ahmed Y; Lindskog, Kristoffer; Siesjo, Peter

2014-01-01

The aim of the present study was to identify predictive factors for outcome after surgery of vestibular schwannomas. This is a retrospective study with partially collected prospective data of patients who were surgically treated for vestibular schwannomas at a single institution from 1979 to 2000. Patients with recurrent tumours, NF2 and those incapable of answering questionnaires were excluded from the study. The short form 36 (SF36) questionnaire and a specific questionnaire regarding neurological status, work status and independent life (IL) status were sent to all eligible patients. The questionnaires were sent to 430 eligible patients (out of 537) and 395 (93%) responded. Scores for work capacity (WC) and IL were compared with SF36 scores as outcome estimates. Patients were divided into two groups (<64, ≥64-years-old) in order to assess them for either WC or IL. Putative preoperative and postoperative predictive factors were tested in univariate and multivariable regression analysis for the outcome scores of WC, IL and SF36. In the group <64 years, age, gender and tumour diameter were independent predictive factors for postoperative WC in multivariate analysis. A high-risk group was identified in women with age >50 years and tumour diameter >25 mm. In patients ≥64, gender and tumour diameter were significant predictive factors for IL in univariate analysis. Perioperative and postoperative objective factors as length of surgery, blood loss and complications did not predict outcome in the multivariable analysis for any age group. Patients' assessment of change in balance function was the only neurological factor that showed significance both in univariate and multivariable analysis in both age cohorts. While SF36 scores were lower in surgically treated patients in relation to normograms for the general population, they did not correlate significantly to WC and IL. The SF36 questionnaire did not correlate to outcome measures as WC and IL in patients undergoing surgery for vestibular schwannomas. Women and patients above 50 years with larger tumours have a high risk for reduced WC after surgical treatment. These results question the validity of quality of life scores in assessment of outcome after surgery of benign skullbase lesions.

Determinants of acquisition and carriage of Staphylococcus aureus in infancy.

PubMed

Peacock, Sharon J; Justice, Anita; Griffiths, D; de Silva, G D I; Kantzanou, M N; Crook, Derrick; Sleeman, Karen; Day, Nicholas P J

2003-12-01

Nasal carriage of Staphylococcus aureus is a major risk factor for invasive S. aureus disease. The aim of this study was to define factors associated with carriage. We conducted a prospective, longitudinal community-based study of infants and their mothers for a period of 6 months following delivery. The epidemiology of carriage was examined for 100 infant-mother pairs. Infant carriage varied significantly with age, falling from 40 to 50% during the first 8 weeks to 21% by 6 months. Determinants of infant S. aureus carriage included maternal carriage, breastfeeding, and number of siblings. Bacterial typing of S. aureus was performed by pulsed-field gel electrophoresis and multilocus sequence typing. The majority of individuals carried a single strain of S. aureus over time, and the mother was the usual source for colonizing isolates in infants. The effect of other components of the normal nasal flora on the development of S. aureus carriage was examined in 157 consecutive infants. Negative associations (putative bacterial interference) between S. aureus and other species occurred early in infancy but were not sustained. An increasing antistaphylococcal effect observed over time was not attributable to bacterial interference. S. aureus carriage in infants is likely to be determined by a combination of host, environmental, and bacterial factors, but bacterial interference does not appear to be an ultimate determinant of carrier status.

Lifestyle Modulators of Neuroplasticity: How Physical Activity, Mental Engagement, and Diet Promote Cognitive Health during Aging.

PubMed

Phillips, Cristy

2017-01-01

The number of the elderly across the globe will approximate 2.1 billion by 2050. Juxtaposed against this burgeoning segment of the population is evidence that nonpathological aging is associated with an increased risk for cognitive decline in a variety of domains, changes that can cause mild disability even before the onset of dementia. Given that pharmacological treatments that mitigate dementia are still outstanding, alternative therapeutic options are being investigated increasingly. The results from translational studies have shown that modifiable lifestyle factors-including physical activity, cognitive engagement, and diet-are a key strategy for maintaining brain health during aging. Indeed, a multiplicity of studies has demonstrated relationships between lifestyle factors, brain structure and function, and cognitive function in aging adults. For example, physical activity and diet modulate common neuroplasticity substrates (neurotrophic signaling, neurogenesis, inflammation, stress response, and antioxidant defense) in the brain whereas cognitive engagement enhances brain and cognitive reserve. The aims of this review are to evaluate the relationship between modifiable lifestyle factors, neuroplasticity, and optimal brain health during aging; to identify putative mechanisms that contribute positive brain aging; and to highlight future directions for scientists and clinicians. Undoubtedly, the translation of cutting-edge knowledge derived from the field of cognitive neuroscience will advance our understanding and enhance clinical treatment interventions as we endeavor to promote brain health during aging.

Self-disgust as a potential mechanism underlying the association between PTSD and suicide risk.

PubMed

Brake, C Alex; Rojas, Sasha M; Badour, Christal L; Dutton, Courtney E; Feldner, Matthew T

2017-04-01

Suicide risk is highly prevalent among individuals with posttraumatic stress disorder (PTSD). Self-disgust, defined as disgust directed internally and comprised of disgust with oneself (disgusting self) and with one's behaviors (disgusting ways), may impact this increased risk. The present study examined self-disgust as a putative mechanism linking PTSD symptoms with suicide risk. A sample of 347 trauma-exposed undergraduates completed measures of PTSD symptoms, suicide risk, self-disgust, and depressive symptoms. Controlling for depressive symptoms, a process model indicated PTSD symptoms were positively linked to suicide risk via increased disgusting self but not disgusting ways. Process models examining individual PTSD symptom clusters revealed positive, indirect links between all PTSD symptom clusters except alterations in arousal and reactivity and suicide risk via disgusting self. These findings expand on growing literature documenting the importance of self-disgust in trauma-related pathology by identifying connections with suicide risk. Future directions and clinical considerations are discussed. Copyright © 2017 Elsevier Ltd. All rights reserved.

Relationship between Added Sugars Consumption and Chronic Disease Risk Factors: Current Understanding.

PubMed

Rippe, James M; Angelopoulos, Theodore J

2016-11-04

Added sugars are a controversial and hotly debated topic. Consumption of added sugars has been implicated in increased risk of a variety of chronic diseases including obesity, cardiovascular disease, diabetes and non-alcoholic fatty liver disease (NAFLD) as well as cognitive decline and even some cancers. Support for these putative associations has been challenged, however, on a variety of fronts. The purpose of the current review is to summarize high impact evidence including systematic reviews, meta-analyses, and randomized controlled trials (RCTs), in an attempt to provide an overview of current evidence related to added sugars and health considerations. This paper is an extension of a symposium held at the Experimental Biology 2015 conference entitled "Sweeteners and Health: Current Understandings, Controversies, Recent Research Findings and Directions for Future Research". We conclude based on high quality evidence from randomized controlled trials (RCT), systematic reviews and meta-analyses of cohort studies that singling out added sugars as unique culprits for metabolically based diseases such as obesity, diabetes and cardiovascular disease appears inconsistent with modern, high quality evidence and is very unlikely to yield health benefits. While it is prudent to consume added sugars in moderation, the reduction of these components of the diet without other reductions of caloric sources seems unlikely to achieve any meaningful benefit.

Relationship between Added Sugars Consumption and Chronic Disease Risk Factors: Current Understanding

PubMed Central

Rippe, James M.; Angelopoulos, Theodore J.

2016-01-01

Added sugars are a controversial and hotly debated topic. Consumption of added sugars has been implicated in increased risk of a variety of chronic diseases including obesity, cardiovascular disease, diabetes and non-alcoholic fatty liver disease (NAFLD) as well as cognitive decline and even some cancers. Support for these putative associations has been challenged, however, on a variety of fronts. The purpose of the current review is to summarize high impact evidence including systematic reviews, meta-analyses, and randomized controlled trials (RCTs), in an attempt to provide an overview of current evidence related to added sugars and health considerations. This paper is an extension of a symposium held at the Experimental Biology 2015 conference entitled “Sweeteners and Health: Current Understandings, Controversies, Recent Research Findings and Directions for Future Research”. We conclude based on high quality evidence from randomized controlled trials (RCT), systematic reviews and meta-analyses of cohort studies that singling out added sugars as unique culprits for metabolically based diseases such as obesity, diabetes and cardiovascular disease appears inconsistent with modern, high quality evidence and is very unlikely to yield health benefits. While it is prudent to consume added sugars in moderation, the reduction of these components of the diet without other reductions of caloric sources seems unlikely to achieve any meaningful benefit. PMID:27827899

Exome Sequencing in an Admixed Isolated Population Indicates NFXL1 Variants Confer a Risk for Specific Language Impairment

PubMed Central

Villanueva, Pía; Nudel, Ron; Hoischen, Alexander; Fernández, María Angélica; Simpson, Nuala H.; Gilissen, Christian; Reader, Rose H.; Jara, Lillian; Echeverry, Maria Magdalena; Francks, Clyde; Baird, Gillian; Conti-Ramsden, Gina; O’Hare, Anne; Bolton, Patrick F.; Hennessy, Elizabeth R.; Palomino, Hernán; Carvajal-Carmona, Luis; Veltman, Joris A.; Cazier, Jean-Baptiste; De Barbieri, Zulema

2015-01-01

Children affected by Specific Language Impairment (SLI) fail to acquire age appropriate language skills despite adequate intelligence and opportunity. SLI is highly heritable, but the understanding of underlying genetic mechanisms has proved challenging. In this study, we use molecular genetic techniques to investigate an admixed isolated founder population from the Robinson Crusoe Island (Chile), who are affected by a high incidence of SLI, increasing the power to discover contributory genetic factors. We utilize exome sequencing in selected individuals from this population to identify eight coding variants that are of putative significance. We then apply association analyses across the wider population to highlight a single rare coding variant (rs144169475, Minor Allele Frequency of 4.1% in admixed South American populations) in the NFXL1 gene that confers a nonsynonymous change (N150K) and is significantly associated with language impairment in the Robinson Crusoe population (p = 2.04 × 10–4, 8 variants tested). Subsequent sequencing of NFXL1 in 117 UK SLI cases identified four individuals with heterozygous variants predicted to be of functional consequence. We conclude that coding variants within NFXL1 confer an increased risk of SLI within a complex genetic model. PMID:25781923

CHICKEN COOPS, Triatoma dimidiata INFESTATION AND ITS INFECTION WITH Trypanosoma cruzi IN A RURAL VILLAGE OF YUCATAN, MEXICO

PubMed Central

KOYOC-CARDEÑA, Edgar; MEDINA-BARREIRO, Anuar; ESCOBEDO-ORTEGÓN, Francisco Javier; RODRÍGUEZ-BUENFIL, Jorge Carlos; BARRERA-PÉREZ, Mario; REYES-NOVELO, Enrique; CHABLÉ-SANTOS, Juan; SELEM-SALAS, Celia; VAZQUEZ-PROKOPEC, Gonzalo; MANRIQUE-SAIDE, Pablo

2015-01-01

This study longitudinally investigated the association between Triatoma dimidiata infestation, triatomine infection with Trypanosoma cruzi and household/backyard environmental characteristics in 101 homesteads in Molas and Yucatan, Mexico, between November 2009 (rainy season) and May 2010 (dry season). Logistic regression models tested the associations between insect infestation/infection and potential household-level risk factors. A total of 200 T. dimidiata were collected from 35.6% of the homesteads, mostly (73%) from the peridomicile. Of all the insects collected, 48% were infected with T. cruzi. Infected insects were collected in 31.6% of the homesteads (54.1% and 45.9% intra- and peridomiciliary, respectively). Approximately 30% of all triatomines collected were found in chicken coops. The presence of a chicken coop in the backyard of a homestead was significantly associated with both the odds of finding T. dimidiata (OR = 4.10, CI 95% = 1.61-10.43, p = 0.003) and the presence of triatomines infected with T. cruzi (OR = 3.37, CI 95% = 1.36-8.33, p = 0.006). The results of this study emphasize the relevance of chicken coops as a putative source of T. dimidiata populations and a potential risk for T. cruzi transmission. PMID:26200970

Possible determinants and spatial patterns of anaemia among young children in Nigeria: a Bayesian semi-parametric modelling.

PubMed

Gayawan, Ezra; Arogundade, Ekundayo D; Adebayo, Samson B

2014-03-01

Anaemia is a global public health problem affecting both developing and developed countries with major consequences for human health and socioeconomic development. This paper examines the possible relationship between Hb concentration and severity of anaemia with individual and household characteristics of children aged 6-59 months in Nigeria; and explores possible geographical variations of these outcome variables. Data on Hb concentration and severity of anaemia in children aged 6-59 months that participated in the 2010 Nigeria Malaria Indicator Survey were analysed. A semi-parametric model using a hierarchical Bayesian approach was adopted to examine the putative relationship of covariates of different types and possible spatial variation. Gaussian, binary and ordinal outcome variables were considered in modelling. Spatial analyses reveal a distinct North-South divide in Hb concentration of the children analysed and that states in Northern Nigeria possess a higher risk of anaemia. Other important risk factors include the household wealth index, sex of the child, whether or not the child had fever or malaria in the 2 weeks preceding the survey, and children under 24 months of age. There is a need for state level implementation of specific programmes that target vulnerable children as this can help in reversing the existing patterns.

Case-control study of amyotrophic lateral sclerosis

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

Deapen, D.M.; Henderson, B.E.

1986-05-01

The authors conducted a study of 518 amyotrophic lateral sclerosis patients identified between 1977 and 1979 and 518 controls to investigate putative risk factors for this disease. Occupations at risk of electrical exposure were reported more often by patients (odds ratio (OR) = 3.8, 95% confidence interval (CI) = 1.4-13.0) as were electrical shocks producing unconsciousness (OR = 2.8, 95% CI = 1.0-9.9). Although an overall excess of physical trauma associated with unconsciousness was observed in the amyotrophic lateral sclerosis patients (OR = 1.6, 95% CI = 1.0-2.4), the effect was inversely associated with duration of the unconscious episodes, suggestingmore » an effect of recall bias. Only slight differences were found for surgical traumata to the nervous system. Parkinsonism was reported more often among first degree relatives of cases (OR = 2.7, 95% CI = 1.1-7.6). The frequencies of prior poliomyelitis or other central nervous system diseases were similar for patients and controls. Occupational exposure to selected toxic substances was similar for patients and controls except for the manufacture of plastics (OR = 3.7, 95% CI = 1.0-20.5), although few details of these exposures were provided. No differences in occupations with exposure to animal skins or hides were observed.« less

Modelling the Ecological Comorbidity of Acute Respiratory Infection, Diarrhoea and Stunting among Children Under the Age of 5 Years in Somalia.

PubMed

Kinyoki, Damaris K; Manda, Samuel O; Moloney, Grainne M; Odundo, Elijah O; Berkley, James A; Noor, Abdisalan M; Kandala, Ngianga-Bakwin

2017-04-01

The aim of this study was to assess spatial co-occurrence of acute respiratory infections (ARI), diarrhoea and stunting among children of the age between 6 and 59 months in Somalia. Data were obtained from routine biannual nutrition surveys conducted by the Food and Agriculture Organization 2007-2010. A Bayesian hierarchical geostatistical shared component model was fitted to the residual spatial components of the three health conditions. Risk maps of the common spatial effects at 1×1 km resolution were derived. The empirical correlations of the enumeration area proportion were 0.37, 0.63 and 0.66 for ARI and stunting, diarrhoea and stunting and ARI and diarrhoea, respectively. Spatially, the posterior residual effects ranged 0.03-20.98, 0.16-6.37 and 0.08-9.66 for shared component between ARI and stunting, diarrhoea and stunting and ARI and diarrhoea, respectively. The analysis showed clearly that the spatial shared component between ARI, diarrhoea and stunting was higher in the southern part of the country. Interventions aimed at controlling and mitigating the adverse effects of these three childhood health conditions should focus on their common putative risk factors, particularly in the South in Somalia.

Bacterial virulence phenotypes of Escherichia coli and host susceptibility determines risk for urinary tract infections

PubMed Central

Schreiber, Henry L.; Conover, Matt S.; Chou, Wen-Chi; Hibbing, Michael E.; Manson, Abigail L.; Dodson, Karen W.; Hannan, Thomas J.; Roberts, Pacita L.; Stapleton, Ann E.; Hooton, Thomas M.; Livny, Jonathan; Earl, Ashlee M.; Hultgren, Scott J.

2017-01-01

Urinary tract infections (UTIs) are caused by uropathogenic Escherichia coli (UPEC) strains. In contrast to many enteric E. coli pathogroups, no genetic signature has been identified for UPEC strains. We conducted a high-resolution comparative genomic study using E. coli isolates collected from the urine of women suffering from frequent recurrent UTIs. These isolates were genetically diverse and varied in urovirulence, or the ability to infect the bladder of a mouse model of cystitis. Importantly, we found no set of genes, including previously defined putative urovirulence factors (PUFs), that were predictive of urovirulence. In addition, in some patients, the E. coli strain causing a recurrent UTI had fewer PUFs than the supplanted strain. In competitive experimental infections in mice, the supplanting strain was more efficient at colonizing the mouse bladder than the supplanted strain. Despite the lack of a clear genomic signature for urovirulence, comparative transcriptomic and phenotypic analyses revealed that the expression of key conserved functions during culture, such as motility and sugar metabolism, could be used to predict subsequent mouse bladder colonization. Taken together, our findings suggest that UTI risk and outcome may be determined by complex interactions between host susceptibility and the urovirulence potential of diverse bacterial strains. PMID:28330863

Gene expression profiling of the plant pathogenic basidiomycetous fungus Rhizoctonia solani AG 4 reveals putative virulence factors

USDA-ARS?s Scientific Manuscript database

Rhizoctonia solani is a ubiquitous basidiomycetous soilborne fungal pathogen causing damping off of seedlings, aerial blights and postharvest diseases. To gain insight into the molecular mechanisms of pathogenesis a global approach based on analysis of expressed sequence tags (ESTs) was undertaken. ...

Factors Associated With the Prevalence of Prostate Cancer in Rural Saskatchewan: The Saskatchewan Rural Health Study.

PubMed

Sharma, Meenu; Lawson, Joshua A; Kanthan, Rani; Karunanayake, Chandima; Hagel, Louise; Rennie, Donna; Dosman, James A; Pahwa, Punam

2016-01-01

Prostate cancer is the most commonly diagnosed cancer in Canadian males, and it is the third most common cause of cancer-related deaths in men. Some studies suggest that occupational exposure may be associated with prostate cancer. However, the etiology of prostate cancer is ambiguous. The purpose of this study was to assess the rural occupational exposure, including farming, as a determinant of prostate cancer in rural men. We investigated the prevalence of prostate cancer and its putative relationship between rural exposures in the Saskatchewan province of Canada. In 2010, a baseline mailed survey was conducted of 11,982 households located in 4 geographic regions (southwest, southeast, northwest, and northeast) of rural Saskatchewan, Canada. The questionnaires collected information on individual and contextual determinants from a rural population of men. In total 2,938 males older than 45 years were included in the logistic regression analysis. The age-standardized prevalence of prostate cancer was 3.32%. Farm residence was a significant risk factor associated with prevalence of prostate cancer while farming occupation and duration were not. Men who were exposed to insecticides and fungicides together (OR [95% CI] = 2.23 [1.15-4.33], P = .02) at work showed an increased potential risk compared to the nonexposed. The effect of farm/nonfarm residence on prevalence of prostate cancer differed depending on personal smoking history and family history of cancer. Workplace exposure to insecticides and fungicides together were statistically significantly associated with prevalence of prostate cancer. © 2015 National Rural Health Association.

The ROOTS study: a 10-year review of findings on adolescent depression, and recommendations for future longitudinal research.

PubMed

Lewis, Gemma; Jones, Peter B; Goodyer, Ian M

2016-02-01

The purpose of this study is to review longitudinal findings on adolescent mental health from the 'ROOTS study', and provide directions and recommendations for future longitudinal research. To do this, we discuss relevant findings from the ROOTS study, and review its strengths and limitations. We examined all publications from the ROOTS study up to July 2015, selected those examining adolescent mental health, and classified them as investigating (a) childhood risk factors for adolescent depression, (b) genetic and cognitive vulnerability to depression in adolescence, (c) genetic markers, childhood adversities, and neuroendophenotypes, (d) morning cortisol and depression, (e) physical activity and depression symptoms, and (f) the underlying structure of mental health in adolescence. We reviewed the strengths and limitations of the ROOTS study, and how they feed into recommendations for future longitudinal research. There was evidence supporting a putative hormonal biomarker for the emergence of depression in boys. Environmental pathways from child adversity to adolescent depression were confirmed in girls, partly accounted for by negative life events in early adolescence. The preceding role of automatic cognitive biases assessed using behavioural tasks was substantiated, with evidence for genetic susceptibility. Novel latent statistical models of child adversity, depression, anxiety, and psychotic experiences were produced, with concurrent and prospective validity. Our experiences conducting the ROOTS study resulted in a set of strengths, limitations, and recommendations for future longitudinal studies. The ROOTS study has advanced knowledge on the aetiology of adolescent depression by investigating environmental, genetic, hormonal, and neural risk factors. Findings provide a foundation for future research integrating cognitive neuroscience with epidemiology.

Muscle Carnosine Is Associated with Cardiometabolic Risk Factors in Humans.

PubMed

de Courten, Barbora; Kurdiova, Timea; de Courten, Maximilian P J; Belan, Vitazoslav; Everaert, Inge; Vician, Marek; Teede, Helena; Gasperikova, Daniela; Aldini, Giancarlo; Derave, Wim; Ukropec, Jozef; Ukropcova, Barbara

2015-01-01

Carnosine is a naturally present dipeptide abundant in skeletal muscle and an over-the counter food additive. Animal data suggest a role of carnosine supplementation in the prevention and treatment of obesity, insulin resistance, type 2 diabetes and cardiovascular disease but only limited human data exists. Samples of vastus lateralis muscle were obtained by needle biopsy. We measured muscle carnosine levels (high-performance liquid chromatography), % body fat (bioimpedance), abdominal subcutaneous and visceral adiposity (magnetic resonance imaging), insulin sensitivity (euglycaemic hyperinsulinemic clamp), resting energy expenditure (REE, indirect calorimetry), free-living ambulatory physical activity (accelerometers) and lipid profile in 36 sedentary non-vegetarian middle aged men (45±7 years) with varying degrees of adiposity and glucose tolerance. Muscle carnosine content was positively related to % body fat (r = 0.35, p = 0.04) and subcutaneous (r = 0.38, p = 0.02) but not visceral fat (r = 0.17, p = 0.33). Muscle carnosine content was inversely associated with insulin sensitivity (r = -0.44, p = 0.008), REE (r = -0.58, p<0.001) and HDL-cholesterol levels (r = -0.34, p = 0.048). Insulin sensitivity and physical activity were the best predictors of muscle carnosine content after adjustment for adiposity. Our data shows that higher carnosine content in human skeletal muscle is positively associated with insulin resistance and fasting metabolic preference for glucose. Moreover, it is negatively associated with HDL-cholesterol and basal energy expenditure. Intervention studies targeting insulin resistance, metabolic and cardiovascular disease risk factors are necessary to evaluate its putative role in the prevention and management of type 2 diabetes and cardiovascular disease.

[Transduction peptides, the useful face of a new signaling mechanism].

PubMed

Joliot, Alain; Prochiantz, Alain

2005-03-01

Transduction peptides that cross the plasma membrane of live cells are commonly used for the in vitro and in vivo targeting of hydrophilic drugs into the cell interior. Although this family of peptides has recently increased and will probably continue to do so, the two mainly used peptides are derived from transcription factors. Indeed, TAT is a 12 amino acid long arginine-rich peptide present in the HIV transcription factor, and penetratin - or its variants - corresponds to 16 amino acids that define the highly conserved third helix of the DNA-binding domain (homeodomain) of homeoprotein transcription factors. In this review, we shall recall the different steps that have led to the discovery of transduction peptides and present the most likely hypotheses concerning the mechanisms involved in their internalization. At the risk of being incomplete or, even, biased, we shall concentrate on penetratins and TAT. The reason is that these peptides have been studied for over ten years leading to the edification of robust knowledge regarding their properties. This attitude will not preclude comparisons with other peptides, if necessary. Our goal is to describe the mode of action of these transduction peptides, their range of activity in term of cell types that accept them and cargoes that they can transport, and, also, some of the limitations that one can encounter in their use. Finally, based on the idea that peptide transduction is the technological face of a physiological property of some transcription factors, we shall discuss the putative physiological function of homeoprotein transduction, and, as a consequence, the possibility to use these factors as therapeutic proteins.

Ethnic density is not associated with psychological distress in Turkish-Dutch, Moroccan-Dutch and Surinamese-Dutch ethnic minorities in the Netherlands.

PubMed

Schrier, Agnes C; Peen, Jaap; de Wit, Matty A S; van Ameijden, Erik J C; Erdem, Ozcan; Verhoeff, Arnoud P; Dekker, Jack J M; Beekman, Aartjan T F

2014-10-01

Ethnic density, the proportion of people of the same ethnic group in the neighbourhood, has been identified as a protective factor with regard to mental health in ethnic minorities. Research on the putative intermediating factors, exposure to discrimination and improved social support, has not yielded conclusive evidence. We investigated the association between ethnic density and psychological well-being in three ethnic minority groups in the Netherlands. We also assessed whether a protective ethnic density effect is related to the degree to which each group experiences discrimination and social support at group level. Using multi-level linear regression modelling, we studied the influence of ethnic density at neighbourhood level on psychological distress, measured with the Kessler Psychological Distress scale (K10), in 13,864 native Dutch, 1,206 Surinamese-Dutch, 978 Turkish-Dutch and 784 Moroccan-Dutch citizens of the four major cities in the Netherlands. Based on a nationwide survey among ethnic minorities on social integration, ethnic groups were ordered with respect to the intermediating factors. Ethnic density was not associated with psychological distress in any of the three ethnic minority groups. As a consequence, we found no support for either experiences of discrimination or for own-group social interactions at group level as intermediating factors. In all three ethnic minority groups, as well as in the native Dutch group, individual demographic and socio-economic factors emerged as the main explanations for individuals' mental well-being. These results suggest that individual demographic and socio-economic risk characteristics outweigh the influence of neighbourhood attributes on mental health.

Reassessing direct-to-consumer portrayals of unproven stem cell therapies: is it getting better?

PubMed

Ogbogu, Ubaka; Rachul, Christen; Caulfield, Timothy

2013-05-01

To determine whether increased scrutiny of 'stem cell tourism' has resulted in changes to online claims by clinics that provide putative unproven stem cell treatments. We analyzed historical and current versions of clinics' websites. The study sample consisted of 18 websites included in a 2008 peer-reviewed study and an additional 12 clinics identified through the Google™ search engine. Our analysis revealed similarities between historical and current stem cell treatment offerings, claims, representations of risk, benefit and efficacy and attention to social, ethical and regulatory concerns. Claims and representations remain overly optimistic. Current websites provide more detailed descriptions of treatment procedures and outcomes and are more aesthetically appealing. Noteworthy trends in the movements and locations of clinics was observed. Increased scrutiny of stem cell tourism has not had much impact on the online claims of clinics that provide putative unproven stem cell treatments.

Critical review of ropinirole and pramipexole - putative dopamine D(3)-receptor selective agonists - for the treatment of RLS.

PubMed

Varga, L I; Ako-Agugua, N; Colasante, J; Hertweck, L; Houser, T; Smith, J; Watty, A A; Nagar, S; Raffa, R B

2009-10-01

Ropinirole hydrochloride (REQUIP, ADARTREL) and pramipexole dihydrochloride (MIRAPEX, SIFROL) are two putative dopamine D(3) receptor subtype-selective agonists recently approved by the FDA for the treatment of 'restless legs syndrome' (RLS). RLS is a difficult to define condition that is possibly more prevalent than previously thought. Direct-to-consumer advertising has raised public and professional awareness of RLS, but questions, even skepticism about the very existence of the condition, persist. The drugs have adverse effects that can negatively impact on quality of life and thus, as true for all drugs, require consideration of the benefit : risk ratio. We review the definition, diagnostic criteria, pathophysiology, and treatment of RLS, and assess the clinical and preclinical evidence for a pharmacologic rationale for D(3) agonism in general and of the claimed D(3) selectivity of ropinirole and pramipexole in particular.

Pneumococcal vaccination and risk of myocardial infarction

PubMed Central

Lamontagne, François; Garant, Marie-Pierre; Carvalho, Jean-Christophe; Lanthier, Luc; Smieja, Marek; Pilon, Danielle

2008-01-01

Background Based on promising results from laboratory studies, we hypothesized that pneumococcal vaccination would protect patients from myocardial infarction. Methods We conducted a hospital-based case–control study that included patients considered to be at risk of myocardial infarction. We used health databases to obtain hospital diagnoses and vaccination status. We compared patients who had been admitted for treatment of myocardial infarction with patients admitted to a surgical department in the same hospital for a reason other than myocardial infarction between 1997 and 2003. Results We found a total of 43 209 patients who were at risk; of these, we matched 999 cases and 3996 controls according to age, sex and year of hospital admission. Cases were less likely than controls to have been vaccinated (adjusted odds ratio [OR] 0.53, 95% confidence interval [CI] 0.40–0.70). This putative protective role of the vaccine was not observed for patients who had received the vaccine up to 1 year before myocardial infarction (adjusted OR 0.85, 95% CI 0.54–1.33). In contrast, if vaccination had occurred 2 years or more before the hospital admission, the association was stronger (adjusted OR 0.33, 95% CI 0.20–0.46). Interpretation Pneumococcal vaccination was associated with a decrease of more than 50% in the rate myocardial infarction 2 years after exposure. If confirmed, this association should generate interest in exploring the putative mechanisms and may offer another reason to promote pneumococcal vaccination. PMID:18838452

Early-life hygiene-related factors affect risk of central nervous system demyelination and asthma differentially

PubMed Central

Hughes, A-M; Lucas, R M; McMichael, A J; Dwyer, T; Pender, M P; Mei, I; Taylor, B V; Valery, P; Chapman, C; Coulthard, A; Dear, K; Kilpatrick, T J; Williams, D; Ponsonby, A-L

2013-01-01

The increasing prevalence of immune-related diseases, including multiple sclerosis, may be partly explained by reduced microbial burden during childhood. Within a multi-centre case–control study population, we examined: (i) the co-morbid immune diseases profile of adults with a first clinical diagnosis of central nervous system demyelination (FCD) and (ii) sibship structure in relation to an autoimmune (FCD) and an allergic (asthma) disease. FCD cases (n = 282) were aged 18–59 years; controls (n = 558) were matched on age, sex and region. Measures include: history of doctor-diagnosed asthma; sibling profile (number; dates of birth); and regular childcare attendance. FCD cases did not differ from controls with regard to personal or family history of allergy, but had a greater likelihood of chronic fatigue syndrome [odds ratio (OR) = 3·11; 95% confidence interval (CI) 1·11, 8·71]. Having any younger siblings showed reduced odds of FCD (OR = 0·68; 95% CI: 0·49, 0·95) but not asthma (OR = 1·47; 95% CI: 0·91, 2·38). In contrast, an increasing number of older siblings was associated with reduced risk of asthma (P trend = 0·04) but not FCD (P trend = 0·66). Allergies were not over-represented among people presenting with FCD. Sibship characteristics influence both FCD and asthma risk but the underlying mechanisms differ, possibly due to the timing of the putative ‘sibling effect’. PMID:23600835

DNA Repair Mechanism Gene, XRCC1A ( Arg194Trp) but not XRCC3 ( Thr241Met) Polymorphism Increased the Risk of Breast Cancer in Premenopausal Females: A Case-Control Study in Northeastern Region of India.

PubMed

Devi, K Rekha; Ahmed, Jishan; Narain, Kanwar; Mukherjee, Kaustab; Majumdar, Gautam; Chenkual, Saia; Zonunmawia, Jason C

2017-12-01

X-ray repair cross complementary group gene is one of the most studied candidate gene involved in different types of cancers. Studies have shown that X-ray repair cross complementary genes are significantly associated with increased risk of breast cancer in females. Moreover, studies have revealed that X-ray repair cross complementary gene polymorphism significantly varies between and within different ethnic groups globally. The present case-control study was aimed to investigate the association of X-ray repair cross complementary 1A (Arg194Trp) and X-ray repair cross complementary 3 (Thr241Met) polymorphism with the risk of breast cancer in females from northeastern region of India. The present case-control study includes histopathologically confirmed and newly diagnosed 464 cases with breast cancer and 534 apparently healthy neighborhood community controls. Information on sociodemographic factors and putative risk factors were collected from each study participant by conducting face-to-face interviews. Genotyping of X-ray repair cross complementary 1A (Arg194Trp) and X-ray repair cross complementary 3 (Thr241Met) was carried out by polymerase chain reaction-restriction fragment length polymorphism. For statistical analysis, both univariate and multivariate logistic regression analyses were performed. We also performed stratified analysis to find out the association of X-ray repair cross complementary genes with the risk of breast cancer stratified based on menstrual status. This study revealed that tryptophan allele (R/W-W/W genotype) in X-ray repair cross complementary 1A (Arg194Trp) gene significantly increased the risk of breast cancer (adjusted odds ratio = 1.44, 95% confidence interval = 1.06-1.97, P < .05 for R/W-W/W genotype). Moreover, it was found that tryptophan allele (W/W genotype) at codon 194 of X-ray repair cross complementary 1A (Arg194Trp) gene significantly increased the risk of breast cancer in premenopausal females (crude odds ratio = 1.66, 95% confidence interval = 1.11-2.46, P < .05 for R/W-W/W genotype). The present study did not reveal any significant association of X-ray repair cross complementary 3 (Thr241Met) polymorphism with the risk of breast cancer. The present study has explored that X-ray repair cross complementary 1A (Arg194Trp) gene polymorphism is significantly associated with the increased risk of breast cancer in premenopausal females from northeastern region of India which may be beneficial for prognostic purposes.

DNA Repair Mechanism Gene, XRCC1A (Arg194Trp) but not XRCC3 (Thr241Met) Polymorphism Increased the Risk of Breast Cancer in Premenopausal Females: A Case–Control Study in Northeastern Region of India

PubMed Central

Ahmed, Jishan; Narain, Kanwar; Mukherjee, Kaustab; Majumdar, Gautam; Chenkual, Saia; Zonunmawia, Jason C.

2017-01-01

X-ray repair cross complementary group gene is one of the most studied candidate gene involved in different types of cancers. Studies have shown that X-ray repair cross complementary genes are significantly associated with increased risk of breast cancer in females. Moreover, studies have revealed that X-ray repair cross complementary gene polymorphism significantly varies between and within different ethnic groups globally. The present case–control study was aimed to investigate the association of X-ray repair cross complementary 1A (Arg194Trp) and X-ray repair cross complementary 3 (Thr241Met) polymorphism with the risk of breast cancer in females from northeastern region of India. The present case–control study includes histopathologically confirmed and newly diagnosed 464 cases with breast cancer and 534 apparently healthy neighborhood community controls. Information on sociodemographic factors and putative risk factors were collected from each study participant by conducting face-to-face interviews. Genotyping of X-ray repair cross complementary 1A (Arg194Trp) and X-ray repair cross complementary 3 (Thr241Met) was carried out by polymerase chain reaction-restriction fragment length polymorphism. For statistical analysis, both univariate and multivariate logistic regression analyses were performed. We also performed stratified analysis to find out the association of X-ray repair cross complementary genes with the risk of breast cancer stratified based on menstrual status. This study revealed that tryptophan allele (R/W-W/W genotype) in X-ray repair cross complementary 1A (Arg194Trp) gene significantly increased the risk of breast cancer (adjusted odds ratio = 1.44, 95% confidence interval = 1.06-1.97, P < .05 for R/W-W/W genotype). Moreover, it was found that tryptophan allele (W/W genotype) at codon 194 of X-ray repair cross complementary 1A (Arg194Trp) gene significantly increased the risk of breast cancer in premenopausal females (crude odds ratio = 1.66, 95% confidence interval = 1.11-2.46, P < .05 for R/W-W/W genotype). The present study did not reveal any significant association of X-ray repair cross complementary 3 (Thr241Met) polymorphism with the risk of breast cancer. The present study has explored that X-ray repair cross complementary 1A (Arg194Trp) gene polymorphism is significantly associated with the increased risk of breast cancer in premenopausal females from northeastern region of India which may be beneficial for prognostic purposes. PMID:29332455

Novel Gammaherpesviruses in North American Domestic Cats, Bobcats, and Pumas: Identification, Prevalence, and Risk Factors

PubMed Central

Beatty, Julia A.; Stutzman-Rodriguez, Kathryn R.; Carver, Scott; Lozano, Caitlin C.; Lee, Justin S.; Lappin, Michael R.; Riley, Seth P. D.; Serieys, Laurel E. K.; Logan, Kenneth A.; Sweanor, Linda L.; Boyce, Walter M.; Vickers, T. Winston; McBride, Roy; Crooks, Kevin R.; Lewis, Jesse S.; Cunningham, Mark W.; Rovnak, Joel; Quackenbush, Sandra L.; VandeWoude, Sue

2014-01-01

ABSTRACT Gammaherpesviruses (GHVs) are a diverse and rapidly expanding group of viruses associated with a variety of disease conditions in humans and animals. To identify felid GHVs, we screened domestic cat (Felis catus), bobcat (Lynx rufus), and puma (Puma concolor) blood cell DNA samples from California, Colorado, and Florida using a degenerate pan-GHV PCR. Additional pan-GHV and long-distance PCRs were used to sequence a contiguous 3.4-kb region of each putative virus species, including partial glycoprotein B and DNA polymerase genes. We identified three novel GHVs, each present predominantly in one felid species: Felis catus GHV 1 (FcaGHV1) in domestic cats, Lynx rufus GHV 1 (LruGHV1) in bobcats, and Puma concolor GHV 1 (PcoGHV1) in pumas. To estimate infection prevalence, we developed real-time quantitative PCR assays for each virus and screened additional DNA samples from all three species (n = 282). FcaGHV1 was detected in 16% of domestic cats across all study sites. LruGHV1 was detected in 47% of bobcats and 13% of pumas across all study sites, suggesting relatively common interspecific transmission. PcoGHV1 was detected in 6% of pumas, all from a specific region of Southern California. The risk of infection for each host varied with geographic location. Age was a positive risk factor for bobcat LruGHV1 infection, and age and being male were risk factors for domestic cat FcaGHV1 infection. Further characterization of these viruses may have significant health implications for domestic cats and may aid studies of free-ranging felid ecology. IMPORTANCE Gammaherpesviruses (GHVs) establish lifelong infection in many animal species and can cause cancer and other diseases in humans and animals. In this study, we identified the DNA sequences of three GHVs present in the blood of domestic cats (Felis catus), bobcats (Lynx rufus), and pumas (Puma concolor; also known as mountain lions, cougars, and panthers). We found that these viruses were closely related to, but distinct from, other known GHVs of animals and represent the first GHVs identified to be native to these feline species. We developed techniques to rapidly and specifically detect the DNA of these viruses in feline blood and found that the domestic cat and bobcat viruses were widespread across the United States. In contrast, puma virus was found only in a specific region of Southern California. Surprisingly, the bobcat virus was also detected in some pumas, suggesting relatively common virus transmission between these species. Adult domestic cats and bobcats were at greater risk for infection than juveniles. Male domestic cats were at greater risk for infection than females. This study identifies three new viruses that are widespread in three feline species, indicates risk factors for infection that may relate to the route of infection, and demonstrates cross-species transmission between bobcats and pumas. These newly identified viruses may have important effects on feline health and ecology. PMID:24453374

Genetic polymorphism in three glutathione s-transferase genes and breast cancer risk

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

Woldegiorgis, S.; Ahmed, R.C.; Zhen, Y.

The role of the glutathione S-transferase (GST) enzyme family is to detoxify environmental toxins and carcinogens and to protect organisms from their adverse effects, including cancer. The genes GSTM1, GSTP1, and GSTT1 code for three GSTs involved in the detoxification of carcinogens, such as polycyclic aromatic hydrocarbons (PAHs) and benzene. In humans, GSTM1 is deleted in about 50% of the population, GSTT1 is absent in about 20%, whereas the GSTP1 gene has a single base polymorphism resulting in an enzyme with reduced activity. Epidemiological studies indicate that GST polymorphisms increase the level of carcinogen-induced DNA damage and several studies havemore » found a correlation of polymorphisms in one of the GST genes and an increased risk for certain cancers. We examined the role of polymorphisms in genes coding for these three GST enzymes in breast cancer. A breast tissue collection consisting of specimens of breast cancer patients and non-cancer controls was analyzed by polymerase chain reaction (PCR) for the presence or absence of the GSTM1 and GSTT1 genes and for GSTP1 single base polymorphism by PCR/RFLP. We found that GSTM1 and GSTT1 deletions occurred more frequently in cases than in controls, and GSTP1 polymorphism was more frequent in controls. The effective detoxifier (putative low-risk) genotype (defined as presence of both GSTM1 and GSTT1 genes and GSTP1 wild type) was less frequent in cases than controls (16% vs. 23%, respectively). The poor detoxifier (putative high-risk) genotype was more frequent in cases than controls. However, the sample size of this study was too small to provide conclusive results.« less

Rice phytochrome-interacting factor protein OsPIFff14 represses OsDREB1B gene expression through an extended N-box and interacts preferentially with the active form of phytochrome B

USDA-ARS?s Scientific Manuscript database

DREB1/CBF genes, known as major regulators of plant stress responses, are rapidly and transiently induced by low temperatures. Using a Yeast one Hybrid screening, we identified a putative Phytochrome-Interacting bHLH Factor (OsPIF14), as binding to the OsDREB1B promoter. bHLH proteins are able to bi...

The role of leptin, melanocortin, and neurotrophin system genes on body weight in anorexia nervosa and bulimia nervosa.

PubMed

Yilmaz, Zeynep; Kaplan, Allan S; Tiwari, Arun K; Levitan, Robert D; Piran, Sara; Bergen, Andrew W; Kaye, Walter H; Hakonarson, Hakon; Wang, Kai; Berrettini, Wade H; Brandt, Harry A; Bulik, Cynthia M; Crawford, Steven; Crow, Scott; Fichter, Manfred M; Halmi, Katherine A; Johnson, Craig L; Keel, Pamela K; Klump, Kelly L; Magistretti, Pierre; Mitchell, James E; Strober, Michael; Thornton, Laura M; Treasure, Janet; Woodside, D Blake; Knight, Joanne; Kennedy, James L

2014-08-01

Although low weight is a key factor contributing to the high mortality in anorexia nervosa (AN), it is unclear how AN patients sustain low weight compared with bulimia nervosa (BN) patients with similar psychopathology. Studies of genes involved in appetite and weight regulation in eating disorders have yielded variable findings, in part due to small sample size and clinical heterogeneity. This study: (1) assessed the role of leptin, melanocortin, and neurotrophin genetic variants in conferring risk for AN and BN; and (2) explored the involvement of these genes in body mass index (BMI) variations within AN and BN. Our sample consisted of 745 individuals with AN without a history of BN, 245 individuals with BN without a history of AN, and 321 controls. We genotyped 20 markers with known or putative function among genes selected from leptin, melanocortin, and neurotrophin systems. There were no significant differences in allele frequencies among individuals with AN, BN, and controls. AGRP rs13338499 polymorphism was associated with lowest illness-related BMI in those with AN (p = 0.0013), and NTRK2 rs1042571 was associated with highest BMI in those with BN (p = 0.0018). To our knowledge, this is the first study to address the issue of clinical heterogeneity in eating disorder genetic research and to explore the role of known or putatively functional markers in genes regulating appetite and weight in individuals with AN and BN. If replicated, our results may serve as an important first step toward gaining a better understanding of weight regulation in eating disorders. Copyright © 2014 Elsevier Ltd. All rights reserved.