A systems approach defining constraints of the genome architecture on lineage selection and evolvability during somatic cancer evolution

PubMed Central

Rübben, Albert; Nordhoff, Ole

2013-01-01

Summary Most clinically distinguishable malignant tumors are characterized by specific mutations, specific patterns of chromosomal rearrangements and a predominant mechanism of genetic instability but it remains unsolved whether modifications of cancer genomes can be explained solely by mutations and selection through the cancer microenvironment. It has been suggested that internal dynamics of genomic modifications as opposed to the external evolutionary forces have a significant and complex impact on Darwinian species evolution. A similar situation can be expected for somatic cancer evolution as molecular key mechanisms encountered in species evolution also constitute prevalent mutation mechanisms in human cancers. This assumption is developed into a systems approach of carcinogenesis which focuses on possible inner constraints of the genome architecture on lineage selection during somatic cancer evolution. The proposed systems approach can be considered an analogy to the concept of evolvability in species evolution. The principal hypothesis is that permissive or restrictive effects of the genome architecture on lineage selection during somatic cancer evolution exist and have a measurable impact. The systems approach postulates three classes of lineage selection effects of the genome architecture on somatic cancer evolution: i) effects mediated by changes of fitness of cells of cancer lineage, ii) effects mediated by changes of mutation probabilities and iii) effects mediated by changes of gene designation and physical and functional genome redundancy. Physical genome redundancy is the copy number of identical genetic sequences. Functional genome redundancy of a gene or a regulatory element is defined as the number of different genetic elements, regardless of copy number, coding for the same specific biological function within a cancer cell. Complex interactions of the genome architecture on lineage selection may be expected when modifications of the genome architecture have multiple and possibly opposed effects which manifest themselves at disparate times and progression stages. Dissection of putative mechanisms mediating constraints exerted by the genome architecture on somatic cancer evolution may provide an algorithm for understanding and predicting as well as modifying somatic cancer evolution in individual patients. PMID:23336076

Neuroendocrine regulation of somatic growth in fishes.

PubMed

Dai, XiangYan; Zhang, Wei; Zhuo, ZiJian; He, JiangYan; Yin, Zhan

2015-02-01

Growth is a polygenic trait that is under the influence of multiple physiological pathways regulating energy metabolism and muscle growth. Among the possible growth-regulating pathways in vertebrates, components of the somatotropic axis are thought to have the greatest influence. There is growing body of literature focusing on the somatotropic axis and its role regulating growth in fish. This includes research into growth hormone, upstream hypothalamic hormones, insulin-like growth factors, and downstream signaling molecules. Many of these signals have both somatic effects stimulating the growth of tissues and metabolic effects that play a role in nutrient metabolism. Signals of other endocrine axes exhibit profound effects on the function of the somatotropic axis in vivo. In this review we highlight recent advances in our understanding of the teleost fish endocrine somatotropic axis, including emerging research using genetic modified models. These studies have revealed new aspects and challenges associated with regulation of the important steps of somatic growth.

Validation of patient health questionnaire (PHQ) for major depression in Chinese outpatients with multiple somatic symptoms: a multicenter cross-sectional study.

PubMed

Xiong, Nana; Fritzsche, Kurt; Wei, Jing; Hong, Xia; Leonhart, Rainer; Zhao, Xudong; Zhang, Lan; Zhu, Liming; Tian, Guoqing; Nolte, Sandra; Fischer, Felix

2015-03-15

Despite the high co-morbidity of depressive symptoms in patients with multiple somatic symptoms, the validity of the 9-item Patient Health Questionnaire (PHQ-9) has not yet been investigated in Chinese patients with multiple somatic symptoms. The multicenter cross-sectional study was conducted in ten outpatient departments located in four cities in China. The psychometric properties of the PHQ-9 were examined by confirmative factor analysis (CFA). Criterion validation was undertaken by comparing results with depression diagnoses obtained from the Mini International Neuropsychiatric Interview (MINI) as the gold standard. Overall, 491 patients were recruited of whom 237 had multiple somatic symptoms (SOM+ group, PHQ-15≥10). Cronbach׳s α of the PHQ-9 was 0.87, 0.87, and 0.90 for SOM+ patients, SOM- patients, and total sample respectively. All items and the total score were moderately correlated. The factor models of PHQ-9 tested by CFA yielded similar diagnostic performance when compared to sum score estimation. Multi-group confirmatory factor analysis based on unidimensional model showed similar psychometric properties over the groups with low and high somatic symptom burden. The optimal cut-off point to detect depression in Chinese outpatients was 10 for PHQ-9 (sensitivity=0.77, specificity=0.76) and 3 for PHQ-2 (sensitivity=0.77, specificity=0.74). Potential selection bias and nonresponse bias with applied sampling method. PHQ-9 (cut-off point=10) and PHQ-2 (cut-off point=3) were reliable and valid to detect major depression in Chinese patients with multiple somatic symptoms. Copyright © 2014 Elsevier B.V. All rights reserved.

Are ecstasy users biased toward endorsing somatic mental health symptoms? Results from a general community sample.

PubMed

George, Amanda M; Windsor, Tim D; Rodgers, Bryan

2011-04-01

Whether the reported poorer mental health of ecstasy users is due to a bias in endorsement of somatic symptoms has been postulated, but rarely examined. The purpose of this study is to investigate whether levels of ecstasy use were associated with differential probabilities of endorsing somatic mental health symptoms. Current ecstasy users aged 24-30 years (n = 316) were identified from a population-based Australian study. Measures included frequency of ecstasy, meth/amphetamine, and cannabis use and the Goldberg anxiety/depression symptom scales. Multiple indicator, multiple cause models demonstrated no bias towards endorsing somatic symptoms with higher ecstasy use, both with and without adjustment for gender, cannabis, and meth/amphetamine use. Other studies using alternate measures of mental health should adopt this approach to determine if there is a bias in the endorsement of somatic symptoms among ecstasy users.

[Disease at any price: psychological challenge and the financial costs of somatization].

PubMed

Matalon, A

1996-01-01

In clinical medicine we sometimes deal with patients with unexplained somatic complaints. In a 45-year-old woman with multiple somatic complaints, 2 years of medical examinations in search of a disease diagnosis cost almost 250,000 shekels (about +84,000). The differential diagnosis between somatization, hypochondriasis and psychosomatic pain, and the reasons why physicians are tempted to participate in the "investigation dance" are presented.

De novo assembly and characterization of global transcriptome of coconut palm (Cocos nucifera L.) embryogenic calli using Illumina paired-end sequencing.

PubMed

Rajesh, M K; Fayas, T P; Naganeeswaran, S; Rachana, K E; Bhavyashree, U; Sajini, K K; Karun, Anitha

2016-05-01

Production and supply of quality planting material is significant to coconut cultivation but is one of the major constraints in coconut productivity. Rapid multiplication of coconut through in vitro techniques, therefore, is of paramount importance. Although somatic embryogenesis in coconut is a promising technique that will allow for the mass production of high quality palms, coconut is highly recalcitrant to in vitro culture. In order to overcome the bottlenecks in coconut somatic embryogenesis and to develop a repeatable protocol, it is imperative to understand, identify, and characterize molecular events involved in coconut somatic embryogenesis pathway. Transcriptome analysis (RNA-Seq) of coconut embryogenic calli, derived from plumular explants of West Coast Tall cultivar, was undertaken on an Illumina HiSeq 2000 platform. After de novo transcriptome assembly and functional annotation, we have obtained 40,367 transcripts which showed significant BLASTx matches with similarity greater than 40 % and E value of ≤10(-5). Fourteen genes known to be involved in somatic embryogenesis were identified. Quantitative real-time PCR (qRT-PCR) analyses of these 14 genes were carried in six developmental stages. The result showed that CLV was upregulated in the initial stage of callogenesis. Transcripts GLP, GST, PKL, WUS, and WRKY were expressed more in somatic embryo stage. The expression of SERK, MAPK, AP2, SAUR, ECP, AGP, LEA, and ANT were higher in the embryogenic callus stage compared to initial culture and somatic embryo stages. This study provides the first insights into the gene expression patterns during somatic embryogenesis in coconut.

Androgen Receptor Gene Polymorphisms and Alterations in Prostate Cancer: Of Humanized Mice and Men

PubMed Central

Robins, Diane M.

2011-01-01

Germline polymorphisms and somatic mutations of the androgen receptor (AR) have been intensely investigated in prostate cancer but even with genomic approaches their impact remains controversial. To assess the functional significance of AR genetic variation, we converted the mouse gene to the human sequence by germline recombination and engineered alleles to query the role of a polymorphic glutamine (Q) tract implicated in cancer risk. In a prostate cancer model, AR Q tract length influences progression and castration response. Mutation profiling in mice provides direct evidence that somatic AR variants are selected by therapy, a finding validated in human metastases from distinct treatment groups. Mutant ARs exploit multiple mechanisms to resist hormone ablation, including alterations in ligand specificity, target gene selectivity, chaperone interaction and nuclear localization. Regardless of their frequency, these variants permute normal function to reveal novel means to target wild type AR and its key interacting partners. PMID:21689727

Germ cell regeneration-mediated, enhanced mutagenesis in the ascidian Ciona intestinalis reveals flexible germ cell formation from different somatic cells.

PubMed

Yoshida, Keita; Hozumi, Akiko; Treen, Nicholas; Sakuma, Tetsushi; Yamamoto, Takashi; Shirae-Kurabayashi, Maki; Sasakura, Yasunori

2017-03-15

The ascidian Ciona intestinalis has a high regeneration capacity that enables the regeneration of artificially removed primordial germ cells (PGCs) from somatic cells. We utilized PGC regeneration to establish efficient methods of germ line mutagenesis with transcription activator-like effector nucleases (TALENs). When PGCs were artificially removed from animals in which a TALEN pair was expressed, somatic cells harboring mutations in the target gene were converted into germ cells, this germ cell population exhibited higher mutation rates than animals not subjected to PGC removal. PGC regeneration enables us to use TALEN expression vectors of specific somatic tissues for germ cell mutagenesis. Unexpectedly, cis elements for epidermis, neural tissue and muscle could be used for germ cell mutagenesis, indicating there are multiple sources of regenerated PGCs, suggesting a flexibility of differentiated Ciona somatic cells to regain totipotency. Sperm and eggs of a single hermaphroditic, PGC regenerated animal typically have different mutations, suggesting they arise from different cells. PGCs can be generated from somatic cells even though the maternal PGCs are not removed, suggesting that the PGC regeneration is not solely an artificial event but could have an endogenous function in Ciona. This study provides a technical innovation in the genome-editing methods, including easy establishment of mutant lines. Moreover, this study suggests cellular mechanisms and the potential evolutionary significance of PGC regeneration in Ciona. Copyright © 2017 Elsevier Inc. All rights reserved.

Functional characterization of somatic mutations in cancer using network-based inference of protein activity | Office of Cancer Genomics

Cancer.gov

Identifying the multiple dysregulated oncoproteins that contribute to tumorigenesis in a given patient is crucial for developing personalized treatment plans. However, accurate inference of aberrant protein activity in biological samples is still challenging as genetic alterations are only partially predictive and direct measurements of protein activity are generally not feasible.

The Ying and Yang of STAT3 in Human Disease.

PubMed

Vogel, Tiphanie P; Milner, Joshua D; Cooper, Megan A

2015-10-01

The transcription factor signal transducer and activator of transcription 3 (STAT3) is a critical regulator of multiple, diverse cellular processes. Heterozgyous, germline, loss-of-function mutations in STAT3 lead to the primary immune deficiency Hyper-IgE syndrome. Heterozygous, somatic, gain-of-function mutations in STAT3 have been reported in malignancy. Recently, germline, heterozygous mutations in STAT3 that confer a gain-of-function have been discovered and result in early-onset, multi-organ autoimmunity. This review summarizes what is known about the role of STAT3 in human disease.

Serotonin transporter gene and childhood trauma--a G × E effect on anxiety sensitivity.

PubMed

Klauke, Benedikt; Deckert, Jürgen; Reif, Andreas; Pauli, Paul; Zwanzger, Peter; Baumann, Christian; Arolt, Volker; Glöckner-Rist, Angelika; Domschke, Katharina

2011-12-21

Genetic factors and environmental factors are assumed to interactively influence the pathogenesis of anxiety disorders. Thus, a gene-environment interaction (G × E) study was conducted with respect to anxiety sensitivity (AS) as a promising intermediate phenotype of anxiety disorders. Healthy subjects (N = 363) were assessed for AS, childhood maltreatment (Childhood Trauma Questionnaire), and genotyped for functional serotonin transporter gene variants (5-HTTLPR/5-HTT rs25531). The influence of genetic and environmental variables on AS and its subdimensions was determined by a step-wise hierarchical regression and a multiple indicator multiple cause (MIMIC) model. A significant G × E effect of the more active 5-HTT genotypes and childhood maltreatment on AS was observed. Furthermore, genotype (LL)-childhood trauma interaction particularly influenced somatic AS subdimensions, whereas cognitive subdimensions were affected by childhood maltreatment only. Results indicate a G × E effect of the more active 5-HTT genotypes and childhood maltreatment on AS, with particular impact on its somatic subcomponent. © 2011 Wiley Periodicals, Inc.

Somatization Increases Disability Independent of Comorbidity

PubMed Central

Orav, E. John; Bates, David W.; Barsky, Arthur J.

2008-01-01

Background Somatoform disorders are an important factor in functional disability and role impairment, though their independent contribution to disability has been unclear because of prevalent medical and psychiatric comorbidity. Objectives To assess the extent of the overlap of somatization with other psychiatric disorders and medical problems, to compare the functional disability and role impairment of somatizing and non-somatizing patients, and to determine the independent contribution of somatization to functional disability and role impairment. Design Patients were surveyed with self-report questionnaires assessing somatization, psychiatric disorder, and role impairment. Medical morbidity was indexed with a computerized medical record audit. Participants Consecutive adults making scheduled visits to their primary care physicians at two hospital-affiliated primary care practices on randomly chosen days. Measurements Intermediate activities of daily living, social activities, and occupational disability. Results Patients with somatization, as well as those with serious medical and psychiatric illnesses, had significantly more impairment of activities of daily life and social activities. When these predictors were considered simultaneously in a multivariable regression, the association with somatization remained highly significant and was comparable to or greater than many major medical conditions. Conclusions Patients with somatization had substantially greater functional disability and role impairment than non-somatizing patients. The degree of disability was equal to or greater than that associated with many major, chronic medical disorders. Adjusting the results for psychiatric and medical co-morbidity had little effect on these findings. PMID:19031038

Hypochondriasis and somatization: two distinct aspects of somatoform disorders?

PubMed

Leibbrand, R; Hiller, W; Fichter, M M

2000-01-01

We investigated boundaries and overlap between somatization and hypochondriasis on different levels of psychopathology: (1) comorbidity between hypochondriasis and somatization on the level of diagnoses in the Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition (DSM-IV; American Psychiatric Association, 1994): (2) comorbidity with other mental disorders; (3) differences in clinical characteristics: and (4) overlap on the level of psychometric measures. The sample consisted of 120 psycho somatic inpatients. Somatoform, hypochondriacal, and depressive symptomatology, cognitions about body and health, and further aspects of general symptomatology were investigated. Diagnoses of Axis I and II were based on DSM-IV Our results suggest a large overlap on the level of DSM-IV-diagnoses: only 3 of 31 hypochondriacal patients had no multiple somatoform symptoms, while 58 of 86 patients with multiple somatoform symptoms had no hypochondriasis. However, the overlap between hypochondriacal and somatization symptomatology on the level of psychometric measurement is only moderate, indicating that hypochondriasis is a markedly distinct aspect of somatoform disorders.

Posttraumatic headache: biopsychosocial comparisons with multiple control groups.

PubMed

Tatrow, Kristin; Blanchard, Edward B; Hickling, Edward J; Silverman, Daniel J

2003-01-01

This study examined somatic, psychological, and cognitive functioning of subjects with posttraumatic headache in comparison with multiple control groups. Posttraumatic headache is not as widely studied as other forms of headache (eg, tension-type, migraine). Previous research has suggested poor psychological functioning in patients with posttraumatic headache in comparison with other groups of patients with pain; however, this group has yet to be compared with a group of persons who have experienced trauma but are headache-free. Nineteen subjects with posttraumatic headache were studied, with full assessments available for 14 participants. Comparison groups, containing 16 participants each, included another headache group, a nonheadache group, and a trauma (motor vehicle accident) survivor nonheadache group. Participants completed several measures assessing somatic, psychological, and cognitive functioning. Findings revealed that the posttraumatic headache group exhibited significantly poorer functioning than the comparison groups on several measures including the Psychosomatic Symptom Checklist, Postconcussion Syndrome Checklist, axis II psychiatric diagnoses, Minnesota Multiphasic Personality Inventory, and the Daily Hassles Scale (frequency and total). Additionally, they scored higher on the following: number of axis I psychiatric diagnoses, the Daily Hassles Scale (intensity), Beck Depression Inventory, State-Trait Anxiety Inventory, and State-Trait Anger Expression Inventory. The posttraumatic headache group was similar to the other trauma group on the Posttraumatic Stress Disorder Symptom Checklist and the Life-Trauma Checklist. This study confirmed the distress seen in this understudied population of persons with headache and highlights areas of focus for proper assessment and treatment of those with headache and who have had an accident.

Continuity of Functional-Somatic Symptoms from Late Childhood to Young Adulthood in a Community Sample

ERIC Educational Resources Information Center

Steinhausen, Hans-Christoph; Metzke, Christa Winkler

2007-01-01

Background: The goal of this study was to assess the course of functional-somatic symptoms from late childhood to young adulthood and the associations of these symptoms with young adult psychopathology. Methods: Data were collected in a large community sample at three different points in time (1994, 1997, and 2001). Functional-somatic symptoms…

Life Course Pathways of Adversities Linking Adolescent Socioeconomic Circumstances and Functional Somatic Symptoms in Mid-Adulthood: A Path Analysis Study

PubMed Central

Jonsson, Frida; San Sebastian, Miguel; Strömsten, Lotta M. J.; Hammarström, Anne; Gustafsson, Per E.

2016-01-01

While research examining the health impact of early socioeconomic conditions suggests that effects may exist independently of or jointly with adult socioeconomic position, studies exploring other potential pathways are few. Following a chain of risk life course model, this prospective study seeks to examine whether pathways of occupational class as well as material and social adversities across the life course link socioeconomic disadvantage in adolescent to functional somatic symptoms in mid-adulthood. Applying path analysis, a multiple mediator model was assessed using prospective data collected during 26 years through the Northern Swedish Cohort. The sample contained 987 individuals residing in the municipality of Luleå, Sweden, who participated in questionnaire surveys at age 16, 21, 30 and 42. Socioeconomic conditions (high/low) in adolescence (age 16) were operationalized using the occupation of the parents, while occupational class in adulthood (manual/non-manual) was measured using the participant’s own occupation at age 21 and 30. The adversity measurements were constructed as separate age specific parcels at age 21 and 30. Social adversity included items pertaining to stressful life events that could potentially harm salient relationships, while material adversity was operationalized using items concerning unfavorable financial and material circumstances. Functional somatic symptoms at age 42 was a summary measure of self-reported physical symptoms, palpitation and sleeping difficulties that had occurred during the last 12 months. An association between socioeconomic conditions at age 16 and functional somatic symptoms at age 42 (r = 0.068) which was partially explained by people’s own occupational class at age 21 and then material as well as social adversity at age 30 was revealed. Rather than proposing a direct and independent health effect of the socioeconomic conditions of the family, the present study suggests that growing up in an unfavorable socioeconomic environment might be a source for a chain of adverse material and social living situations, which in turn affects adult health. PMID:27214206

[Somatization disorders of the urogenital tract].

PubMed

Günthert, E A

2002-11-01

Diffuse symptoms in the urogenital region can frequently be explained by somatization disorders. Since they cannot be proven either by laboratory tests or with common technical diagnostic methods, somatization disorders should always be taken into consideration. Somatization disorders are to be considered functional disorders. Since somatization disorders due to muscular tension prevail in the urogenital region, the functional disturbance can be explained by the muscular tension. Subsequently, muscular tension causes the pathophysiological development of symptoms. As a rule they appear as myofascial pain or disorder. Muscular tension can have a psychic origin. The absence of urological findings is typical. Males and females between the ages of 16 and 75 can be affected by somatization disorders in the urogenital region. Somatization disorders due to muscular tension belong to the large group of symptoms due to tension. Diagnostic and therapeutic procedures as well as the pathophysiology of somatization disorders due to muscular tension are illustrated by two detailed case-reports.

Control of female gamete formation by a small RNA pathway in Arabidopsis.

PubMed

Olmedo-Monfil, Vianey; Durán-Figueroa, Noé; Arteaga-Vázquez, Mario; Demesa-Arévalo, Edgar; Autran, Daphné; Grimanelli, Daniel; Slotkin, R Keith; Martienssen, Robert A; Vielle-Calzada, Jean-Philippe

2010-03-25

In the ovules of most sexual flowering plants female gametogenesis is initiated from a single surviving gametic cell, the functional megaspore, formed after meiosis of the somatically derived megaspore mother cell (MMC). Because some mutants and certain sexual species exhibit more than one MMC, and many others are able to form gametes without meiosis (by apomixis), it has been suggested that somatic cells in the ovule are competent to respond to a local signal likely to have an important function in determination. Here we show that the Arabidopsis protein ARGONAUTE 9 (AGO9) controls female gamete formation by restricting the specification of gametophyte precursors in a dosage-dependent, non-cell-autonomous manner. Mutations in AGO9 lead to the differentiation of multiple gametic cells that are able to initiate gametogenesis. The AGO9 protein is not expressed in the gamete lineage; instead, it is expressed in cytoplasmic foci of somatic companion cells. Mutations in SUPPRESSOR OF GENE SILENCING 3 and RNA-DEPENDENT RNA POLYMERASE 6 exhibit an identical defect to ago9 mutants, indicating that the movement of small RNA (sRNAs) silencing out of somatic companion cells is necessary for controlling the specification of gametic cells. AGO9 preferentially interacts with 24-nucleotide sRNAs derived from transposable elements (TEs), and its activity is necessary to silence TEs in female gametes and their accessory cells. Our results show that AGO9-dependent sRNA silencing is crucial to specify cell fate in the Arabidopsis ovule, and that epigenetic reprogramming in companion cells is necessary for sRNA-dependent silencing in plant gametes.

Effects and mediators of psychosocial work characteristics on somatic symptoms six years later: Prospective findings from the Mannheim Industrial Cohort Studies (MICS).

PubMed

Herr, Raphael M; Li, Jian; Loerbroks, Adrian; Angerer, Peter; Siegrist, Johannes; Fischer, Joachim E

2017-07-01

Ample evidence documented the adverse health effects of work stressors, and recent research has increasingly focused on somatic symptoms which are very common and costly. Prospective evidence is however sparse and yielded mixed findings. Furthermore, there is reason to assume that depression and anxiety might mediate the effects of adverse psychosocial work conditions on somatic symptoms. This study aimed to investigate longitudinal effects of work stressors on somatic symptoms and the potential mediation by anxiety and/or depression. Six year follow-up data from 352 individuals - free of potentially stress-related chronic disease - were utilized. Somatic symptoms were assessed by 19 items of an established list of complaints at baseline and follow-up. The effort-reward-imbalance (ERI) model measured adverse psychosocial work conditions and over-commitment (OC). Linear regressions adjusted for socio-demographics, social status, lifestyle, and baseline symptoms estimated the effects of the ERI ratio, effort, reward, OC, and the ERI ratio×OC interaction on somatic symptoms six years later. Furthermore, single and multiple mediation by anxiety and/or depression was investigated. There was a strong longitudinal effect of the ERI ratio, as well as of its subcomponents, and OC on somatic symptoms (all Bs≥|0.49|; p-values ≤0.004). Moreover, the ERI ratio×OC interaction was significant (p-value=0.047). Multiple mediation analyses revealed especially anxiety to mediate the effect of work stressors on somatic symptoms (Sobel test=0.007). Adverse psychosocial work conditions seem to longitudinally affect somatic symptoms, potentially moderated by OC, and mediated by anxiety. Copyright © 2017 Elsevier Inc. All rights reserved.

Transposable elements at the center of the crossroads between embryogenesis, embryonic stem cells, reprogramming, and long non-coding RNAs.

PubMed

Hutchins, Andrew Paul; Pei, Duanqing

Transposable elements (TEs) are mobile genomic sequences of DNA capable of autonomous and non-autonomous duplication. TEs have been highly successful, and nearly half of the human genome now consists of various families of TEs. Originally thought to be non-functional, these elements have been co-opted by animal genomes to perform a variety of physiological functions ranging from TE-derived proteins acting directly in normal biological functions, to innovations in transcription factor logic and influence on epigenetic control of gene expression. During embryonic development, when the genome is epigenetically reprogrammed and DNA-demethylated, TEs are released from repression and show embryonic stage-specific expression, and in human and mouse embryos, intact TE-derived endogenous viral particles can even be detected. A similar process occurs during the reprogramming of somatic cells to pluripotent cells: When the somatic DNA is demethylated, TEs are released from repression. In embryonic stem cells (ESCs), where DNA is hypomethylated, an elaborate system of epigenetic control is employed to suppress TEs, a system that often overlaps with normal epigenetic control of ESC gene expression. Finally, many long non-coding RNAs (lncRNAs) involved in normal ESC function and those assisting or impairing reprogramming contain multiple TEs in their RNA. These TEs may act as regulatory units to recruit RNA-binding proteins and epigenetic modifiers. This review covers how TEs are interlinked with the epigenetic machinery and lncRNAs, and how these links influence each other to modulate aspects of ESCs, embryogenesis, and somatic cell reprogramming.

A polymorphism in the MSH3 mismatch repair gene is associated with the levels of somatic instability of the expanded CTG repeat in the blood DNA of myotonic dystrophy type 1 patients.

PubMed

Morales, Fernando; Vásquez, Melissa; Santamaría, Carolina; Cuenca, Patricia; Corrales, Eyleen; Monckton, Darren G

2016-04-01

Somatic mosaicism of the expanded CTG repeat in myotonic dystrophy type 1 is age-dependent, tissue-specific and expansion-biased, contributing toward the tissue-specificity and progressive nature of the symptoms. Previously, using regression modelling of repeat instability we showed that variation in the rate of somatic expansion in blood DNA contributes toward variation in age of onset, directly implicating somatic expansion in the disease pathway. Here, we confirm these results using a larger more genetically homogenous Costa Rican DM1 cohort (p<0.001). Interestingly, we also provide evidence that supports subtle sex-dependent differences in repeat length-dependent age at onset and somatic mutational dynamics. Previously, we demonstrated that variation in the rate of somatic expansion was a heritable quantitative trait. Given the important role that DNA mismatch repair genes play in mediating expansions in mouse models, we tested for modifier gene effects with 13 DNA mismatch gene polymorphisms (one each in MSH2, PMS2, MSH6 and MLH1; and nine in MSH3). After correcting for allele length and age effects, we identified three polymorphisms in MSH3 that were associated with variation in somatic instability: Rs26279 (p=0.003); Rs1677658 (p=0.009); and Rs10168 (p=0.031). However, only the association with Rs26279 remained significant after multiple testing correction. Although we revealed a statistically significant association between Rs26279 and somatic instability, we did not detect an association with the age at onset. Individuals with the A/A genotype for Rs26279 tended to show a greater propensity to expand the CTG repeat than other genotypes. Interestingly, this SNP results in an amino acid change in the critical ATPase domain of MSH3 and is potentially functionally dimorphic. These data suggest that MSH3 is a key player in generating somatic variation in DM1 patients and further highlight MSH3 as a potential therapeutic target. Copyright © 2016 Elsevier B.V. All rights reserved.

Germline loss-of-function mutations in LZTR1 predispose to an inherited disorder of multiple schwannomas

PubMed Central

Piotrowski, Arkadiusz; Xie, Jing; Liu, Ying F; Poplawski, Andrzej B; Gomes, Alicia R; Madanecki, Piotr; Fu, Chuanhua; Crowley, Michael R; Crossman, David K; Armstrong, Linlea; Babovic-Vuksanovic, Dusica; Bergner, Amanda; Blakeley, Jaishri O; Blumenthal, Andrea L; Daniels, Molly S; Feit, Howard; Gardner, Kathy; Hurst, Stephanie; Kobelka, Christine; Lee, Chung; Nagy, Rebecca; Rauen, Katherine A; Slopis, John M; Suwannarat, Pim; Westman, Judith A; Zanko, Andrea; Korf, Bruce R; Messiaen, Ludwine M

2015-01-01

Constitutional SMARCB1 mutations at 22q11.23 have been found in ~50% of familial and <10% of sporadic schwannomatosis cases1. We sequenced highly conserved regions along 22q from eight individuals with schwannomatosis whose schwannomas involved somatic loss of one copy of 22q, encompassing SMARCB1 and NF2, with a different somatic mutation of the other NF2 allele in every schwannoma but no mutation of the remaining SMARCB1 allele in blood and tumor samples. LZTR1 germline mutations were identified in seven of the eight cases. LZTR1 sequencing in 12 further cases with the same molecular signature identified 9 additional germline mutations. Loss of heterozygosity with retention of an LZTR1 mutation was present in all 25 schwannomas studied. Mutations segregated with disease in all available affected first-degree relatives, although four asymptomatic parents also carried an LZTR1 mutation. Our findings identify LZTR1 as a gene predisposing to an autosomal dominant inherited disorder of multiple schwannomas in ~80% of 22q-related schwannomatosis cases lacking mutation in SMARCB1. PMID:24362817

Impact of perinatal somatic and common mental disorder symptoms on functioning in Ethiopian women: The P-MaMiE population-based cohort study

PubMed Central

Senturk, Vesile; Hanlon, Charlotte; Medhin, Girmay; Dewey, Michael; Araya, Mesfin; Alem, Atalay; Prince, Martin; Stewart, Robert

2012-01-01

Background Little is known of the relationship between perinatal somatic and common mental disorder (CMD) symptoms and impaired functioning in women from settings where the burden of undernutrition and infectious disease morbidity is high. Methods A population-based sample of 1065 women from Butajira, Ethiopia, was recruited in pregnancy (86.4% of those eligible) and reassessed two months postnatal (954 with singleton, live infants). At both time-points, women were administered a modified version of the Patient Health Questionnaire-15 and the Self-Reporting Questionnaire (locally-validated) to assess somatic and CMD symptoms, respectively. Negative binomial regression was used to investigate associations of CMD and somatic symptoms with functional impairment (World Health Organisation Disability Assessment Scale, version-II), after adjusting for maternal anthropometric measures, physical ill-health and sociodemographic factors. Results In pregnancy, somatic and CMD symptoms were independently associated with worse maternal functional impairment after adjustment for confounders (WHODAS-II score multiplied by 1.09 (95%CI 1.06, 1.13) and 1.11 (95%CI 1.08, 1.14) respectively for each additional symptom). In the postnatal period, the size of association between somatic symptoms and functional impairment was diminished, but the association with CMD symptoms was virtually unchanged (multiplier value 1.04 (95%CI 1.00, 1.09) and 1.11 (95%CI 1.07, 1.16) respectively). Limitations Use of largely self-report measures. Conclusions Somatic and CMD symptoms were independently associated with functional impairment in both pregnancy and the postnatal period, with CMD symptoms showing a stronger and more consistent association. This emphasises the public health relevance of both CMD and somatic symptoms in the perinatal period. PMID:22196052

The Effects of Attention Problems on Psychosocial Functioning in Childhood Brain Tumor Survivors: A 2-Year Postcraniospinal Irradiation Follow-up.

PubMed

Oh, Yunhye; Seo, Hyunjung; Sung, Ki Woong; Joung, Yoo Sook

2017-03-01

To examine the psychosocial outcomes and impact of attention problems in survivors of pediatric brain tumor. The survivors' cognitive functioning was measured using the Wechsler Intelligence Scale for Children. The Child Behavior Checklist-Attention Problems scale was used to screen for attention problems, and participants were classified as having attention problems (n=15) or normal attention (n=36). Psychosocial functioning was examined with the Korean Personality Rating scale for Children (K-PRC) at precraniospinal radiation and at 2-year follow-up. The attention problem group showed significantly higher depression and externalizing symptoms (delinquency, hyperactivity) and more significant impairment in family relationships than did the normal attention group at baseline. At follow-up, the attention problem group demonstrated significantly more delinquency and impaired family and social relationships. With the K-PRC scores, except for the somatization, social relationship subscale, there were significant differences between groups, but not in terms of treatment by time interaction or within time. At follow-up, multiple linear regressions showed that age at diagnosis significantly predicted K-PRC somatization (B=-1.7, P=0.004) and social relationships (B=-1.7, P=0.004), baseline full-scale intelligence quotient predicted K-PRC depression (B=-0.4, P=0.032) and somatization (B=-0.3, P=0.015), and attention problems at baseline predicted K-PRC depression (B=-15.2, P=0.036) and social relationships (B=-11.6, P=0.016). Pediatric brain tumor survivors, in particular, patients with attention problems, had worse psychosocial functioning at baseline and follow-up. Attention problems at baseline need to be carefully evaluated in assessing psychosocial functioning of pediatric brain tumor survivors.

A Somatic HIF2α Mutation-Induced Multiple and Recurrent Pheochromocytoma/Paraganglioma with Polycythemia: Clinical Study with Literature Review.

PubMed

Liu, Qiuli; Wang, Yan; Tong, Dali; Liu, Gaolei; Yuan, Wenqiang; Zhang, Jun; Ye, Jin; Zhang, Yao; Yuan, Gang; Feng, Qingxing; Zhang, Dianzheng; Jiang, Jun

2017-03-01

A syndrome known as pheochromocytomas (PCC)/paragangliomas (PGL) and polycythemia resulted from gain-of-function mutation of hypoxia-inducible factor 2α (HIF2α) has been reported recently. However, clinical features of this syndrome vary from patient to patient. In our study, we described the clinical features of the patient within 15-year follow-up with a literature review. The patient presented with "red face" since childhood and was diagnosed with polycythemia and pheochromocytoma in 2000, and then, tumor was removed at his age of 27 (year 2000). However, 13 years later (2013), he was diagnosed with multiple paragangliomas. Moreover, 2 years later (2015), another two paragangaliomas were also confirmed. Genetic analysis of hereditary PCC/PGL-related genes was conducted. A somatic heterozygous missense mutation of HIF2α (c.1589C>T) was identified at exon 12, which is responsible for the elevated levels of HIF2α and erythropoietin (EPO) and subsequent development of paragangaliomas. However, this mutation was only found in the tumors from three different areas, not in the blood. So far, 13 cases of PCC/PGL with polycythemia have been reported. Among them, somatic mutations of HIF2α at exon 12 are responsible for 12 cases, and only 1 case was caused by germline mutation of HIF2α at exon 9. The HIF2α mutation-induced polycythemia with PCC/PGL is a rare syndrome with no treatment for cure. Comprehensive therapies for this disease include removal of the tumors and intermittent phlebotomies; administration of medications to control blood pressure and to prevent complications or death resulted from high concentration of red blood cell (RBC). Genetic test is strongly recommended for patients with early onset of polycythemia and multiple/recurrent PCC/PGL.

Passive dendrites enable single neurons to compute linearly non-separable functions.

PubMed

Cazé, Romain Daniel; Humphries, Mark; Gutkin, Boris

2013-01-01

Local supra-linear summation of excitatory inputs occurring in pyramidal cell dendrites, the so-called dendritic spikes, results in independent spiking dendritic sub-units, which turn pyramidal neurons into two-layer neural networks capable of computing linearly non-separable functions, such as the exclusive OR. Other neuron classes, such as interneurons, may possess only a few independent dendritic sub-units, or only passive dendrites where input summation is purely sub-linear, and where dendritic sub-units are only saturating. To determine if such neurons can also compute linearly non-separable functions, we enumerate, for a given parameter range, the Boolean functions implementable by a binary neuron model with a linear sub-unit and either a single spiking or a saturating dendritic sub-unit. We then analytically generalize these numerical results to an arbitrary number of non-linear sub-units. First, we show that a single non-linear dendritic sub-unit, in addition to the somatic non-linearity, is sufficient to compute linearly non-separable functions. Second, we analytically prove that, with a sufficient number of saturating dendritic sub-units, a neuron can compute all functions computable with purely excitatory inputs. Third, we show that these linearly non-separable functions can be implemented with at least two strategies: one where a dendritic sub-unit is sufficient to trigger a somatic spike; another where somatic spiking requires the cooperation of multiple dendritic sub-units. We formally prove that implementing the latter architecture is possible with both types of dendritic sub-units whereas the former is only possible with spiking dendrites. Finally, we show how linearly non-separable functions can be computed by a generic two-compartment biophysical model and a realistic neuron model of the cerebellar stellate cell interneuron. Taken together our results demonstrate that passive dendrites are sufficient to enable neurons to compute linearly non-separable functions.

Passive Dendrites Enable Single Neurons to Compute Linearly Non-separable Functions

PubMed Central

Cazé, Romain Daniel; Humphries, Mark; Gutkin, Boris

2013-01-01

Local supra-linear summation of excitatory inputs occurring in pyramidal cell dendrites, the so-called dendritic spikes, results in independent spiking dendritic sub-units, which turn pyramidal neurons into two-layer neural networks capable of computing linearly non-separable functions, such as the exclusive OR. Other neuron classes, such as interneurons, may possess only a few independent dendritic sub-units, or only passive dendrites where input summation is purely sub-linear, and where dendritic sub-units are only saturating. To determine if such neurons can also compute linearly non-separable functions, we enumerate, for a given parameter range, the Boolean functions implementable by a binary neuron model with a linear sub-unit and either a single spiking or a saturating dendritic sub-unit. We then analytically generalize these numerical results to an arbitrary number of non-linear sub-units. First, we show that a single non-linear dendritic sub-unit, in addition to the somatic non-linearity, is sufficient to compute linearly non-separable functions. Second, we analytically prove that, with a sufficient number of saturating dendritic sub-units, a neuron can compute all functions computable with purely excitatory inputs. Third, we show that these linearly non-separable functions can be implemented with at least two strategies: one where a dendritic sub-unit is sufficient to trigger a somatic spike; another where somatic spiking requires the cooperation of multiple dendritic sub-units. We formally prove that implementing the latter architecture is possible with both types of dendritic sub-units whereas the former is only possible with spiking dendrites. Finally, we show how linearly non-separable functions can be computed by a generic two-compartment biophysical model and a realistic neuron model of the cerebellar stellate cell interneuron. Taken together our results demonstrate that passive dendrites are sufficient to enable neurons to compute linearly non-separable functions. PMID:23468600

Linking Anger Trait with Somatization in Low-Grade College Students: Moderating Roles of Family Cohesion and Adaptability.

PubMed

Liu, Liang; Liu, Cuilian; Zhao, Xudong

2017-02-25

Between 22% and 58% of patients in primary care settings complain of somatic symptoms. Previous research has found that somatization was associated with anger traits and family functions. However, studies that specifically assess the moderating effect of family function in how anger traits become somatic complaints are lacking. This study was designed to examine whether the variances in family cohesion and family adaptability moderated the strength of the relationship between anger traits and somatization. A cross-section design was conducted and 2008 college students were recruited from a comprehensive university in Shanghai. All participants finished questionnaires including Symptom Check List- 90 (SCL-90), State-Trait Anger Expression Inventory 2 (STAXI-2, Chinese version) and Family Adaptability and Cohesion Scale, second edition (FACES II, Chinese Version) to assess their degree of current somatization, anger trait and family function. Hierarchical linear regression analysis (Enter) was conducted respectively for men and women to examine the moderation effect of family cohesion and family adaptability in the association between anger and somatization. Somatic symptoms were significantly linked in the expected directions with depression and anger trait for both genders. Family cohesion and family adaptability were negatively associated with somatic symptoms. For female college students family cohesion was found to moderate the link between anger trait and somatization, but for male college students the moderation effect of family cohesion was marginally significant. The moderating role of family adaptability was significant for neither male nor female after current depressive symptoms were accounted for. Proneness to anger is an independent predictor of somatization. For women, a high level of family cohesion was a protective factor which could reduce the influence of anger trait on somatic symptoms. Without comorbidity of current depression, family adaptability to some degree exempted individuals with anger proneness from developing somatic complaints. Interventions that integrate family cohesion cultivation, family flexibility fostering and depression treatment might be more effective for somatic patients high in anger trait.

Alexithymia and illness behaviour among female Indian outpatients with multiple somatic symptoms

PubMed Central

Sarkar, Jaydip; Chandra, Prabha

2003-01-01

Sixty Indian muslim women outpatients with multiple somatic complaints of nonorganic origin were assessed for alexithymia and abnormal illness behavior using the Toronto Alexithymia Scale (TAS) and the Illness Behaviour Assessment Schedule (IBAS). Alexithymia represented by TAS scores correlated best with the IBAS variables of communication of affect, somatic illness causal beliefs and denial. Correlation with other IBAS variables was modest to poor.There was no correlation of IBAS variables with age of patient, duration of illness or nature of diagnosis: somatoform disorder or anxiety and depressive disorders, The study showed that alexithymia and illness behaviour are overlapping constructs and confirmed the usefulness of TAS as an instrument to discriminate between patients with anxiety/ depressive disorders and somatoform disorders PMID:21206863

Sex-specific impact of early-life adversity on chronic pain: a large population-based study in Japan.

PubMed

Yamada, Keiko; Matsudaira, Ko; Tanaka, Eizaburo; Oka, Hiroyuki; Katsuhira, Junji; Iso, Hiroyasu

2017-01-01

Responses to early-life adversity may differ by sex. We investigated the sex-specific impact of early-life adversity on chronic pain, chronic multisite pain, and somatizing tendency with chronic pain. We examined 4229 respondents aged 20-79 years who participated in the Pain Associated Cross-Sectional Epidemiological Survey in Japan. Outcomes were: 1) chronic pain prevalence, 2) multisite pain (≥3 sites) prevalence, and 3) multiple somatic symptoms (≥3 symptoms) among respondents with chronic pain related to the presence or absence of early-life adversity. Multivariable-adjusted odds ratios (ORs) were calculated with 95% confidence intervals using a logistic regression model including age, smoking status, exercise routine, sleep time, body mass index, household expenditure, and the full distribution of scores on the Mental Health Inventory-5. We further adjusted for pain intensity when we analyzed the data for respondents with chronic pain. The prevalence of chronic pain was higher among respondents reporting the presence of early-life adversity compared with those reporting its absence, with multivariable ORs of 1.62 (1.22-2.15, p <0.01) in men and 1.47 (1.13-1.90, p <0.01) in women. Among women with chronic pain, early-life adversity was associated with multisite pain and multiple somatic symptoms; multivariable ORs were 1.78 (1.22-2.60, p <0.01) for multisite pain and 1.89 (1.27-2.83, p <0.01) for ≥3 somatic symptoms. No associations were observed between early-life adversity and chronic multisite pain or multiple somatic symptoms among men with chronic pain. Early-life adversity may be linked to a higher prevalence of chronic pain among both sexes and to multisite pain and somatizing tendency among women with chronic pain.

Somatization in survivors of catastrophic trauma: a methodological review.

PubMed Central

North, Carol S

2002-01-01

The literature on mental health effects of catastrophic trauma such as community disasters focuses on posttraumatic stress disorder. Somatization disorder is not listed among the classic responses to disaster, nor have other somatoform disorders been described in this literature. Nondiagnostic "somatization," "somatization symptoms," and "somatic symptoms" form the basis of most information about somatization in the literature. However, these concepts have not been validated, and therefore this work suffers from multiple methodological problems of ascertainment and interpretation. Future research is encouraged to consider many methodological issues in obtaining adequate data to address questions about the association of somatization with traumatic events, including a) appropriate comparison groups, b) satisfactory definition and measurement of somatization, c) exclusion of medical explanations for the symptoms, d) recognition of somatizers' spurious attribution of symptoms to medical causes, e) collection of data from additional sources beyond single-subject interviews, f) validation of diagnosis-unrelated symptom reporting or reconsideration of symptoms within diagnostic frameworks, g) separation of somatization after an event into new (incident) and preexisting categories, h) development of research models that include sufficient variables to examine the broader scope of potential relationships, and i) novel consideration of alternative causal directionalities. PMID:12194899

Somatic mutations contribute to genotypic diversity in sterile and fertile populations of the threatened shrub, Grevillea rhizomatosa (Proteaceae).

PubMed

Gross, C L; Nelson, Penelope A; Haddadchi, Azadeh; Fatemi, Mohammad

2012-02-01

Grevillea rhizomatosa is a spreading shrub which exhibits multiple breeding strategies within a narrow area in the fire-prone heathlands of eastern Australia. Reproductive strategies include self-compatibility, self-incompatibility and clonality (with and without sterility). The close proximity of contrasting breeding systems provides an opportunity to explore the evolution of sterility and to compare and contrast the origins of genotypic diversity (recombinant or somatic) against degrees of sexual expression. ISSR markers for 120 band positions (putative loci) were used to compare genetic diversity among five populations at a macro-scale of 5 m between samples (n = 244 shrubs), and at a micro-scale of nearest neighbours for all plants in five 25-m(2) quadrats with contrasting fertilities (n = 162 shrubs). Nearest-neighbour sampling included several clusters of connected ramets. Matrix incompatibility (MIC) analyses were used to evaluate the relative contribution of recombination and somatic mutation to genotype diversity. High levels of genotypic diversity were found in all populations regardless of fertilities (fertile populations, G/N ≥ 0·94; sterile populations, G/N ≥ 0·97) and most sterile populations had a unique genetic profile. Somatic mutations were detected along connected ramets in ten out of 42 ramet clusters. MIC analyses showed that somatic mutations have contributed to diversity in all populations and particularly so in sterile populations. Somatic mutations contribute significantly to gene diversity in sterile populations of Grevillea rhizomatosa, the accumulation of which is the likely cause of male and female sterility. High levels of genetic diversity therefore may not always be synonymous with sexual fitness and genetic health. We hypothesize that frequent fires drive selection for clonal reproduction, at the cost of flowering such that sexual functions are not maintained through selection, and the build-up of somatic mutations in meristems results in high genotype diversity at the cost of pollen and ovule fertilities.

The DSM-IV nosology of chronic pain: a comparison of pain disorder and multiple somatization syndrome.

PubMed

Hiller, W; Heuser, J; Fichter, M M

2000-01-01

This study evaluates the classification of pain from the perspective of the DSM-IV system. Of 60 in-patients with long-standing and disabling pain syndromes, 29 with pain disorder (PD) and 31 with pain as part of a multiple somatization syndrome (MSS) were compared before and after a structured cognitive-behavioral treatment. It was hypothesized that MSS patients show more psychological distress, are more severely disabled, and respond less to the treatment. Both groups were similar with respect to sociodemographic status, history of pain symptomatology and comorbidity with DSM-IV mental disorders. The results show that MSS patients had higher levels of affective and sensoric pain sensations as well as more pain-related disabilities. They were also less successful during treatment to reduce their pain-related depression and anxiety. Psychosocial functioning was improved only by PD patients, but remained almost unchanged in the MSS group. However, there were no group differences concerning general depression and hypochondriasis, dysfunctional attitudes towards body and health, and use of pain coping strategies. It is concluded that the DSM-IV distinction between 'pure' pain disorder and syndromes involving pain plus multiple somatoform symptoms cannot generally be confirmed, but further studies of validation are needed. Copyright 2000 European Federation of Chapters of the International Association for the Study of Pain.

Psychosomatic symptoms in medical outpatients: an investigation of self-handicapping theory.

PubMed

Organista, P B; Miranda, J

1991-01-01

Investigated self-handicapping theory as it relates to somatization in medical patients. We predicted that medical outpatients (N = 113) would report psychosomatic symptoms in response to events that threaten their self-esteem. As predicted, results of hierarchical multiple regression indicated that high-perfectionism patients reported somatic symptoms positively related to the number of events that jeopardize their sense of accomplishment, whereas low-perfectionism patients' somatic symptoms were not related to these events (p = .005). Contrary to prediction, high-dependency patients did not differ significantly from low-dependency patients in the relationship of somatic symptoms and events that threatened their interpersonal relationships (p = .115). Implications of these findings and the utility of self-handicapping theory for predicting somatization in medical patients are discussed.

Production of Prnp-/- goats by gene targeting in adult fibroblasts.

PubMed

Zhu, Caihong; Li, Bei; Yu, Guohua; Chen, Jianquan; Yu, Huiqing; Chen, Juan; Xu, Xujun; Wu, Youbing; Zhang, Aimin; Cheng, Guoxiang

2009-04-01

Homozygous mice devoid of functional Prnp are resistant to scrapie and prion propagation, but heterozygous mice for Prnp disruption still suffer from prion disease and prion deposition. We have previously generated heterozygous cloned goats with one allele of Prnp functional disruption. To obtain goats with both alleles of Prnp be disrupted which would be resistant to scrapie completely, a second-round gene targeting was applied to disrupt the wild type allele of Prnp in the heterozygous goats. By second-round gene targeting, we successfully disrupted the wild type allele of Prnp in primary Prnp (+/-) goat skin fibroblasts and obtained a Prnp (-/-) cell line without Prnp expression. This is the first report on successful targeting modification in primary adult somatic cells of animals. These cells were used as nuclear donors for somatic cell cloning to produce Prnp (-/-) goats. A total of 57 morulae or blastocytes developed from the reconstructed embryos were transferred to 31 recipients, which produced 7 pregnancies at day 35. At 73 days of gestation, we obtained one cloned fetus with Prnp (-/-) genotype. Our research not only indicated that multiple genetic modifications could be accomplished by multi-round gene targeting in primary somatic cells, but also provided strong evidence that gene targeting in adult cells other than fetal cells could be applied to introduce precise genetic modifications in animals without destroying the embryos.

Prognostic significance of functional somatic symptoms in adolescence: a 15-year community-based follow-up study of adolescents with depression compared with healthy peers

PubMed Central

2012-01-01

Background There is a lack of population-based long-term longitudinal research on mental health status and functional physical/somatic symptoms. Little is known about the long-term mental health outcomes associated with somatic symptoms or the temporal relationship between depression and such symptoms. This 15-year study followed up adolescents with depression and matched controls, screened from a population-based sample, who reported different numbers of somatic symptoms. Methods The total population of 16–17-year-olds in Uppsala, Sweden, was screened for depression in 1991–1993. Adolescents who screened positive and an equal number of healthy controls took part in a semi-structured diagnostic interview. In addition, 21 different self-rated somatic symptoms were assessed. Sixty-four percent of those adolescents participated in a follow-up structured interview 15 years later. Results Somatic symptoms in adolescence predicted depression and other adult mental disorders regardless of the presence of adolescent depression. In adolescents with depression, the number of functional somatic symptoms predicted, in a dose response relationship, suicidal behavior, bipolar episodes, and psychotic episodes as well as chronic and recurrent depression. Contrary to expectations, the somatic symptoms of abdominal pain and perspiration without exertion better predicted depression than all DSM-IV depressive symptoms. Abdominal pain persisted as an independent strong predictor of depression and anxiety, even after controlling for other important confounders. Conclusions Somatic symptoms in adolescence can predict severe adult mental health disorders. The number of somatic symptoms concurrent with adolescent depression is, in a stepwise manner, linked to suicidal attempts, bipolar disorders, psychotic disorders, and recurrent and chronic depression. These findings can be useful in developing treatment guidelines for patients with somatic symptoms. PMID:22839681

Somatic embryogenesis from corolla tubes of interspecific amphiploids between cultivated sunflower (Helianthus annuus L.) and its wild species

USDA-ARS?s Scientific Manuscript database

Somatic embryogenesis in vitro provides an efficient means of plant multiplication, facilitating sunflower improvement and germplasm innovation. In the present study, using interspecific amphiploids (2n=4x=68) between cultivated sunflower and wild perennial Helianthus species as explant donors, soma...

Somatic mutations of the histone H3K27 demethylase gene UTX in human cancer.

PubMed

van Haaften, Gijs; Dalgliesh, Gillian L; Davies, Helen; Chen, Lina; Bignell, Graham; Greenman, Chris; Edkins, Sarah; Hardy, Claire; O'Meara, Sarah; Teague, Jon; Butler, Adam; Hinton, Jonathan; Latimer, Calli; Andrews, Jenny; Barthorpe, Syd; Beare, Dave; Buck, Gemma; Campbell, Peter J; Cole, Jennifer; Forbes, Simon; Jia, Mingming; Jones, David; Kok, Chai Yin; Leroy, Catherine; Lin, Meng-Lay; McBride, David J; Maddison, Mark; Maquire, Simon; McLay, Kirsten; Menzies, Andrew; Mironenko, Tatiana; Mulderrig, Lee; Mudie, Laura; Pleasance, Erin; Shepherd, Rebecca; Smith, Raffaella; Stebbings, Lucy; Stephens, Philip; Tang, Gurpreet; Tarpey, Patrick S; Turner, Rachel; Turrell, Kelly; Varian, Jennifer; West, Sofie; Widaa, Sara; Wray, Paul; Collins, V Peter; Ichimura, Koichi; Law, Simon; Wong, John; Yuen, Siu Tsan; Leung, Suet Yi; Tonon, Giovanni; DePinho, Ronald A; Tai, Yu-Tzu; Anderson, Kenneth C; Kahnoski, Richard J; Massie, Aaron; Khoo, Sok Kean; Teh, Bin Tean; Stratton, Michael R; Futreal, P Andrew

2009-05-01

Somatically acquired epigenetic changes are present in many cancers. Epigenetic regulation is maintained via post-translational modifications of core histones. Here, we describe inactivating somatic mutations in the histone lysine demethylase gene UTX, pointing to histone H3 lysine methylation deregulation in multiple tumor types. UTX reintroduction into cancer cells with inactivating UTX mutations resulted in slowing of proliferation and marked transcriptional changes. These data identify UTX as a new human cancer gene.

Somatic mutations of the histone H3K27 demethylase, UTX, in human cancer

PubMed Central

van Haaften, Gijs; Dalgliesh, Gillian L; Davies, Helen; Chen, Lina; Bignell, Graham; Greenman, Chris; Edkins, Sarah; Hardy, Claire; O’Meara, Sarah; Teague, Jon; Butler, Adam; Hinton, Jonathan; Latimer, Calli; Andrews, Jenny; Barthorpe, Syd; Beare, Dave; Buck, Gemma; Campbell, Peter J; Cole, Jennifer; Dunmore, Rebecca; Forbes, Simon; Jia, Mingming; Jones, David; Kok, Chai Yin; Leroy, Catherine; Lin, Meng-Lay; McBride, David J; Maddison, Mark; Maquire, Simon; McLay, Kirsten; Menzies, Andrew; Mironenko, Tatiana; Lee, Mulderrig; Mudie, Laura; Pleasance, Erin; Shepherd, Rebecca; Smith, Raffaella; Stebbings, Lucy; Stephens, Philip; Tang, Gurpreet; Tarpey, Patrick S; Turner, Rachel; Turrell, Kelly; Varian, Jennifer; West, Sofie; Widaa, Sara; Wray, Paul; Collins, V Peter; Ichimura, Koichi; Law, Simon; Wong, John; Yuen, Siu Tsan; Leung, Suet Yi; Tonon, Giovanni; DePinho, Ronald A; Tai, Yu-Tzu; Anderson, Kenneth C; Kahnoski, Richard J.; Massie, Aaron; Khoo, Sok Kean; Teh, Bin Tean; Stratton, Michael R; Futreal, P Andrew

2010-01-01

Somatically acquired epigenetic changes are present in many cancers. Epigenetic regulation is maintained via post-translational modifications of core histones. Here, we describe inactivating somatic mutations in the histone lysine demethylase, UTX, pointing to histone H3 lysine methylation deregulation in multiple tumour types. UTX reintroduction into cancer cells with inactivating UTX mutations resulted in slowing of proliferation and marked transcriptional changes. These data identify UTX as a new human cancer gene. PMID:19330029

Linking Anger Trait with Somatization in Low-Grade College Students: Moderating Roles of Family Cohesion and Adaptability

PubMed Central

LIU, Liang; LIU, Cuilian; ZHAO, Xudong

2017-01-01

Background Between 22% and 58% of patients in primary care settings complain of somatic symptoms. Previous research has found that somatization was associated with anger traits and family functions. However, studies that specifically assess the moderating effect of family function in how anger traits become somatic complaints are lacking. Aim This study was designed to examine whether the variances in family cohesion and family adaptability moderated the strength of the relationship between anger traits and somatization. Methods A cross-section design was conducted and 2008 college students were recruited from a comprehensive university in Shanghai. All participants finished questionnaires including Symptom Check List- 90 (SCL-90), State-Trait Anger Expression Inventory 2 (STAXI-2, Chinese version) and Family Adaptability and Cohesion Scale, second edition (FACES II, Chinese Version) to assess their degree of current somatization, anger trait and family function. Hierarchical linear regression analysis (Enter) was conducted respectively for men and women to examine the moderation effect of family cohesion and family adaptability in the association between anger and somatization. Results Somatic symptoms were significantly linked in the expected directions with depression and anger trait for both genders. Family cohesion and family adaptability were negatively associated with somatic symptoms. For female college students family cohesion was found to moderate the link between anger trait and somatization, but for male college students the moderation effect of family cohesion was marginally significant. The moderating role of family adaptability was significant for neither male nor female after current depressive symptoms were accounted for. Conclusion Proneness to anger is an independent predictor of somatization. For women, a high level of family cohesion was a protective factor which could reduce the influence of anger trait on somatic symptoms. Without comorbidity of current depression, family adaptability to some degree exempted individuals with anger proneness from developing somatic complaints. Interventions that integrate family cohesion cultivation, family flexibility fostering and depression treatment might be more effective for somatic patients high in anger trait. PMID:28769543

When somatization is not the only thing you suffer from: Examining comorbid syndromes using latent profile analysis, parenting practices and adolescent functioning.

PubMed

Scharf, Miri; Mayseless, Ofra; Rousseau, Sofie

2016-10-30

Understanding somatization presents a challenge to clinicians because it is often associated with other syndromes. We addressed somatization's comorbidity with other internalizing syndromes (anxiety, depression, withdrawal) using latent profile analysis. A representative sample of 3496 Israeli middle and high-school youths reported their internalizing symptoms, perceived parenting practices, psychosocial functioning, and health behaviors. Four profiles, similar across age and gender, were identified: overall-low (65.4%), moderately-high anxiety/depression/withdrawal (24.4%), high somatization (4.8%), and overall-high (5.4%). MANOVAs and follow-up ANOVAs revealed that for the most part the overall-high profile evinced the worst parenting, psychosocial functioning, and health behaviors (smoking and drinking), while the overall-low group evinced the best. For most variables the high somatization and moderately high profiles displayed midway results. However, the moderately-high profile reported higher levels of harsh parenting than the high somatization profile. The high somatization profile reported similar or higher levels of smoking, risk taking, vandalism, and rule violation than the overall-high group. High somatization, either alone or alongside anxiety, depression, and withdrawal, was associated with disruptive and risk-taking behaviors. This link might reflect problems in emotion and anger regulation and become stronger in adolescence because of dysregulation processes characterizing this period. Implications for practice are discussed. Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.

The Effects of Prior Combat Experience on the Expression of Somatic and Affective Symptoms in Deploying Soldiers

DTIC Science & Technology

2006-01-01

Journal of Psychosomatic ResThe effects of prior combat experience on the expression of somatic and affective symptoms in deploying soldiers William...rates of somatic complaints compared with combat-naive soldiers. Methods: Self-reports of posttraumatic stress disorder (PTSD) and affective and somatic ...identical for the experienced and inexperienced groups, scores on the Affective and Somatic scales differed as a function of prior combat history. Previous

Somatic-Affective, But Not Cognitive-Depressive Symptoms are Associated With Reduced Health-Related Quality of Life in Patients With Congestive Heart Failure.

PubMed

Patron, Elisabetta; Messerotti Benvenuti, Simone; Lopriore, Vincenzo; Aratari, Jenny; Palomba, Daniela

Depression has been associated with poor health-related quality of life (HRQoL) in patients with congestive heart failure (CHF). However, to date, whether somatic-affective and cognitive-depressive symptoms differently contribute to poor HRQoL and behavioral functional capacity in patients with CHF has yet to be investigated. To examine the differential influence of somatic-affective vs cognitive-depressive symptoms on HRQoL and behavioral functional capacity in CHF patients. Overall, 55 patients with CHF completed a psychologic evaluation, including the Minnesota Living with Heart Failure Questionnaire, the Beck Depression Inventory-II, and the Beck Anxiety Inventory for HRQoL, depressive, and anxiety symptoms, respectively. The patients completed the Instrumental Activities of Daily Living Questionnaire and the 6-minute walk test for behavioral functional capacity. Hierarchical regression analyses were used to predict HRQoL and behavioral functional capacity from Beck Depression Inventory-II and Beck Anxiety Inventory scores. Somatic-affective depressive symptoms were associated with physical (β = 0.37, p = 0.005) and emotional (β = 0.39, p = 0.008) Minnesota Living with Heart Failure Questionnaire subscale scores. Likewise, somatic-affective depressive symptoms predicted Instrumental Activities of Daily Livings Scores (β = 0.43, p = 0.004) and distance ambulated during the 6-minute walk test (β = -0.36, p = 0.029). By contrast, cognitive-depressive symptoms and anxiety were unrelated to HRQoL and behavioral functional capacity (all p > 0.05). These findings showed that somatic-affective depressive symptoms, but not cognitive-depressive symptoms and anxiety, are associated with poor HRQoL and behavioral functional capacity independent of age, clinical functional status, and medical comorbidities. This study suggests that patients with CHF with somatic-affective rather than cognitive-depressive symptoms or anxiety may be at greater risk of poor HRQoL and behavioral functional capacity. Copyright © 2017 The Academy of Psychosomatic Medicine. Published by Elsevier Inc. All rights reserved.

Youth unemployment and functional somatic symptoms in adulthood: results from the Northern Swedish cohort.

PubMed

Brydsten, Anna; Hammarström, Anne; Strandh, Mattias; Johansson, Klara

2015-10-01

Little is known about the possible long-term health consequences of youth unemployment. Research indicates that unemployment may lead to socioeconomic downward mobility and mental health problems, but we still lack knowledge of the long-term health consequences of youth unemployment. This article examines the potential long-term association between youth unemployment and functional somatic symptoms in adulthood. The 'Northern Swedish cohort' was used with data from five data collections, from 1981 (age 16) until 2007 (age 42). Youth unemployment was measured as months in unemployment between age 16 and 21, and health outcome as functional somatic symptoms (an index of 10 items of self-reported symptoms). Linear regression was used to analyse the relationship between months in youth unemployment and functional somatic symptoms at age 21 and age 42, stratified for women and men and adjusted for potential confounders, such as time spent in education at age 21 and later unemployment between age 21 and 42. Youth unemployment was significantly related to functional somatic symptoms at age 21 for men after controlling for confounders, but not for women. Among men, the association remained for functional somatic symptoms at age 42, after controlling for confounders. Adolescence seems to be a sensitive period during which unemployment could have remaining health effects in adulthood, at least for men, though assumptions of causality are tentative and more research is needed. © The Author 2015. Published by Oxford University Press on behalf of the European Public Health Association. All rights reserved.

Fip1 regulates mRNA alternative polyadenylation to promote stem cell self-renewal

PubMed Central

Lackford, Brad; Yao, Chengguo; Charles, Georgette M; Weng, Lingjie; Zheng, Xiaofeng; Choi, Eun-A; Xie, Xiaohui; Wan, Ji; Xing, Yi; Freudenberg, Johannes M; Yang, Pengyi; Jothi, Raja; Hu, Guang; Shi, Yongsheng

2014-01-01

mRNA alternative polyadenylation (APA) plays a critical role in post-transcriptional gene control and is highly regulated during development and disease. However, the regulatory mechanisms and functional consequences of APA remain poorly understood. Here, we show that an mRNA 3′ processing factor, Fip1, is essential for embryonic stem cell (ESC) self-renewal and somatic cell reprogramming. Fip1 promotes stem cell maintenance, in part, by activating the ESC-specific APA profiles to ensure the optimal expression of a specific set of genes, including critical self-renewal factors. Fip1 expression and the Fip1-dependent APA program change during ESC differentiation and are restored to an ESC-like state during somatic reprogramming. Mechanistically, we provide evidence that the specificity of Fip1-mediated APA regulation depends on multiple factors, including Fip1-RNA interactions and the distance between APA sites. Together, our data highlight the role for post-transcriptional control in stem cell self-renewal, provide mechanistic insight on APA regulation in development, and establish an important function for APA in cell fate specification. PMID:24596251

The relationship between ataque de nervios and unexplained neurological symptoms: a preliminary analysis.

PubMed

Interian, Alejandro; Guarnaccia, Peter J; Vega, William A; Gara, Michael A; Like, Robert C; Escobar, Javier I; Díaz-Martínez, Angélica M

2005-01-01

Within somatization, unexplained neurological symptoms (UNSs) have been shown to mark a distinct subgroup with greater clinical severity. However, some UNSs resemble ataque de nervios somatic symptoms. This raises questions about cultural factors related to Hispanics with somatization characterized by UNSs. To examine cultural factors, preliminary analyses examined the relationship between Hispanic ethnicity, UNSs, and ataque de nervios. Data were obtained from 127 primary care patients (95 Hispanic, 32 European American) with somatization. The Composite International Diagnostic Interview provided somatization data, whereas the Primary Care Evaluation of Mental Disorders was used for data on Axis I disorders. Ataque de nervios was assessed via a proxy measure. Within each ethnic group, cross-tabs examined the relationship between ataque de nervios and multiple UNSs, and ataque de nervios and selected Axis I disorders. Only among Hispanics, a significant overlap was found between ataque de nervios and having four or more UNSs (p < .001), and ataque de nervios and a diagnosis of panic disorder (p = .05). Although equal percentages of European Americans and Hispanics experience multiple UNSs, these results show that the presentation of UNSs among some Hispanics may be qualitatively different, because it may involve features related to ataque de nervios. A diagnosis of panic disorder also appears to interact with cultural factors.

RNA-Mediated Epigenetic Programming of Genome Rearrangements

PubMed Central

Nowacki, Mariusz; Shetty, Keerthi; Landweber, Laura F.

2012-01-01

RNA, normally thought of as a conduit in gene expression, has a novel mode of action in ciliated protozoa. Maternal RNA templates provide both an organizing guide for DNA rearrangements and a template that can transport somatic mutations to the next generation. This opportunity for RNA-mediated genome rearrangement and DNA repair is profound in the ciliate Oxytricha, which deletes 95% of its germline genome during development in a process that severely fragments its chromosomes and then sorts and reorders the hundreds of thousands of pieces remaining. Oxytricha’s somatic nuclear genome is therefore an epigenome formed through RNA templates and signals arising from the previous generation. Furthermore, this mechanism of RNA-mediated epigenetic inheritance can function across multiple generations, and the discovery of maternal template RNA molecules has revealed new biological roles for RNA and has hinted at the power of RNA molecules to sculpt genomic information in cells. PMID:21801022

The topography of mutational processes in breast cancer genomes.

PubMed

Morganella, Sandro; Alexandrov, Ludmil B; Glodzik, Dominik; Zou, Xueqing; Davies, Helen; Staaf, Johan; Sieuwerts, Anieta M; Brinkman, Arie B; Martin, Sancha; Ramakrishna, Manasa; Butler, Adam; Kim, Hyung-Yong; Borg, Åke; Sotiriou, Christos; Futreal, P Andrew; Campbell, Peter J; Span, Paul N; Van Laere, Steven; Lakhani, Sunil R; Eyfjord, Jorunn E; Thompson, Alastair M; Stunnenberg, Hendrik G; van de Vijver, Marc J; Martens, John W M; Børresen-Dale, Anne-Lise; Richardson, Andrea L; Kong, Gu; Thomas, Gilles; Sale, Julian; Rada, Cristina; Stratton, Michael R; Birney, Ewan; Nik-Zainal, Serena

2016-05-02

Somatic mutations in human cancers show unevenness in genomic distribution that correlate with aspects of genome structure and function. These mutations are, however, generated by multiple mutational processes operating through the cellular lineage between the fertilized egg and the cancer cell, each composed of specific DNA damage and repair components and leaving its own characteristic mutational signature on the genome. Using somatic mutation catalogues from 560 breast cancer whole-genome sequences, here we show that each of 12 base substitution, 2 insertion/deletion (indel) and 6 rearrangement mutational signatures present in breast tissue, exhibit distinct relationships with genomic features relating to transcription, DNA replication and chromatin organization. This signature-based approach permits visualization of the genomic distribution of mutational processes associated with APOBEC enzymes, mismatch repair deficiency and homologous recombinational repair deficiency, as well as mutational processes of unknown aetiology. Furthermore, it highlights mechanistic insights including a putative replication-dependent mechanism of APOBEC-related mutagenesis.

The Vascular Wall: a Plastic Hub of Activity in Cardiovascular Homeostasis and Disease.

PubMed

Awgulewitsch, Cassandra P; Trinh, Linh T; Hatzopoulos, Antonis K

2017-06-01

This review aims to summarize recent findings regarding the plasticity and fate switching among somatic and progenitor cells residing in the vascular wall of blood vessels in health and disease. Cell lineage tracing methods have identified multiple origins of stem cells, macrophages, and matrix-producing cells that become mobilized after acute or chronic injury of cardiovascular tissues. These studies also revealed that in the disease environment, resident somatic cells become plastic, thereby changing their stereotypical identities to adopt proinflammatory and profibrotic phenotypes. Currently, the functional significance of this heterogeneity among reparative cells is unknown. Furthermore, mechanisms that control cellular plasticity and fate decisions in the disease environment are poorly understood. Cardiovascular diseases are responsible for the majority of deaths worldwide. From a therapeutic perspective, these novel discoveries may identify new targets to improve the repair and regeneration of the cardiovascular system.

Attachment, social support, and responses following the death of a companion animal.

PubMed

King, Loren C; Werner, Paul D

This research tested hypotheses concerning attachment, social support, and grief responses to the loss of animal companionship. Participants whose companion cat or dog had recently died (N = 429) completed the Attachment Style Questionnaire, the Inventory of Complicated Grief, and the Multidimensional Health Profile-Psychosocial Functioning questionnaires. Both attachment anxiety and attachment avoidance were found to be positively associated with respondents' grief, depression, anxiety, and somatic symptoms. Social support was found to be negatively associated with these outcomes as well as with attachment anxiety and attachment avoidance. In multiple regression analyses, attachment anxiety incrementally predicted grief, anxiety and somatic symptoms, attachment avoidance incrementally predicted grief and depression, and social support incrementally predicted all outcomes. Interaction effects of attachment and social support in relation to outcomes were not found. The present study's implications and limitations are discussed, as are directions for future research.

Are child anxiety and somatization associated with pain in pain-related functional gastrointestinal disorders?

USDA-ARS?s Scientific Manuscript database

This study investigated individual and incremental contributions of somatization and trait anxiety to pain report in children with pain-related functional gastrointestinal disorders. Eighty children (7-10 years) with pain-related functional gastrointestinal disorders completed the State-Trait Anxiet...

Stress and Coping with War: The Experience of Deployment and Reunion for Mortuary Affairs Units, Reserve Units, and First-Term Army Wives

DTIC Science & Technology

1992-08-01

presented with multiple somatic complaints and fears of having been exposwd to toxic substances or infectious diseases (123rd ARCOM). The final...soldiers who presented with multiple somatic complaints and fears of having been exposed to toxic substances or infectious diseases while in the Gulf (the...lazy people." "Our CO complicated things by involving himself in business that he had no business being involved in." "To try to get supply was a real

Self-Report of Depressive Symptoms in Low Back Pain Patients.

ERIC Educational Resources Information Center

Crisson, James; And Others

1986-01-01

Presents two studies designed to examine the self-report of depressive symptoms in low back pain patients (N=134). Both studies found that patients were more likely to report somatic than cognitive symptoms of depression. Patients with multiple physical findings were not more likely to report somatic symptoms than patients with few physical…

FOXP3 Orchestrates H4K16 Acetylation and H3K4 Tri-Methylation for Activation of Multiple Genes through Recruiting MOF and Causing Displacement of PLU-1

PubMed Central

Katoh, Hiroto; Qin, Zhaohui S.; Liu, Runhua; Wang, Lizhong; Li, Weiquan; Li, Xiangzhi; Wu, Lipeng; Du, Zhanwen; Lyons, Robert; Liu, Chang-Gong; Liu, Xiuping; Dou, Yali; Zheng, Pan; Liu, Yang

2011-01-01

SUMMARY Both H4K16 acetylation and H3K4 tri-methylation are required for gene activation. However, it is still largely unclear how these modifications are orchestrated by transcriptional factors. Here we analyzed the mechanism of the transcriptional activation by FOXP3, an X-linked suppressor of autoimmune diseases and cancers. FOXP3 binds near transcriptional start sites of its target genes. By recruiting MOF and displacing histone H3K4 demethylase PLU-1, FOXP3 increases both H4K16 acetylation and H3K4 tri-methylation at the FOXP3-associated chromatins of multiple FOXP3-activated genes. RNAi-mediated silencing of MOF reduced both gene activation and tumor suppression by FOXP3, while both somatic mutations in clinical cancer samples and targeted mutation of FOXP3 in mouse prostate epithelial disrupted nuclear localization of MOF. Our data demonstrate a pull-push model in which a single transcription factor orchestrates two epigenetic alterations necessary for gene activation and provide a mechanism for somatic inactivation of the FOXP3 protein function in cancer cells. PMID:22152480

Screening for depression in arthritis populations: an assessment of differential item functioning in three self-reported questionnaires.

PubMed

Hu, Jinxiang; Ward, Michael M

2017-09-01

To determine if persons with arthritis differ systematically from persons without arthritis in how they respond to questions on three depression questionnaires, which include somatic items such as fatigue and sleep disturbance. We extracted data on the Centers for Epidemiological Studies Depression (CES-D) scale, the Patient Health Questionnaire-9 (PHQ-9), and the Kessler-6 (K-6) scale from three large population-based national surveys. We assessed items on these questionnaires for differential item functioning (DIF) between persons with and without self-reported physician-diagnosed arthritis using multiple indicator multiple cause models, which controlled for the underlying level of depression and important confounders. We also examined if DIF by arthritis status was similar between women and men. Although five items of the CES-D, one item of the PHQ-9, and five items of the K-6 scale had evidence of DIF based on statistical comparisons, the magnitude of each difference was less than the threshold of a small effect. The statistical differences were a function of the very large sample sizes in the surveys. Effect sizes for DIF were similar between women and men except for two items on the Patient Health Questionnaire-9. For each questionnaire, DIF accounted for 8% or less of the arthritis-depression association, and excluding items with DIF did not reduce the difference in depression scores between those with and without arthritis. Persons with arthritis respond to items on the CES-D, PHQ-9, and K-6 depression scales similarly to persons without arthritis, despite the inclusion of somatic items in these scales.

Cognitive aspects of hypochondriasis and the somatization syndrome.

PubMed

Rief, W; Hiller, W; Margraf, J

1998-11-01

The aim of this study was to evaluate whether specific cognitive aspects are present in patients suffering from somatoform disorders. With a sample of 493 patients from a center for behavioral medicine, the authors evaluated a questionnaire assessing typical cognitions concerning body perception, illness behavior, and health. The authors further examined 225 participants, including patients with a somatization syndrome, patients with somatization syndrome and additional hypochondriasis, patients with hypochondriasis, patients with other mental disorders (clinical control group), and nonclinical controls. The results showed that not only patients with hypochondriasis but also patients with somatization syndrome had cognitive concerns and assumptions that were specific for the disorder. These patients had a self-concept of being weak and unable to tolerate stress. A catastrophizing interpretation of minor bodily complaints found in hypochondriacal patients in earlier studies was also found for patients with multiple somatization symptoms.

Cellular Mechanisms of Somatic Stem Cell Aging

PubMed Central

Jung, Yunjoon

2014-01-01

Tissue homeostasis and regenerative capacity rely on rare populations of somatic stem cells endowed with the potential to self-renew and differentiate. During aging, many tissues show a decline in regenerative potential coupled with a loss of stem cell function. Cells including somatic stem cells have evolved a series of checks and balances to sense and repair cellular damage to maximize tissue function. However, during aging the mechanisms that protect normal cell function begin to fail. In this review, we will discuss how common cellular mechanisms that maintain tissue fidelity and organismal lifespan impact somatic stem cell function. We will highlight context-dependent changes and commonalities that define aging, by focusing on three age-sensitive stem cell compartments: blood, neural, and muscle. Understanding the interaction between extrinsic regulators and intrinsic effectors that operate within different stem cell compartments is likely to have important implications for identifying strategies to improve health span and treat age-related degenerative diseases. PMID:24439814

Alexithymia and Somatization in Depressed Patients: The Role of the Type of Somatic Symptom Attribution

PubMed Central

TAYCAN, Okan; ÖZDEMİR, Armağan; ERDOĞAN TAYCAN, Serap

2017-01-01

Introduction This study aimed to establish the association between alexithymia and various factors, mainly somatization, and to determine the predictors of alexithymia in depressed patients. Methods A total of 90 patients with major depressive disorder who met The Diagnostic and Statistical Manual of Mental Disorders-Fourth Edition (DSM-IV) diagnostic criteria were administered the Toronto Alexithymia Scale (TAS), Beck Depression Inventory, Symptom Checklist-90 (SCL-90), Somatosensory Amplification Scale, and Symptom Interpretation Questionnaire. The patients were classified into two groups as alexithymic and non-alexithymic with respect to the TAS cut-off points (≥59=alexithymic). Predictors of alexithymia were tested by multiple linear regression analysis. Results Of all patients, 36 (40%) were in the alexithymic group. The percentage of women, depression severity, level of general psychopathology and distress, and somatic symptom reporting (SCL-90), as well as the tendency to somatosensory amplification and three forms of somatic symptom attributions, were significantly higher in alexithymic patients than in non-alexithymic patients. Furthermore, age, depression severity, somatic symptom reporting, and the tendency to attribute physical symptoms to somatic causes were predictors of alexithymia. Conclusion The results indicated an intimate association between alexithymia and somatization in depressed patients. Therefore, when evaluating depressed patients with alexithymia, their tendency for somatization should be considered, and alexithymic individuals should be assessed with particular attention, considering that somatization can mask the underlying depressive condition. PMID:28680305

Differential relationships of somatic and cognitive anxiety with measures of processing speed in older adults.

PubMed

Schoen, Chelsea B; Holtzer, Roee

2017-09-01

Research suggests a reciprocal relationship between late-life anxiety and cognition, particularly attention and executive functions. Whereas evidence supports a conceptual distinction between cognitive and somatic dimensions of anxiety, their differential relationship with cognitive outcomes has not been examined, particularly on tests of attention/executive functions that rely on processing speed. Study goals were threefold: (a) to describe levels of overall, cognitive, and somatic anxiety in a sample of older adults without dementia, (b) to determine if overall anxiety is associated with performance on select measures of attention/executive functions that rely on processing speed, and (c) to determine if a differential relationship exists between cognitive and somatic anxiety and cognitive performance. Participants were 368 community-dwelling older adults. Results showed that elevated levels of somatic, but not cognitive anxiety were associated with poorer performance across measures. Findings suggest that the nature of anxiety symptoms may have important implications for cognitive performance in older adults.

Cell lineage analysis in human brain using endogenous retroelements

PubMed Central

Evrony, Gilad D.; Lee, Eunjung; Mehta, Bhaven K.; Benjamini, Yuval; Johnson, Robert M.; Cai, Xuyu; Yang, Lixing; Haseley, Psalm; Lehmann, Hillel S.; Park, Peter J.; Walsh, Christopher A.

2015-01-01

Summary Somatic mutations occur during brain development and are increasingly implicated as a cause of neurogenetic disease. However, the patterns in which somatic mutations distribute in the human brain are unknown. We used high-coverage whole-genome sequencing of single neurons from a normal individual to identify spontaneous somatic mutations as clonal marks to track cell lineages in human brain. Somatic mutation analyses in >30 locations throughout the nervous system identified multiple lineages and sub-lineages of cells marked by different LINE-1 (L1) retrotransposition events and subsequent mutation of poly-A microsatellites within L1. One clone contained thousands of cells limited to the left middle frontal gyrus, whereas a second distinct clone contained millions of cells distributed over the entire left hemisphere. These patterns mirror known somatic mutation disorders of brain development, and suggest that focally distributed mutations are also prevalent in normal brains. Single-cell analysis of somatic mutation enables tracing of cell lineage clones in human brain. PMID:25569347

Functional Somatic Symptoms Across Cultures: Perceptual and Health Care Issues.

PubMed

Löwe, Bernd; Gerloff, Christian

2018-06-01

Functional neurological disorders are conceptualized as patterns of neurological symptoms that cannot be attributed to a clear organic etiology. The study by Wilkins et al. in this issue of Psychosomatic Medicine reveals that 8.2% of patients who were initially presented with suspected stroke were later diagnosed with functional disorders, i.e., "functional stroke mimics." However, the percentage of functional stroke mimics varied substantially with patients' nationality, age, and sex. In this editorial comment, we discuss potential reasons for the intercultural variation of the frequency of functional stroke mimics.The current models of symptom perception, in which symptom perception is guided by top-down processes of the central nervous system, are helpful in explaining the intercultural variation of functional symptoms. According to these models, cultural beliefs, previous illnesses, and stressful life situations influence patients' expectations, sensory input, and finally the perception of somatic symptoms. In addition, differences in insurance status, health literacy, and health care experiences are strong predictors of health care use in patients who experience somatic symptoms.This article provides a conceptual model that integrates sociocultural factors with symptom perception and health care use relevant to the different rates of functional somatic symptoms in emergency departments across nationalities. Considering these factors, future attempts to improve care for patients with functional disorders should enhance access to effective treatment for all patient groups, empower patients through education and early participation in the treatment process, and foster interdisciplinary collaboration among specialists from somatic and mental health disciplines.

Somatization among persons with Turkish origin: Results of the pretest of the German National Cohort Study.

PubMed

Morawa, Eva; Dragano, Nico; Jöckel, Karl-Heinz; Moebus, Susanne; Brand, Tilman; Erim, Yesim

2017-05-01

Despite the emerging need to examine mental health of immigrants, there are no investigations designed to analyze representative samples in Germany. The aim of the present study was to explore the severity of somatic symptoms/somatization among a sample of considerable size consisting of persons with Turkish origin. We studied whether somatization was associated with sociodemographic and migration-related characteristics. This examination was part of a pretest for a large national epidemiological cohort study in Germany. We applied the somatization (PHQ-15) and the depression module (PHQ-9) from the Patient Health Questionnaire in a subsample of 335 Turkish immigrants. We analyzed the distribution of the sum score. Differences in degree of somatization in relation to relevant socio-demographic (gender) and migrant-related characteristics (generation of immigration) were tested with analysis of covariance (ANCOVA), controlling for age. A multiple linear regression analysis was also conducted. Women had significantly higher age-adjusted mean scores than men (M=10.4, SD=6.3 vs. M=8.1, SD=6.3; F=10.467, p=0.001), a significant effect of age was also found (F=4.853, p=0.028). First generation immigrants had a higher age-adjusted mean number of symptoms in relation to the second generation immigrants (M=10.0, SD=6.5 vs. M=7.4, SD=7.0; F=6.042, p=0.014), the effect of age was not significant (F=0.466, p=0.495). Multiple regression analysis revealed that lower severity of somatization was associated with lower numbers of diagnosed physical illnesses (β=0.271, p<0.001) and better language proficiency (β=0.197, p=0.003, explained variance: 15.6%). The degree of somatization among Turkish immigrants in Germany is associated with gender and generation of immigration. Copyright © 2017 Elsevier Inc. All rights reserved.

Multiple physical healthcare needs among outpatients with schizophrenia: findings from a health examination study.

PubMed

Eskelinen, Saana; Sailas, Eila; Joutsenniemi, Kaisla; Holi, Matti; Koskela, Tuomas H; Suvisaari, Jaana

2017-08-01

Despite the abundant literature on physical comorbidity, the full range of the concurrent somatic healthcare needs among individuals with schizophrenia has rarely been studied. This observational study aimed to assess the distressing somatic symptoms and needs for physical health interventions in outpatients with schizophrenia, and factors predicting those needs. A structured, comprehensive health examination was carried out, including a visit to a nurse and a general practitioner on 275 outpatients with schizophrenia. The required interventions were classified by type of disease. Logistic regression was used to assess the influence of sociodemographic factors, lifestyle, functional limitations, factors related to psychiatric disorder, and healthcare use on the need for interventions. In total, 44.9% of the patients (mean age 44.9 years) reported somatic symptoms affecting daily life; 87.6% needed specific interventions for a disease or condition, most commonly for cardiovascular, dermatological, dental, ophthalmological, and gastrointestinal conditions, and for altered glucose homeostasis. Smoking and obesity predicted significantly a need of any intervention, but the predictors varied in each disease category. Strikingly, use of general practitioner services during the previous year did not reduce the need for interventions. Health examinations for outpatients with schizophrenia revealed numerous physical healthcare needs. The health examinations for patients with schizophrenia should contain a medical history taking and a physical examination, in addition to basic measurements and laboratory tests. Prevention and treatment of obesity and smoking should be given priority in order to diminish somatic comorbidities in schizophrenia.

Selection and validation of suitable reference genes for miRNA expression normalization by quantitative RT-PCR in citrus somatic embryogenic and adult tissues.

PubMed

Kou, Shu-Jun; Wu, Xiao-Meng; Liu, Zheng; Liu, Yuan-Long; Xu, Qiang; Guo, Wen-Wu

2012-12-01

miRNAs have recently been reported to modulate somatic embryogenesis (SE), a key pathway of plant regeneration in vitro. For expression level detection and subsequent function dissection of miRNAs in certain biological processes, qRT-PCR is one of the most effective and sensitive techniques, for which suitable reference gene selection is a prerequisite. In this study, three miRNAs and eight non-coding RNAs (ncRNA) were selected as reference candidates, and their expression stability was inspected in developing citrus SE tissues cultured at 20, 25, and 30 °C. Stability of the eight non-miRNA ncRNAs was further validated in five adult tissues without temperature treatment. The best single reference gene for SE tissues was snoR14 or snoRD25, while for the adult tissues the best one was U4; although they were not as stable as the optimal multiple references snoR14 + U6 for SE tissues and snoR14 + U5 for adult tissues. For expression normalization of less abundant miRNAs in SE tissues, miR3954 was assessed as a viable reference. Single reference gene snoR14 outperformed multiple references for the overall SE and adult tissues. As one of the pioneer systematic studies on reference gene identification for plant miRNA normalization, this study benefits future exploration on miRNA function in citrus and provides valuable information for similar studies in other higher plants. Three miRNAs and eight non-coding RNAs were tested as reference candidates on developing citrus SE tissues. Best single references snoR14 or snoRD25 and optimal multiple references snoR14 + U6, snoR14 + U5 were identified.

Somatic symptoms beyond those generally associated with a whiplash injury are increased in self-reported chronic whiplash. A population-based cross sectional study: the Hordaland Health Study (HUSK)

PubMed Central

2012-01-01

Background Chronic whiplash leads to considerable patient suffering and substantial societal costs. There are two competing hypothesis on the etiology of chronic whiplash. The traditional organic hypothesis considers chronic whiplash and related symptoms a result of a specific injury. In opposition is the hypothesis that chronic whiplash is a functional somatic syndrome, and related symptoms a result of society-induced expectations and amplification of symptoms. According to both hypotheses, patients reporting chronic whiplash are expected to have more neck pain, headache and symptoms of anxiety and depression than the general population. Increased prevalence of somatic symptoms beyond those directly related to a whiplash neck injury is less investigated. The aim of this study was to test an implication derived from the functional hypothesis: Is the prevalence of somatic symptoms as seen in somatization disorder, beyond symptoms related to a whiplash neck injury, increased in individuals self-reporting chronic whiplash? We further aimed to explore recall bias by comparing the symptom profile displayed by individuals self-reporting chronic whiplash to that among those self-reporting a non-functional injury: fractures of the hand or wrist. We explored symptom load, etiologic origin could not be investigated in this study. Methods Data from the Norwegian population-based “Hordaland Health Study” (HUSK, 1997–99); N = 13,986 was employed. Chronic whiplash was self-reported by 403 individuals and fractures by 1,746. Somatization tendency was measured using a list of 17 somatic symptoms arising from different body parts and organ systems, derived from the research criteria for somatization disorder (ICD-10, F45). Results Chronic whiplash was associated with an increased level of all 17 somatic symptoms investigated (p<0.05). The association was moderately strong (group difference of 0.60 standard deviation), only partly accounted for by confounding. For self-reported fractures symptoms were only slightly elevated. Recent whiplash was more commonly reported than whiplash-injury a long time ago, and the association of interest weakly increased with time since whiplash (r = 0.016, p = 0.032). Conclusions The increased prevalence of somatic symptoms beyond symptoms expected according to the organic injury model for chronic whiplash, challenges the standard injury model for whiplash, and is indicative evidence of chronic whiplash being a functional somatic syndrome. PMID:22935146

The impact of somatic symptoms on the course of major depressive disorder.

PubMed

Bekhuis, Ella; Boschloo, Lynn; Rosmalen, Judith G M; de Boer, Marrit K; Schoevers, Robert A

2016-11-15

Somatic symptoms have been suggested to negatively affect the course of major depressive disorder (MDD). Mechanisms behind this association, however, remain elusive. This study examines the impact of somatic symptoms on MDD prognosis and aims to determine whether this effect can be explained by psychiatric characteristics, somatic diseases, lifestyle factors, and disability. In 463 MDD patients (mean age=44.9 years, 69.8% female) from the Netherlands Study of Depression and Anxiety (NESDA), we examined whether the type and number of somatic symptom clusters predicted the two-year persistence of MDD. Diagnoses of MDD were established with the Composite International Diagnostic Interview (CIDI) and somatic symptom clusters were assessed with the Four-Dimensional Symptom Questionnaire (4DSQ) somatization scale. Psychiatric characteristics, somatic diseases, lifestyle factors, and disability were taken into account as factors potentially underlying the association. The cardiopulmonary, gastrointestinal, and general cluster significantly predicted the two-year persistence of MDD, but only when two or more of these clusters were present (OR=2.32, 95% CI=1.51-3.57, p=<0.001). Although the association was partly explained by MDD severity, the presence of multiple somatic symptom clusters remained a significant predictor after considering all potentially underlying factors (OR=1.69, 95%CI=1.07-2.68, p=0.03). Somatic symptoms are predictors of a worse prognosis of MDD independent of psychiatric characteristics, somatic diseases, lifestyle factors, and disability. These results stress the importance of considering somatic symptoms in the diagnostic and treatment trajectory of patients with MDD. Future research should focus on identifying treatment modalities targeting depressive as well as somatic symptoms. Copyright © 2016 Elsevier B.V. All rights reserved.

Electronic Support Groups: An Open Line of Communication in Contested Illness

PubMed Central

Murphy, Michael; Kontos, Nicholas; Freudenreich, Oliver

2017-01-01

Background Patients with functional somatic syndromes are often difficult to treat. The relationship between doctors and patients can be strained, which limits communication. Instead, patients often communicate with each other over the Internet in electronic support groups. Objective This perspective summarizes studies of patient-to-patient communication over the Internet and uses the concept of contested illness to provide insights into the experiences of patients with functional somatic disorders. Discussion Conflict between a patient and their physician is a key feature of functional somatic syndromes. Physicians and patients do not have a shared understanding or appreciation of the patient’s experiences. Patients with functional somatic syndromes often value their own embodied experience over medical knowledge. At the same time, they remain deeply invested in finding a “good doctor” who believes that the patient is suffering, agrees with their conception of the cause, and assents to the treatment as directed by the patient. Electronic support groups reinforce these beliefs. Conclusion Patients may benefit from a compromising, collaborative approach that is realistic about the limitations of medical knowledge. However, physicians should not engage in unsafe treatment practices. Electronic support groups exist for a wide range of illnesses and the issues that rise to the surface in functional somatic syndromes likely occur to some extent with almost every patient. PMID:27421707

Long interspersed nuclear elements (LINEs) show tissue-specific, mosaic genome and methylation-unrestricted, widespread expression of noncoding RNAs in somatic tissues of the rat

PubMed Central

Singh, Deepak K.; Rath, Pramod C.

2012-01-01

We report strong somatic and germ line expression of LINE RNAs in eight different tissues of rat by using a novel ~2.8 kb genomic PstI-LINE DNA (P1-LINE) isolated from the rat brain. P1-LINE is present in a 93 kb LINE-SINE-cluster in sub-telomeric region of chromosome 12 (12p12) and as multiple truncated copies interspersed in all rat chromosomes. P1-LINEs occur as inverted repeats at multiple genomic loci in tissue-specific and mosaic patterns. P1-LINE RNAs are strongly expressed in brain, liver, lungs, heart, kidney, testes, spleen and thymus into large to small heterogeneous RNAs (~5.0 to 0.2 kb) in tissue-specific and dynamic patterns in individual rats. P1-LINE DNA is strongly methylated at CpG-dinucleotides in most genomic copies in all the tissues and weakly hypomethylated in few copies in some tissues. Small (700–75 nt) P1-LINE RNAs expressed in all tissues may be possible precursors for small regulatory RNAs (PIWI-interacting/piRNAs) bioinformatically derived from P1-LINE. The strong and dynamic expression of LINE RNAs from multiple chromosomal loci and the putative piRNAs in somatic tissues of rat under normal physiological conditions may define functional chromosomal domains marked by LINE RNAs as long noncoding RNAs (lncRNAs) unrestricted by DNA methylation. The tissue-specific, dynamic RNA expression and mosaic genomic distribution of LINEs representing a steady-state genomic flux of retrotransposon RNAs suggest for biological role of LINE RNAs as long ncRNAs and small piRNAs in mammalian tissues independent of their cellular fate for translation, reverse-transcription and retrotransposition. This may provide evolutionary advantages to LINEs and mammalian genomes. PMID:23064113

The visceromotor and somatic afferent nerves of the penis.

PubMed

Diallo, Djibril; Zaitouna, Mazen; Alsaid, Bayan; Quillard, Jeanine; Ba, Nathalie; Allodji, Rodrigue Sètchéou; Benoit, Gérard; Bedretdinova, Dina; Bessede, Thomas

2015-05-01

Innervation of the penis supports erectile and sensory functions. This article aims to study the efferent autonomic (visceromotor) and afferent somatic (sensory) nervous systems of the penis and to investigate how these systems relate to vascular pathways. Penises obtained from five adult cadavers were studied via computer-assisted anatomic dissection (CAAD). The number of autonomic and somatic nerve fibers was compared using the Kruskal-Wallis test. Proximally, penile innervation was mainly somatic in the extra-albugineal sector and mainly autonomic in the intracavernosal sector. Distally, both sectors were almost exclusively supplied by somatic nerve fibers, except the intrapenile vascular anastomoses that accompanied both somatic and autonomic (nitrergic) fibers. From this point, the neural immunolabeling within perivascular nerve fibers was mixed (somatic labeling and autonomic labeling). Accessory afferent, extra-albugineal pathways supplied the outer layers of the penis. There is a major change in the functional type of innervation between the proximal and distal parts of the intracavernosal sector of the penis. In addition to the pelvis and the hilum of the penis, the intrapenile neurovascular routes are the third level where the efferent autonomic (visceromotor) and the afferent somatic (sensory) penile nerve fibers are close. Intrapenile neurovascular pathways define a proximal penile segment, which guarantees erectile rigidity, and a sensory distal segment. © 2015 International Society for Sexual Medicine.

Empirical Testing of an Algorithm for Defining Somatization in Children

PubMed Central

Eisman, Howard D.; Fogel, Joshua; Lazarovich, Regina; Pustilnik, Inna

2007-01-01

Introduction A previous article proposed an algorithm for defining somatization in children by classifying them into three categories: well, medically ill, and somatizer; the authors suggested further empirical validation of the algorithm (Postilnik et al., 2006). We use the Child Behavior Checklist (CBCL) to provide this empirical validation. Method Parents of children seen in pediatric clinics completed the CBCL (n=126). The physicians of these children completed specially-designed questionnaires. The sample comprised of 62 boys and 64 girls (age range 2 to 15 years). Classification categories included: well (n=53), medically ill (n=55), and somatizer (n=18). Analysis of variance (ANOVA) was used for statistical comparisons. Discriminant function analysis was conducted with the CBCL subscales. Results There were significant differences between the classification categories for the somatic complaints (p=<0.001), social problems (p=0.004), thought problems (p=0.01), attention problems (0.006), and internalizing (p=0.003) subscales and also total (p=0.001), and total-t (p=0.001) scales of the CBCL. Discriminant function analysis showed that 78% of somatizers and 66% of well were accurately classified, while only 35% of medically ill were accurately classified. Conclusion The somatization classification algorithm proposed by Postilnik et al. (2006) shows promise for classification of children and adolescents with somatic symptoms. PMID:18421368

Hypochondriasis and somatization.

PubMed

Kellner, R

1987-11-20

Between 60% and 80% of healthy individuals experience somatic symptoms in any one week. About 10% to 20% of a random sample of people worry intermittently about illness. A substantial proportion of patients present physicians with somatic complaints for which no organic cause can be found. Patients who are hypochondriacal do not understand the benign nature of functional somatic symptoms and interpret these as evidence of disease. Hypochondriacal concerns range from common short-lived worries to persistent and distressing fears or convictions of having a disease. Hypochondriasis can be secondary to other psychiatric disorders (eg, melancholia or panic disorder), and hypochondriacal attitudes remit when the primary disorder is successfully treated. Patients with primary hypochondriasis are also anxious or depressed, but the fear of disease, or the false belief of having a disease, persists and is the most important feature of their psychopathology. There are substantial differences among hypochondriacal patients in their personalities and psychopathologies. Psychotherapy as well as psychotropic drugs are effective in the treatment of functional somatic symptoms. There are no adequate controlled studies on the value of psychotherapy in hypochondriasis; the recommended guidelines are based on uncontrolled studies of hypochondriasis and on controlled studies of the psychotherapy in similar disorders. The prognosis of functional somatic symptoms as well as that of hypochondriasis is good in a substantial proportion of patients.

Cancer treatment in childhood and testicular function: the importance of the somatic environment.

PubMed

Stukenborg, Jan-Bernd; Jahnukainen, Kirsi; Hutka, Marsida; Mitchell, Rod T

2018-02-01

Testicular function and future fertility may be affected by cancer treatment during childhood. Whilst survival of the germ (stem) cells is critical for ensuring the potential for fertility in these patients, the somatic cell populations also play a crucial role in providing a suitable environment to support germ cell maintenance and subsequent development. Regulation of the spermatogonial germ-stem cell niche involves many signalling pathways with hormonal influence from the hypothalamo-pituitary-gonadal axis. In this review, we describe the somatic cell populations that comprise the testicular germ-stem cell niche in humans and how they may be affected by cancer treatment during childhood. We also discuss the experimental models that may be utilized to manipulate the somatic environment and report the results of studies that investigate the potential role of somatic cells in the protection of the germ cells in the testis from cancer treatment. © 2018 The authors.

Cancer treatment in childhood and testicular function: the importance of the somatic environment

PubMed Central

Stukenborg, Jan-Bernd; Jahnukainen, Kirsi; Hutka, Marsida

2018-01-01

Testicular function and future fertility may be affected by cancer treatment during childhood. Whilst survival of the germ (stem) cells is critical for ensuring the potential for fertility in these patients, the somatic cell populations also play a crucial role in providing a suitable environment to support germ cell maintenance and subsequent development. Regulation of the spermatogonial germ-stem cell niche involves many signalling pathways with hormonal influence from the hypothalamo-pituitary-gonadal axis. In this review, we describe the somatic cell populations that comprise the testicular germ-stem cell niche in humans and how they may be affected by cancer treatment during childhood. We also discuss the experimental models that may be utilized to manipulate the somatic environment and report the results of studies that investigate the potential role of somatic cells in the protection of the germ cells in the testis from cancer treatment. PMID:29351905

Somatic dysfunction and its association with chronic low back pain, back-specific functioning, and general health: results from the OSTEOPATHIC Trial.

PubMed

Licciardone, John C; Kearns, Cathleen M

2012-07-01

Somatic dysfunction is diagnosed by the presence of any of 4 TART criteria: tissue texture abnormality, asymmetry, restriction of motion, or tenderness. To measure the prevalence of somatic dysfunction in patients with chronic low back pain (LBP) and to study the associations of somatic dysfunction with LBP severity, back-specific functioning, and general health. Cross-sectional study nested within a randomized controlled trial. University-based study in Dallas-Fort Worth, Texas. A total of 455 adult research patients with non-specific chronic LBP. Somatic dysfunction in the lumbar, sacrum/pelvis, and pelvis/innominate regions, including key lesions representing severe somatic dysfunction. A 10-cm visual analog scale (VAS), the Roland-Morris Disability Questionnaire (RMDQ), and the Medical Outcomes Study Short Form-36 Health Survey (SF-36) were used to measure LBP severity, back-specific functioning, and general health, respectively. Severe somatic dysfunction was most prevalent in the lumbar (225 [49%]), sacrum/pelvis (129 [28%]), and pelvis/innominate (48 [11%]) regions. Only 30 patients (7%) had no somatic dysfunction in the lumbar, sacrum/pelvis, or pelvis/innominate regions. There were 4 statistically significant pairwise correlations for severe somatic dysfunction: thoracic (T) 10-12 with ribs; T10-12 with lumbar; lumbar with sacrum/pelvis; and sacrum/pelvis with pelvis/innominate. Having a key lesion in the lumbar region (ρ=0.80) or sacrum/pelvis region (ρ=0.71) was strongly correlated with the overall number of key lesions. There were no consistent demographic or clinical predictors of somatic dysfunction. The presence (vs absence) of severe somatic dysfunction in the lumbar region was associated with greater LBP severity (median VAS score, 4.7 vs 3.8, respectively; P=.003) and greater back-specific disability (median RMDQ score, 6 vs 4, respectively; P=.01). The presence (vs absence) of severe somatic dysfunction in the sacrum/pelvis region was associated with greater back-specific disability (median RMDQ score, 6 vs 5, respectively; P=.02) and poorer general health (median SF-36 score, 62 vs 72, respectively; P=.002). An increasing number of key lesions was associated with back-specific disability (P=.009) and poorer general health (P=.02). The present study demonstrates that somatic dysfunction, particularly in the lumbar and sacrum/pelvis regions, is common in patients with chronic LBP. Forthcoming extensions of the OSTEOPATHIC Trial will assess the efficacy of OMT according to baseline levels of somatic dysfunction.

Effects of fidarestat, an aldose reductase inhibitor, on nerve conduction velocity and bladder function in streptozotocin-treated female rats.

PubMed

Zotova, Elena G; Christ, George J; Zhao, Weixin; Tar, Moses; Kuppam, Srini D; Arezzo, Joseph C

2007-01-01

The effects of fidarestat, an aldose reductase inhibitor (ARI), were assessed on nerve conduction velocity (NCV) in somatic nerves and on multiple measures of bladder function in rats made hyperglycemic with streptozotocin (STZ) and in age-matched controls. Nerve conduction velocity was recorded at baseline and at 10, 20, 30, and 50 days after confirmation of the STZ-induced hyperglycemia in all rats (N=47); bladder function was assessed in a representative subset of rats (N=20) at Day 50. Caudal NCV was markedly slowed by STZ, and this effect was significantly reversed by fidarestat. The initial deficit and treatment-related improvement were especially evident for responses driven by high-frequency repetitive stimulation. Of the 11 parameters of bladder activity assessed, four measures-bladder capacity, micturition volume, micturition frequency, and bladder weight-were significantly different in the control and STZ-treated groups. These deficits were not affected by fidarestat. At Day 50, the induced deficits in bladder function were highly correlated with caudal NCV (r values ranging from 0.70 to 0.96; P values ranging from .02 to <.0001). These results suggested that fidarestat improved the slowing of somatic nerve NCV in hyperglycemic rats, but it was not effective in reversing associated bladder dysfunction, in spite of the highly significant correlation between these two diabetes-induced deficits. Possible explanations for this dissociation are discussed.

Three forms of somatization in primary care: prevalence, co-occurrence, and sociodemographic characteristics.

PubMed

Kirmayer, L J; Robbins, J M

1991-11-01

Three definitions of somatization were operationalized: (a) high levels of functional somatic distress, measured by the Somatic Symptom Index (SSI) of the Diagnostic Interview Schedule; (b) hypochondriasis measured by high scores on a measure of illness worry in the absence of evidence for serious illness; and (c) exclusively somatic clinical presentations among patients with current major depression or anxiety. Of 685 patients attending two family medicine clinics, 26.3% met criteria for one or more forms of somatization. While DSM-III somatization disorder had a prevalence of only 1% in this population, 16.6% of the patients met abridged criteria for subsyndromal somatization disorder (SSI 4,6). Hypochondriacal worry had a prevalence of 7.7% in the clinic sample. Somatized presentations of current major depression or anxiety disorder had a prevalence of 8%. The three forms of somatization were associated with different sociodemographic and illness behavior characteristics. A majority of patients met criteria for only one type of somatization, suggesting that distinct pathogenic processes may be involved in each of the three types.

RNA-binding protein GLD-1/quaking genetically interacts with the mir-35 and the let-7 miRNA pathways in Caenorhabditis elegans

PubMed Central

Akay, Alper; Craig, Ashley; Lehrbach, Nicolas; Larance, Mark; Pourkarimi, Ehsan; Wright, Jane E.; Lamond, Angus; Miska, Eric; Gartner, Anton

2013-01-01

Messenger RNA translation is regulated by RNA-binding proteins and small non-coding RNAs called microRNAs. Even though we know the majority of RNA-binding proteins and microRNAs that regulate messenger RNA expression, evidence of interactions between the two remain elusive. The role of the RNA-binding protein GLD-1 as a translational repressor is well studied during Caenorhabditis elegans germline development and maintenance. Possible functions of GLD-1 during somatic development and the mechanism of how GLD-1 acts as a translational repressor are not known. Its human homologue, quaking (QKI), is essential for embryonic development. Here, we report that the RNA-binding protein GLD-1 in C. elegans affects multiple microRNA pathways and interacts with proteins required for microRNA function. Using genome-wide RNAi screening, we found that nhl-2 and vig-1, two known modulators of miRNA function, genetically interact with GLD-1. gld-1 mutations enhance multiple phenotypes conferred by mir-35 and let-7 family mutants during somatic development. We used stable isotope labelling with amino acids in cell culture to globally analyse the changes in the proteome conferred by let-7 and gld-1 during animal development. We identified the histone mRNA-binding protein CDL-1 to be, in part, responsible for the phenotypes observed in let-7 and gld-1 mutants. The link between GLD-1 and miRNA-mediated gene regulation is further supported by its biochemical interaction with ALG-1, CGH-1 and PAB-1, proteins implicated in miRNA regulation. Overall, we have uncovered genetic and biochemical interactions between GLD-1 and miRNA pathways. PMID:24258276

Symptom Presentation and Symptom Meaning Among Traumatized Cambodian Refugees: Relevance to a Somatically Focused Cognitive-Behavior Therapy

PubMed Central

Hinton, Devon E.; Otto, Michael W.

2009-01-01

Among psychologically distressed Cambodian refugees, somatic complaints are particularly prominent. Cambodians interpret anxiety-related somatic sensations in terms of “Wind” (khyâl), an ethnophysiology that gives rise to multiple catastrophic interpretations; and they have prominent trauma-memory associations to anxiety-related somatic symptoms. In this article, we detail some of the common sensation-related dysphoric networks of Cambodian refugees, focusing on catastrophic cognitions and trauma associations. We argue that delineating symptom-related dysphoric networks is crucial to successfully adapt cognitive-behavioral interventions to treat panic disorder and posttraumatic stress disorder among Cambodian refugees, and that such an approach may be useful for the culturally sensitive adaptation of cognitive-behavior therapy for other traumatized non-Western groups. PMID:19823603

Electronic Support Groups: An Open Line of Communication in Contested Illness.

PubMed

Murphy, Michael; Kontos, Nicholas; Freudenreich, Oliver

Patients with functional somatic syndromes are often difficult to treat. The relationship between doctors and patients can be strained, which limits communication. Instead, patients often communicate with each other over the Internet in electronic support groups. This perspective summarizes studies of patient-to-patient communication over the Internet and uses the concept of contested illness to provide insights into the experiences of patients with functional somatic disorders. Conflict between a patient and their physician is a key feature of functional somatic syndromes. Physicians and patients do not have a shared understanding or appreciation of the patient's experiences. Patients with functional somatic syndromes often value their own embodied experience over medical knowledge. At the same time, they remain deeply invested in finding a "good doctor" who believes that the patient is suffering, agrees with their conception of the cause, and assents to the treatment as directed by the patient. Electronic support groups reinforce these beliefs. Patients may benefit from a compromising, collaborative approach that is realistic about the limitations of medical knowledge. However, physicians should not engage in unsafe treatment practices. Electronic support groups exist for a wide range of illnesses and the issues that rise to the surface in functional somatic syndromes likely occur to some extent with almost every patient. Copyright © 2016 The Academy of Psychosomatic Medicine. Published by Elsevier Inc. All rights reserved.

THE MOLECULAR PATHOLOGY OF MELANOMA: AN INTEGRATED TAXONOMY OF MELANOCYTIC NEOPLASIA

PubMed Central

Bastian, Boris C.

2016-01-01

Melanomas are comprised of multiple biologically distinct categories, which differ in cell of origin, age of onset, clinical and histologic presentation, pattern of metastasis, ethnic distribution, causative role of UV radiation, predisposing germ line alterations, mutational processes, and patterns of somatic mutations. Neoplasms are initiated by gain of function mutations in one of several primary oncogenes, typically leading to benign melanocytic nevi with characteristic histologic features. The progression of nevi is restrained by multiple tumor suppressive mechanisms. Secondary genetic alterations override these barriers and promote intermediate or overtly malignant tumors along distinct progression trajectories. The current knowledge about pathogenesis, clinical, histological and genetic features of primary melanocytic neoplasms is reviewed and integrated into a taxonomic framework. PMID:24460190

Are we Genomic Mosaics? Variations of the Genome of Somatic Cells can Contribute to Diversify our Phenotypes.

PubMed

Astolfi, P A; Salamini, F; Sgaramella, V

2010-09-01

Theoretical and experimental evidences support the hypothesis that the genomes and the epigenomes may be different in the somatic cells of complex organisms. In the genome, the differences range from single base substitutions to chromosome number; in the epigenome, they entail multiple postsynthetic modifications of the chromatin. Somatic genome variations (SGV) may accumulate during development in response both to genetic programs, which may differ from tissue to tissue, and to environmental stimuli, which are often undetected and generally irreproducible. SGV may jeopardize physiological cellular functions, but also create novel coding and regulatory sequences, to be exposed to intraorganismal Darwinian selection. Genomes acknowledged as comparatively poor in genes, such as humans', could thus increase their pristine informational endowment. A better understanding of SGV will contribute to basic issues such as the "nature vs nurture" dualism and the inheritance of acquired characters. On the applied side, they may explain the low yield of cloning via somatic cell nuclear transfer, provide clues to some of the problems associated with transdifferentiation, and interfere with individual DNA analysis. SGV may be unique in the different cells types and in the different developmental stages, and thus explain the several hundred gaps persisting in the human genomes "completed" so far. They may compound the variations associated to our epigenomes and make of each of us an "(epi)genomic" mosaic. An ensuing paradigm is the possibility that a single genome (the ephemeral one assembled at fertilization) has the capacity to generate several different brains in response to different environments.

Borderline Personality in the Medical Setting

PubMed Central

Sansone, Lori A.

2015-01-01

Objective: Individuals with borderline personality disorder in mental health settings tend to present with relationship difficulties, mood instability/dysphoria, and overt self-harm behavior. In contrast, it appears that individuals with borderline personality disorder in medical settings manifest physical symptoms that are medically difficult to substantiate. Through a review of the literature, we examine 2 symptom manifestations among patients with borderline personality in primary care and general medical settings—namely pain sensitivity and multiple somatic complaints. In addition to reviewing the research of others, we also highlight our own investigations into these 2 areas. Data Sources: We conducted a literature search of the PubMed database and a previous version of the PsycINFO search engine (no restrictions). Search terms included borderline personality, borderline personality disorder, personality disorders; chronic pain, pain, pain syndromes; and somatization disorder, Briquet’s syndrome, somatic preoccupation, somatic. Study Selection: Published articles related to borderline personality, pain and somatic symptoms (ie, somatization disorder, somatic preoccupation) were examined. Results: According to our review, the literature indicates higher-than-expected rates of borderline personality disorder among patients in primary care and general medical settings who present with chronic pain conditions and/or somatic preoccupation. Conclusions: Unlike patients with borderline personality disorder in mental health settings, who tend to present with relationship difficulties, mood instability/dysphoria, and overt self-harm behavior, patients with borderline personality disorder in primary care settings tend to present with unsubstantiated chronic pain of various types as well as somatic preoccupation. PMID:26644960

The topography of mutational processes in breast cancer genomes

DOE PAGES

Morganella, Sandro; Alexandrov, Ludmil B.; Glodzik, Dominik; ...

2016-01-01

Somatic mutations in human cancers show unevenness in genomic distribution that correlate with aspects of genome structure and function. These mutations are, however, generated by multiple mutational processes operating through the cellular lineage between the fertilized egg and the cancer cell, each composed of specific DNA damage and repair components and leaving its own characteristic mutational signature on the genome. Using somatic mutation catalogues from 560 breast cancer whole-genome sequences, here we show that each of 12 base substitution, 2 insertion/deletion (indel) and 6 rearrangement mutational signatures present in breast tissue, exhibit distinct relationships with genomic features relating to transcription,more » DNA replication and chromatin organization. This signature-based approach permits visualization of the genomic distribution of mutational processes associated with APOBEC enzymes, mismatch repair deficiency and homologous recombinational repair deficiency, as well as mutational processes of unknown aetiology. Lastly, it highlights mechanistic insights including a putative replication-dependent mechanism of APOBEC-related mutagenesis.« less

The Effectiveness of Somatization in Communicating Distress in Korean and American Cultural Contexts

PubMed Central

Choi, Eunsoo; Chentsova-Dutton, Yulia; Parrott, W. Gerrod

2016-01-01

Previous research has documented that Asians tend to somatize negative experiences to a greater degree than Westerners. It is posited that somatization may be a more functional communication strategy in Korean than American context. We examined the effects of somatization in communications of distress among participants from the US and Korea. We predicted that the communicative benefits of somatic words used in distress narratives would depend on the cultural contexts. In Study 1, we found that Korean participants used more somatic words to communicate distress than US participants. Among Korean participants, but not US participants, use of somatic words predicted perceived effectiveness of the communication and expectations of positive reactions (e.g., empathy) from others. In Study 2, we found that when presented with distress narratives of others, Koreans (but not Americans) showed more sympathy in response to narratives using somatic words than narratives using emotional words. These findings suggest that cultural differences in use of somatization may reflect differential effectiveness of somatization in communicating distress across cultural contexts. PMID:27047414

Mild Social Stress in Mice Produces Opioid-Mediated Analgesia in Visceral but Not Somatic Pain States.

PubMed

Pitcher, Mark H; Gonzalez-Cano, Rafael; Vincent, Kathleen; Lehmann, Michael; Cobos, Enrique J; Coderre, Terence J; Baeyens, José M; Cervero, Fernando

2017-06-01

Visceral pain has a greater emotional component than somatic pain. To determine if the stress-induced analgesic response is differentially expressed in visceral versus somatic pain states, we studied the effects of a mild social stressor in either acute visceral or somatic pain states in mice. We show that the presence of an unfamiliar conspecific mouse (stranger) in an adjacent cubicle of a standard transparent observation box produced elevated plasma corticosterone levels compared with mice tested alone, suggesting that the mere presence of a stranger is stressful. We then observed noxious visceral or somatic stimulation-induced nociceptive behavior in mice tested alone or in mildly stressful conditions (ie, beside an unfamiliar stranger). Compared with mice tested alone, the presence of a stranger produced a dramatic opioid-dependent reduction in pain behavior associated with visceral but not somatic pain. This social stress-induced reduction of visceral pain behavior relied on visual but not auditory/olfactory cues. These findings suggest that visceral pain states may provoke heightened responsiveness to mild stressors, an effect that could interfere with testing outcomes during simultaneous behavioral testing of multiple rodents. In mice, mild social stress due to the presence of an unfamiliar conspecific mouse reduces pain behavior associated with noxious visceral but not somatic stimulation, suggesting that stress responsiveness may be enhanced in visceral pain versus somatic pain states. Published by Elsevier Inc.

Oncodomains: A protein domain-centric framework for analyzing rare variants in tumor samples

PubMed Central

Peterson, Thomas A.; Park, Junyong

2017-01-01

The fight against cancer is hindered by its highly heterogeneous nature. Genome-wide sequencing studies have shown that individual malignancies contain many mutations that range from those commonly found in tumor genomes to rare somatic variants present only in a small fraction of lesions. Such rare somatic variants dominate the landscape of genomic mutations in cancer, yet efforts to correlate somatic mutations found in one or few individuals with functional roles have been largely unsuccessful. Traditional methods for identifying somatic variants that drive cancer are ‘gene-centric’ in that they consider only somatic variants within a particular gene and make no comparison to other similar genes in the same family that may play a similar role in cancer. In this work, we present oncodomain hotspots, a new ‘domain-centric’ method for identifying clusters of somatic mutations across entire gene families using protein domain models. Our analysis confirms that our approach creates a framework for leveraging structural and functional information encapsulated by protein domains into the analysis of somatic variants in cancer, enabling the assessment of even rare somatic variants by comparison to similar genes. Our results reveal a vast landscape of somatic variants that act at the level of domain families altering pathways known to be involved with cancer such as protein phosphorylation, signaling, gene regulation, and cell metabolism. Due to oncodomain hotspots’ unique ability to assess rare variants, we expect our method to become an important tool for the analysis of sequenced tumor genomes, complementing existing methods. PMID:28426665

Electronic screen use and selected somatic symptoms in 10-12 year old children.

PubMed

Taehtinen, Richard E; Sigfusdottir, Inga Dora; Helgason, Asgeir R; Kristjansson, Alfgeir L

2014-10-01

Screen-based media use by children and adolescents has increased in recent years but the consequences of their use are not well understood. The objective of this study was to provide a comprehensive examination of the relationship between screen-based activities and a selection of single and multiple self-reported somatic symptoms in a large sample of 10-12 year old children. We use data from the population-based 2011 Youth in Iceland school survey (N=10,829, response rate: 84.5%, boys: 49.9%) that is conducted triennially in 5th-7th grades in all secondary schools in Iceland. Self-reported measures of common screen-based activities were hypothesized to predict the odds of dizziness, tremors, headaches, stomach aches, and multiple symptoms. In general the reported prevalence of symptoms increased with greater number of hours reported on screen based activity for boys and girls. This held for all individual screen activities as well as the cumulative measure of daily minutes spent on screen-based media and prevalence of one or more somatic symptoms. This study confirms previous findings and puts forth additional information concerning the relationship between the prevalence of electronic screen use and somatic symptoms in 10-12 year old children. Copyright © 2014 Elsevier Inc. All rights reserved.

Genome-wide analysis reveals divergent patterns of gene expression during zygotic and somatic embryo maturation of Theobroma cacao L., the chocolate tree.

PubMed

Maximova, Siela N; Florez, Sergio; Shen, Xiangling; Niemenak, Nicolas; Zhang, Yufan; Curtis, Wayne; Guiltinan, Mark J

2014-07-16

Theobroma cacao L. is a tropical fruit tree, the seeds of which are used to create chocolate. In vitro somatic embryogenesis (SE) of cacao is a propagation system useful for rapid mass-multiplication to accelerate breeding programs and to provide plants directly to farmers. Two major limitations of cacao SE remain: the efficiency of embryo production is highly genotype dependent and the lack of full cotyledon development results in low embryo to plant conversion rates. With the goal to better understand SE development and to improve the efficiency of SE conversion we examined gene expression differences between zygotic and somatic embryos using a whole genome microarray. The expression of 28,752 genes was determined at 4 developmental time points during zygotic embryogenesis (ZE) and 2 time points during cacao somatic embryogenesis (SE). Within the ZE time course, 10,288 differentially expressed genes were enriched for functions related to responses to abiotic and biotic stimulus, metabolic and cellular processes. A comparison ZE and SE expression profiles identified 10,175 differentially expressed genes. Many TF genes, putatively involved in ethylene metabolism and response, were more strongly expressed in SEs as compared to ZEs. Expression levels of genes involved in fatty acid metabolism, flavonoid biosynthesis and seed storage protein genes were also differentially expressed in the two types of embryos. Large numbers of genes were differentially regulated during various stages of both ZE and SE development in cacao. The relatively higher expression of ethylene and flavonoid related genes during SE suggests that the developing tissues may be experiencing high levels of stress during SE maturation caused by the in vitro environment. The expression of genes involved in the synthesis of auxin, polyunsaturated fatty acids and secondary metabolites was higher in SEs relative to ZEs despite lack of lipid and metabolite accumulation. These differences in gene transcript levels associated with critical processes during seed development are consistent with the fact that somatic embryos do not fully develop the large storage cotyledons found in zygotic embryos. These results provide insight towards design of improved protocols for cacao somatic embryogenesis.

Genome-wide analysis reveals divergent patterns of gene expression during zygotic and somatic embryo maturation of Theobroma cacao L., the chocolate tree

PubMed Central

2014-01-01

Background Theobroma cacao L. is a tropical fruit tree, the seeds of which are used to create chocolate. In vitro somatic embryogenesis (SE) of cacao is a propagation system useful for rapid mass-multiplication to accelerate breeding programs and to provide plants directly to farmers. Two major limitations of cacao SE remain: the efficiency of embryo production is highly genotype dependent and the lack of full cotyledon development results in low embryo to plant conversion rates. With the goal to better understand SE development and to improve the efficiency of SE conversion we examined gene expression differences between zygotic and somatic embryos using a whole genome microarray. Results The expression of 28,752 genes was determined at 4 developmental time points during zygotic embryogenesis (ZE) and 2 time points during cacao somatic embryogenesis (SE). Within the ZE time course, 10,288 differentially expressed genes were enriched for functions related to responses to abiotic and biotic stimulus, metabolic and cellular processes. A comparison ZE and SE expression profiles identified 10,175 differentially expressed genes. Many TF genes, putatively involved in ethylene metabolism and response, were more strongly expressed in SEs as compared to ZEs. Expression levels of genes involved in fatty acid metabolism, flavonoid biosynthesis and seed storage protein genes were also differentially expressed in the two types of embryos. Conclusions Large numbers of genes were differentially regulated during various stages of both ZE and SE development in cacao. The relatively higher expression of ethylene and flavonoid related genes during SE suggests that the developing tissues may be experiencing high levels of stress during SE maturation caused by the in vitro environment. The expression of genes involved in the synthesis of auxin, polyunsaturated fatty acids and secondary metabolites was higher in SEs relative to ZEs despite lack of lipid and metabolite accumulation. These differences in gene transcript levels associated with critical processes during seed development are consistent with the fact that somatic embryos do not fully develop the large storage cotyledons found in zygotic embryos. These results provide insight towards design of improved protocols for cacao somatic embryogenesis. PMID:25030026

Trauma-informed schools: Child disaster exposure, community violence and somatic symptoms.

PubMed

Lai, Betty S; Osborne, Melissa C; Lee, NaeHyung; Self-Brown, Shannon; Esnard, Ann-Margaret; Kelley, Mary Lou

2018-06-15

Given the increasing prevalence of natural disasters, trauma-informed school settings should include efficient methods for assessing child health and mental health in post-disaster environments. To develop such methods, factors that contribute to children's vulnerability and key signs of distress reactions after disasters need to be understood. To address these issues, we evaluated pre-disaster community violence exposure as a vulnerability factor for children's post-disaster reactions and somatic symptoms as a key post-disaster outcome. We evaluated 426 children exposed to Hurricane Katrina at two timepoints (3-7 months and 13-17 months post-disaster). Structural equation models evaluated community violence exposure, hurricane exposure, and posttraumatic stress and somatic symptoms. Community violence exposure was associated with increased levels of posttraumatic stress symptoms among disaster-impacted youth, and did not moderate the relationship between disaster exposure and posttraumatic stress symptoms. Posttraumatic stress symptoms were associated with somatic symptoms in the short-term recovery period (3-7 months), but not associated with somatic symptoms during the longer-term recovery period (13-17 months). This study did not include school-level factors, and somatic symptoms were based on parent reports. The study did not include parent functioning information or distinguish between whether somatic symptoms were medical or functional in nature. Post-disaster school-based screeners may need to incorporate questions related to children's past exposure to community violence and their somatic symptoms to provide trauma-informed care for children. Copyright © 2018. Published by Elsevier B.V.

Long-Term Hyperphagia and Caloric Restriction Caused by Low- or High-Density Husbandry Have Differential Effects on Zebrafish Postembryonic Development, Somatic Growth, Fat Accumulation and Reproduction

PubMed Central

Leibold, Sandra; Hammerschmidt, Matthias

2015-01-01

In recent years, the zebrafish (Danio rerio) has emerged as an alternative vertebrate model for energy homeostasis and metabolic diseases, including obesity and anorexia. It has been shown that diet-induced obesity (DIO) in zebrafish shares multiple pathophysiological features with obesity in mammals. However, a systematic and comprehensive analysis of the different pathways of energy expenditure in obese and starved fish had been missing thus far. Here, we carry out long-term ad libitum feeding (hyperphagia) and caloric restriction studies induced by low- or high-density husbandry, respectively, to investigate the impact of caloric intake on the timing of scale formation, a crucial step of postembryonic development and metamorphosis, and on somatic growth, body weight, fat storage and female reproduction. We show that all of them are positively affected by increased caloric intake, that middle-aged fish develop severe DIO, and that the body mass index (BMI) displays a strict linear correlation with whole-body triglyceride levels in adult zebrafish. Interestingly, juvenile fish are largely resistant to DIO, while BMI and triglyceride values drop in aged fish, pointing to aging-associated anorexic effects. Histological analyses further indicate that increased fat storage in white adipose tissue involves both hyperplasia and hypertrophy of adipocytes. Furthermore, in ovaries, caloric intake primarily affects the rate of oocyte growth, rather than total oocyte numbers. Finally, comparing the different pathways of energy expenditure with each other, we demonstrate that they are differentially affected by caloric restriction / high-density husbandry. In juvenile fish, scale formation is prioritized over somatic growth, while in sexually mature adults, female reproduction is prioritized over somatic growth, and somatic growth over fat storage. Our data will serve as a template for future functional studies to dissect the neuroendocrine regulators of energy homeostasis mediating differential energy allocation. PMID:25799180

Long-term hyperphagia and caloric restriction caused by low- or high-density husbandry have differential effects on zebrafish postembryonic development, somatic growth, fat accumulation and reproduction.

PubMed

Leibold, Sandra; Hammerschmidt, Matthias

2015-01-01

In recent years, the zebrafish (Danio rerio) has emerged as an alternative vertebrate model for energy homeostasis and metabolic diseases, including obesity and anorexia. It has been shown that diet-induced obesity (DIO) in zebrafish shares multiple pathophysiological features with obesity in mammals. However, a systematic and comprehensive analysis of the different pathways of energy expenditure in obese and starved fish had been missing thus far. Here, we carry out long-term ad libitum feeding (hyperphagia) and caloric restriction studies induced by low- or high-density husbandry, respectively, to investigate the impact of caloric intake on the timing of scale formation, a crucial step of postembryonic development and metamorphosis, and on somatic growth, body weight, fat storage and female reproduction. We show that all of them are positively affected by increased caloric intake, that middle-aged fish develop severe DIO, and that the body mass index (BMI) displays a strict linear correlation with whole-body triglyceride levels in adult zebrafish. Interestingly, juvenile fish are largely resistant to DIO, while BMI and triglyceride values drop in aged fish, pointing to aging-associated anorexic effects. Histological analyses further indicate that increased fat storage in white adipose tissue involves both hyperplasia and hypertrophy of adipocytes. Furthermore, in ovaries, caloric intake primarily affects the rate of oocyte growth, rather than total oocyte numbers. Finally, comparing the different pathways of energy expenditure with each other, we demonstrate that they are differentially affected by caloric restriction / high-density husbandry. In juvenile fish, scale formation is prioritized over somatic growth, while in sexually mature adults, female reproduction is prioritized over somatic growth, and somatic growth over fat storage. Our data will serve as a template for future functional studies to dissect the neuroendocrine regulators of energy homeostasis mediating differential energy allocation.

Somatic symptoms: an important index in predicting the outcome of depression at six-month and two-year follow-up points among outpatients with major depressive disorder.

PubMed

Hung, Ching-I; Liu, Chia-Yih; Wang, Shuu-Jiun; Juang, Yeong-Yuh; Yang, Ching-Hui

2010-09-01

Few studies have simultaneously compared the ability of depression, anxiety, and somatic symptoms to predict the outcome of major depressive disorder (MDD). This study aimed to compare the MDD outcome predictive ability of depression, anxiety, and somatic severity at 6-month and 2-year follow-ups. One-hundred and thirty-five outpatients (men/women=34/101) with MDD were enrolled. Depression and anxiety were evaluated by the Hamilton Depression Rating Scale, Hospital Anxiety and Depression Scale, and depression subscale of the Depression and Somatic Symptoms Scale (DSSS). Somatic severity was evaluated by the somatic subscale of the DSSS. Subjects undergoing pharmacotherapy in the follow-up month were categorized into the treatment group; the others were categorized into the no-treatment group. Multiple linear regressions were used to identify the scales most powerful in predicting MDD outcome. Among the 135 subjects, 119 and 106 completed the 6-month and 2-year follow-ups, respectively. Somatic severity at baseline was correlated with the outcomes of the three scales at the two follow-ups. After controlling for demographic variables, somatic severity independently predicted most outcomes of the three scales at the two follow-ups in the no-treatment group and the cost of pharmacotherapy and DSSS score at the 6-month follow-up in the treatment group. Division of the subjects into treatment and no-treatment groups was not based on randomization and bias might have been introduced. Somatic severity was the most powerful index in predicting MDD outcome. Psychometric scales with appropriate somatic symptom items may be more accurate in predicting MDD outcome. 2010 Elsevier B.V. All rights reserved.

Dimensional analysis of depressive, anxious and somatic symptoms presented by primary care patients and their relationship with ICD-11 PHC proposed diagnoses.

PubMed

Ziebold, Carolina; Goldberg, David P; Reed, Geoffrey M; Minhas, Fareed; Razzaque, Bushra; Fortes, Sandra; Robles, Rebeca; Lam, Tai Pong; Bobes, Julio; Iglesias, Celso; Cogo-Moreira, Hugo; García, José Ángel; Mari, Jair J

2018-06-04

A study conducted as part of the development of the Eleventh International Classification of Mental Disorders for Primary Health Care (ICD-11 PHC) provided an opportunity to test the relationships among depressive, anxious and somatic symptoms in PHC. Primary care physicians participating in the ICD-11 PHC field studies in five countries selected patients who presented with somatic symptoms not explained by known physical pathology by applying a 29-item screening on somatic complaints that were under study for bodily stress disorder. Patients were interviewed using the Clinical Interview Schedule-Revised and assessed using two five-item scales that measure depressive and anxious symptoms. Structural models of anxious-depressive symptoms and somatic complaints were tested using a bi-factor approach. A total of 797 patients completed the study procedures. Two bi-factor models fit the data well: Model 1 had all symptoms loaded on a general factor, along with one of three specific depression, anxiety and somatic factors [x2 (627) = 741.016, p < 0.0011, RMSEA = 0.015, CFI = 0.911, TLI = 0.9]. Model 2 had a general factor and two specific anxious depression and somatic factors [x2 (627) = 663.065, p = 0.1543, RMSEA = 0.008, CFI = 0.954, TLI = 0.948]. These data along with those of previous studies suggest that depressive, anxious and somatic symptoms are largely different presentations of a common latent phenomenon. This study provides support for the ICD-11 PHC conceptualization of mood disturbance, especially anxious depression, as central among patients who present multiple somatic symptoms.

Oral health-related quality of life and somatization in the elderly.

PubMed

Hassel, Alexander J; Rolko, Claudia; Leisen, Joachim; Schmitter, Marc; Rexroth, Walter; Leckel, Michael

2007-03-01

Somatization disorders are frequent in the elderly, and previous studies have revealed that psychological factors affect the outcome of measurement of oral health-related quality of life (OHRQoL). The objective of this study was, therefore, to investigate the correlation between OHRQoL and somatization. One-hundred and twenty-five participants aged 60 years or older (mean age 76.6 years; 40 males) from a primary geriatric medical hospital participated in this cross-sectional study. OHRQoL was assessed by using the Oral Health Impact Profile (OHIP), somatization by using the somatization subscale of the Symptom Check List (SCL-90-R). To obtain dental data we performed a clinical dental examination. In bivariate analyses the most consistent correlation with somatization was found for overall OHIP sum score and the subscales physical pain and functional limitation (r > 0.4). Participants with high somatization scores had high OHIP sum scores. In multivariate analysis somatization led to additional explanation of the variance of the OHIP sum score and of all OHIP subscales. There is consistent correlation between OHRQoL and somatization. When evaluating OHRQoL in the elderly (using the OHIP) further evaluation of somatization should be considered for thorough interpretation of the results.

What is the role of "nonorganic somatic components" in functional capacity evaluations in patients with chronic nonspecific low back pain undergoing fitness for work evaluation?

PubMed

Oesch, Peter; Meyer, Kathrin; Jansen, Beatrice; Mowinckel, Petter; Bachmann, Stefan; Hagen, Kare Birger

2012-02-15

Analytical cross-sectional study. To assess the association of "nonorganic somatic components" together with physical and other psychosocial factors on functional capacity evaluation (FCE) in patients with chronic nonspecific low back pain (NSLBP) undergoing fitness-for-work evaluation. Functional capacity evaluation is increasingly used for physical fitness-for-work evaluation in patients with chronic NSLBP, but results seem to be influenced by physical as well as psychosocial factors. The influence of nonorganic somatic components together with physical and other psychosocial factors on FCE performance has not yet been investigated. One hundred twenty-six patients with chronic NSLBP referred for physical fitness-for-work evaluation were included. The 4 FCE tests were lifting from floor to waist, forward bend standing, grip strength, and 6-minute walking. Nonorganic somatic components were assessed with the 8 nonorganic somatic signs as defined by Waddell and were adjusted for age, sex, days off work, salary in the previous occupation, pain intensity, fear avoidance belief, and perceived functional ability in multivariate regression analyses. Between 42% and 58% of the variation in the FCE tests was explained in the final multivariate regression models. Nonorganic somatic components were consistent independent predictors for all tests. Their influence was most important on forward bend standing and walking distance, and less on grip strength and lifting performance. The physical factors of age and/or sex were strongly associated with grip strength and lifting, less with walking distance, and not at all with forward bend standing. The influence of at least 1 other psychosocial factor was observed in all FCE tests, having the highest proportion in the 6-minute walking test. Nonorganic somatic components seem to be consistent independent predictors in FCE testing and should be considered for interpretation of test results.

Explaining sex differences in lifespan in terms of optimal energy allocation in the baboon.

PubMed

King, Annette M; Kirkwood, Thomas B L; Shanley, Daryl P

2017-10-01

We provide a quantitative test of the hypothesis that sex role specialization may account for sex differences in lifespan in baboons if such specialization causes the dependency of fitness upon longevity, and consequently the optimal resolution to an energetic trade-off between somatic maintenance and other physiological functions, to differ between males and females. We present a model in which females provide all offspring care and males compete for access to reproductive females and in which the partitioning of available energy between the competing fitness-enhancing functions of growth, maintenance, and reproduction is modeled as a dynamic behavioral game, with the optimal decision for each individual depending upon his/her state and the behavior of other members of the population. Our model replicates the sexual dimorphism in body size and sex differences in longevity and reproductive scheduling seen in natural populations of baboons. We show that this outcome is generally robust to perturbations in model parameters, an important finding given that the same behavior is seen across multiple populations and species in the wild. This supports the idea that sex differences in longevity result from differences in the value of somatic maintenance relative to other fitness-enhancing functions in keeping with the disposable soma theory. © 2017 The Author(s). Evolution © 2017 The Society for the Study of Evolution.

Suicidal function of DNA methylation in age-related genome disintegration.

PubMed

Mazin, Alexander L

2009-10-01

This article is dedicated to the 60th anniversary of 5-methylcytosine discovery in DNA. Cytosine methylation can affect genetic and epigenetic processes, works as a part of the genome-defense system and has mutagenic activity; however, the biological functions of this enzymatic modification are not well understood. This review will put forward the hypothesis that the host-defense role of DNA methylation in silencing and mutational destroying of retroviruses and other intragenomic parasites was extended during evolution to most host genes that have to be inactivated in differentiated somatic cells, where it acquired a new function in age-related self-destruction of the genome. The proposed model considers DNA methylation as the generator of 5mC>T transitions that induce 40-70% of all spontaneous somatic mutations of the multiple classes at CpG and CpNpG sites and flanking nucleotides in the p53, FIX, hprt, gpt human genes and some transgenes. The accumulation of 5mC-dependent mutations explains: global changes in the structure of the vertebrate genome throughout evolution; the loss of most 5mC from the DNA of various species over their lifespan and the Hayflick limit of normal cells; the polymorphism of methylation sites, including asymmetric mCpNpN sites; cyclical changes of methylation and demethylation in genes. The suicidal function of methylation may be a special genetic mechanism for increasing DNA damage and the programmed genome disintegration responsible for cell apoptosis and organism aging and death.

Annual Research Review: Functional Somatic Symptoms and Associated Anxiety and Depression--Developmental Psychopathology in Pediatric Practice

ERIC Educational Resources Information Center

Campo, John V.

2012-01-01

Background: Medically unexplained physical symptoms, commonly referred to as functional somatic symptoms (FSS), are common in pediatric medical settings and associated with suffering, impairment, and medical help seeking. The association of pediatric FSS with anxiety and depressive symptoms and disorders across the life span is reviewed.Method:…

Truncation of LEAFY COTYLEDON1 Protein Is Required for Asexual Reproduction in Kalanchoë daigremontiana1[OPEN

PubMed Central

Garcês, Helena M.P.; Koenig, Daniel; Townsley, Brad T.; Kim, Minsung; Sinha, Neelima R.

2014-01-01

Kalanchoë daigremontiana reproduces asexually by generating numerous plantlets on its leaf margins. The formation of plantlets requires the somatic initiation of organogenic and embryogenic developmental programs in the leaves. However, unlike normal embryogenesis in seeds, leaf somatic embryogenesis bypasses seed dormancy to form viable plantlets. In Arabidopsis (Arabidopsis thaliana), seed dormancy and embryogenesis are initiated by the transcription factor LEAFY COTYLEDON1 (LEC1). The K. daigremontiana ortholog of LEC1 is expressed during leaf somatic embryo development. However, KdLEC1 encodes for a LEC1-type protein that has a unique B domain, with 11 unique amino acids and a premature stop codon. Moreover, the truncated KdLEC1 protein is not functional in Arabidopsis. Here, we show that K. daigremontiana transgenic plants expressing a functional, chimeric KdLEC1 gene under the control of Arabidopsis LEC1 promoter caused several developmental defects to leaf somatic embryos, including seed dormancy characteristics. The dormant plantlets also behaved as typical dormant seeds. Transgenic plantlets accumulated oil bodies and responded to the abscisic acid biosynthesis inhibitor fluridone, which broke somatic-embryo dormancy and promoted their normal development. Our results indicate that having a mutated form of LEC1 gene in K. daigremontiana is essential to bypass dormancy in the leaf embryos and generate viable plantlets, suggesting that the loss of a functional LEC1 promotes viviparous leaf somatic embryos and thus enhances vegetative propagation in K. daigremontiana. Mutations resulting in truncated LEC1 proteins may have been of a selective advantage in creating somatic propagules, because such mutations occurred independently in several Kalanchoë species, which form plantlets constitutively. PMID:24664206

Truncation of LEAFY COTYLEDON1 protein is required for asexual reproduction in Kalanchoë daigremontiana.

PubMed

Garcês, Helena M P; Koenig, Daniel; Townsley, Brad T; Kim, Minsung; Sinha, Neelima R

2014-05-01

Kalanchoë daigremontiana reproduces asexually by generating numerous plantlets on its leaf margins. The formation of plantlets requires the somatic initiation of organogenic and embryogenic developmental programs in the leaves. However, unlike normal embryogenesis in seeds, leaf somatic embryogenesis bypasses seed dormancy to form viable plantlets. In Arabidopsis (Arabidopsis thaliana), seed dormancy and embryogenesis are initiated by the transcription factor LEAFY COTYLEDON1 (LEC1). The K. daigremontiana ortholog of LEC1 is expressed during leaf somatic embryo development. However, KdLEC1 encodes for a LEC1-type protein that has a unique B domain, with 11 unique amino acids and a premature stop codon. Moreover, the truncated KdLEC1 protein is not functional in Arabidopsis. Here, we show that K. daigremontiana transgenic plants expressing a functional, chimeric KdLEC1 gene under the control of Arabidopsis LEC1 promoter caused several developmental defects to leaf somatic embryos, including seed dormancy characteristics. The dormant plantlets also behaved as typical dormant seeds. Transgenic plantlets accumulated oil bodies and responded to the abscisic acid biosynthesis inhibitor fluridone, which broke somatic-embryo dormancy and promoted their normal development. Our results indicate that having a mutated form of LEC1 gene in K. daigremontiana is essential to bypass dormancy in the leaf embryos and generate viable plantlets, suggesting that the loss of a functional LEC1 promotes viviparous leaf somatic embryos and thus enhances vegetative propagation in K. daigremontiana. Mutations resulting in truncated LEC1 proteins may have been of a selective advantage in creating somatic propagules, because such mutations occurred independently in several Kalanchoë species, which form plantlets constitutively.

Retinoic acid signaling is dispensable for somatic development and function in the mammalian ovary.

PubMed

Minkina, Anna; Lindeman, Robin E; Gearhart, Micah D; Chassot, Anne-Amandine; Chaboissier, Marie-Christine; Ghyselinck, Norbert B; Bardwell, Vivian J; Zarkower, David

2017-04-15

Retinoic acid (RA) is a potent inducer of cell differentiation and plays an essential role in sex-specific germ cell development in the mammalian gonad. RA is essential for male gametogenesis and hence fertility. However, RA can also disrupt sexual cell fate in somatic cells of the testis, promoting transdifferentiation of male Sertoli cells to female granulosa-like cells when the male sexual regulator Dmrt1 is absent. The feminizing ability of RA in the Dmrt1 mutant somatic testis suggests that RA might normally play a role in somatic cell differentiation or cell fate maintenance in the ovary. To test for this possibility we disrupted RA signaling in somatic cells of the early fetal ovary using three genetic strategies and one pharmaceutical approach. We found that deleting all three RA receptors (RARs) in the XX somatic gonad at the time of sex determination did not significantly affect ovarian differentiation, follicle development, or female fertility. Transcriptome analysis of adult triple mutant ovaries revealed remarkably little effect on gene expression in the absence of somatic RAR function. Likewise, deletion of three RA synthesis enzymes (Aldh1a1-3) at the time of sex determination did not masculinize the ovary. A dominant-negative RAR transgene altered granulosa cell proliferation, likely due to interference with a non-RA signaling pathway, but did not prevent granulosa cell specification and oogenesis or abolish fertility. Finally, culture of fetal XX gonads with an RAR antagonist blocked germ cell meiotic initiation but did not disrupt sex-biased gene expression. We conclude that RA signaling, although crucial in the ovary for meiotic initiation, is not required for granulosa cell specification, differentiation, or reproductive function. Copyright © 2017 Elsevier Inc. All rights reserved.

E2F1 somatic mutation within miRNA target site impairs gene regulation in colorectal cancer.

PubMed

Lopes-Ramos, Camila M; Barros, Bruna P; Koyama, Fernanda C; Carpinetti, Paola A; Pezuk, Julia; Doimo, Nayara T S; Habr-Gama, Angelita; Perez, Rodrigo O; Parmigiani, Raphael B

2017-01-01

Genetic studies have largely concentrated on the impact of somatic mutations found in coding regions, and have neglected mutations outside of these. However, 3' untranslated regions (3' UTR) mutations can also disrupt or create miRNA target sites, and trigger oncogene activation or tumor suppressor inactivation. We used next-generation sequencing to widely screen for genetic alterations within predicted miRNA target sites of oncogenes associated with colorectal cancer, and evaluated the functional impact of a new somatic mutation. Target sequencing of 47 genes was performed for 29 primary colorectal tumor samples. For 71 independent samples, Sanger methodology was used to screen for E2F1 mutations in miRNA predicted target sites, and the functional impact of these mutations was evaluated by luciferase reporter assays. We identified germline and somatic alterations in E2F1. Of the 100 samples evaluated, 3 had germline alterations at the MIR205-5p target site, while one had a somatic mutation at MIR136-5p target site. E2F1 gene expression was similar between normal and tumor tissues bearing the germline alteration; however, expression was increased 4-fold in tumor tissue that harbored a somatic mutation compared to that in normal tissue. Luciferase reporter assays revealed both germline and somatic alterations increased E2F1 activity relative to wild-type E2F1. We demonstrated that somatic mutation within E2F1:MIR136-5p target site impairs miRNA-mediated regulation and leads to increased gene activity. We conclude that somatic mutations that disrupt miRNA target sites have the potential to impact gene regulation, highlighting an important mechanism of oncogene activation.

The BABY BOOM Transcription Factor Activates the LEC1-ABI3-FUS3-LEC2 Network to Induce Somatic Embryogenesis1[OPEN

PubMed Central

Weemen, Mieke

2017-01-01

Somatic embryogenesis is an example of induced cellular totipotency, where embryos develop from vegetative cells rather than from gamete fusion. Somatic embryogenesis can be induced in vitro by exposing explants to growth regulators and/or stress treatments. The BABY BOOM (BBM) and LEAFY COTYLEDON1 (LEC1) and LEC2 transcription factors are key regulators of plant cell totipotency, as ectopic overexpression of either transcription factor induces somatic embryo formation from Arabidopsis (Arabidopsis thaliana) seedlings without exogenous growth regulators or stress treatments. Although LEC and BBM proteins regulate the same developmental process, it is not known whether they function in the same molecular pathway. We show that BBM transcriptionally regulates LEC1 and LEC2, as well as the two other LAFL genes, FUSCA3 (FUS3) and ABSCISIC ACID INSENSITIVE3 (ABI3). LEC2 and ABI3 quantitatively regulate BBM-mediated somatic embryogenesis, while FUS3 and LEC1 are essential for this process. BBM-mediated somatic embryogenesis is dose and context dependent, and the context-dependent phenotypes are associated with differential LAFL expression. We also uncover functional redundancy for somatic embryogenesis among other Arabidopsis BBM-like proteins and show that one of these proteins, PLETHORA2, also regulates LAFL gene expression. Our data place BBM upstream of other major regulators of plant embryo identity and totipotency. PMID:28830937

Parent-child Communication-centered Rehabilitative Approach for Pediatric Functional Somatic Symptoms.

PubMed

Gerner, Maya; Barak, Sharon; Landa, Jana; Eisenstein, Etzyona

2016-01-01

Functional somatic symptoms (FSS) are a type of somatization phenomenon. Integrative rehabilitation approaches are the preferred treatment for pediatric FSS. Parental roles in the treatment process have not been established. to present 1) a parent-focused treatment (PFT) for pediatric FSS and 2) the approach's preliminary results. The sample included 50 children with physical disabilities due to FSS. All children received PFT including physical and psychological therapy. A detailed description of the program's course and guiding principles is provided. FSS extinction and age-appropriate functioning. Post-program, 84% of participants did not exhibit FSS and 94% returned to age-appropriate functioning. At one-year follow-up, only 5% of participants experienced symptom recurrence. No associations were found between pre-admission symptoms and intervention duration. PFT is beneficial in treating pediatric FSS. Therefore, intensive parental involvement in rehabilitation may be cardinal.

Chemical compound-based direct reprogramming for future clinical applications

PubMed Central

Takeda, Yukimasa; Harada, Yoshinori; Yoshikawa, Toshikazu; Dai, Ping

2018-01-01

Recent studies have revealed that a combination of chemical compounds enables direct reprogramming from one somatic cell type into another without the use of transgenes by regulating cellular signaling pathways and epigenetic modifications. The generation of induced pluripotent stem (iPS) cells generally requires virus vector-mediated expression of multiple transcription factors, which might disrupt genomic integrity and proper cell functions. The direct reprogramming is a promising alternative to rapidly prepare different cell types by bypassing the pluripotent state. Because the strategy also depends on forced expression of exogenous lineage-specific transcription factors, the direct reprogramming in a chemical compound-based manner is an ideal approach to further reduce the risk for tumorigenesis. So far, a number of reported research efforts have revealed that combinations of chemical compounds and cell-type specific medium transdifferentiate somatic cells into desired cell types including neuronal cells, glial cells, neural stem cells, brown adipocytes, cardiomyocytes, somatic progenitor cells, and pluripotent stem cells. These desired cells rapidly converted from patient-derived autologous fibroblasts can be applied for their own transplantation therapy to avoid immune rejection. However, complete chemical compound-induced conversions remain challenging particularly in adult human-derived fibroblasts compared with mouse embryonic fibroblasts (MEFs). This review summarizes up-to-date progress in each specific cell type and discusses prospects for future clinical application toward cell transplantation therapy. PMID:29739872

Three-dimensional analysis of somatic mitochondrial dynamics in fission-deficient injured motor neurons using FIB/SEM.

PubMed

Tamada, Hiromi; Kiryu-Seo, Sumiko; Hosokawa, Hiroki; Ohta, Keisuke; Ishihara, Naotada; Nomura, Masatoshi; Mihara, Katsuyoshi; Nakamura, Kei-Ichiro; Kiyama, Hiroshi

2017-08-01

Mitochondria undergo morphological changes through fusion and fission for their quality control, which are vital for neuronal function. In this study, we examined three-dimensional morphologies of mitochondria in motor neurons under normal, nerve injured, and nerve injured plus fission-impaired conditions using the focused ion beam/scanning electron microscopy (FIB/SEM), because the FIB/SEM technology is a powerful tool to demonstrate both 3D images of whole organelle and the intra-organellar structure simultaneously. Crossing of dynamin-related protein 1 (Drp1) gene-floxed mice with neuronal injury-specific Cre driver mice, Atf3:BAC Tg mice, allowed for Drp1 ablation specifically in injured neurons. FIB/SEM analysis demonstrated that somatic mitochondrial morphologies in motor neurons were not altered before or after nerve injury. However, the fission impairment resulted in prominent somatic mitochondrial enlargement, which initially induced complex morphologies with round regions and long tubular processes, subsequently causing a decrease in the number of processes and further enlargement of the round regions, which eventually resulted in big spheroidal mitochondria without processes. The abnormal mitochondria exhibited several degradative morphologies: local or total cristae collapse, vacuolization, and mitophagy. These suggest that mitochondrial fission is crucial for maintaining mitochondrial integrity in injured motor neurons, and multiple forms of mitochondria degradation may accelerate neuronal degradation. © 2017 Wiley Periodicals, Inc.

[Somatic symptoms in those hospitalized for dizziness or vertigo].

PubMed

Goto, Fumiyuki; Tsutumi, Tomoko; Arai, Motohiro; Ogawa, Kaoru

2010-09-01

Anxiety and depression greatly affect the prognosis of and burden on subjects seen for dizziness or vertigo, who usually report multiple somatic symptoms. We studied the prevalence of these symptoms in 145 subjects hospitalized for dizziness or vertigo and taking part in 4-day group vestibular rehabilitation. Questionnaires given to determine the prevalence of somatic symptoms assessed headache, insomnia, diarrhea, constipation, stomachache, chest pain, palpitations, dyspnea, general fatigue, and stress. Quantitation used aerical rating scale (NRS). Anxiety and depression were assessed using the hospital anxiety and depression scale (HADS). Disability due to dizziness was assessed using the dizziness handicap inventory (DHI). We conducted correlational analysis between dizziness and somatic symptoms. The top four average NRS scores for somatic symptoms were dizziness at 3.5 +/- 2.8, general fatigue at 2.8 +/- 2.6, insomnia at 2.4 +/- 2.6, and headache at 1.8 +/- 2.3. These symptoms resembled those reported for subjects with anxiety and depression. The correlation between headache and dizziness NRS scores was R = 0.48 (P < 0.0001). The total HADS score was 13.9 +/- 8.1 points (anxiety 7.2 +/- 4.3, depression 6.7 +/- 4.3). The average DHI score was 36.3 +/- 24.1 points. These results indicate that those with dizziness reported several somatic symptoms related to anxiety and depression attributable to dizziness. This underscores the need to treat these somatic symptoms when treating subjects seen chiefly dizziness or vertigo.

Do somatic complaints predict subsequent symptoms of depression?

PubMed

Terre, Lisa; Poston, Walker S Carlos; Foreyt, John; St Jeor, Sachiko T

2003-01-01

Evidence suggests substantial comorbidity between symptoms of somatization and depression in clinical as well as nonclinical populations. However, as most existing research has been retrospective or cross-sectional in design, very little is known about the specific nature of this relationship. In particular, it is unclear whether somatic complaints may heighten the risk for the subsequent development of depressive symptoms. We report findings on the link between symptoms of somatization (assessed using the SCL-90-R) and depression 5 years later (assessed using the CES-D) in an initially healthy cohort of community adults, based on prospective data from the RENO Diet-Heart Study. Gender-stratified multiple regression analyses revealed that baseline CES-D scores were the best predictors of subsequent depressive symptoms for men and women. Baseline scores on the SCL-90-R somatization subscale significantly predicted subsequent self-reported symptoms of depressed mood 5 years later, but only in women. However, somatic complaints were a somewhat less powerful predictor than income and age. Our findings suggest that somatic complaints may represent one, but not necessarily the most important, risk factor for the subsequent development of depressive symptoms in women in nonclinical populations. The results also highlight the importance of including social variables in studies on women's depression as well as conducting additional research to further examine predictors of depressive symptoms in men. Copyright 2003 S. Karger AG, Basel

Fibroblast growth factor signaling is required for early somatic gonad development in zebrafish.

PubMed

Leerberg, Dena M; Sano, Kaori; Draper, Bruce W

2017-09-01

The vertebrate ovary and testis develop from a sexually indifferent gonad. During early development of the organism, primordial germ cells (the gamete lineage) and somatic gonad cells coalesce and begin to undergo growth and morphogenesis to form this bipotential gonad. Although this aspect of development is requisite for a fertile adult, little is known about the genetic regulation of early gonadogenesis in any vertebrate. Here, we provide evidence that fibroblast growth factor (Fgf) signaling is required for the early growth phase of a vertebrate bipotential gonad. Based on mutational analysis in zebrafish, we show that the Fgf ligand 24 (Fgf24) is required for proliferation, differentiation, and morphogenesis of the early somatic gonad, and as a result, most fgf24 mutants are sterile as adults. Additionally, we describe the ultrastructural elements of the early zebrafish gonad and show that distinct somatic cell populations can be identified soon after the gonad forms. Specifically, we show that fgf24 is expressed in an epithelial population of early somatic gonad cells that surrounds an inner population of mesenchymal somatic gonad cells that are in direct contact with the germ cells, and that fgf24 is required for stratification of the somatic tissue. Furthermore, based on gene expression analysis, we find that differentiation of the inner mesenchymal somatic gonad cells into functional cell types in the larval and early juvenile-stage gonad is dependent on Fgf24 signaling. Finally, we argue that the role of Fgf24 in zebrafish is functionally analogous to the role of tetrapod FGF9 in early gonad development.

A review of somatoform disorders in DSM-IV and somatic symptom disorders in proposed DSM-V.

PubMed

Ghanizadeh, Ahmad; Firoozabadi, Ali

2012-12-01

Psychiatric care providers should be trained to use current changes in the somatoform disorders criteria. New diagnostic criteria for Somatic Symptom disorders in the proposed DSM-V is discussed and compared with its older counterpart in DSM-IV. A new category called Somatic Syndrome Disorders is suggested. It includes new subcategories such as "Complex Somatic Symptom Disorder" (CSSD) and "Simple Somatic Symptom Disorder" (SSSD). Some of the subcategories of DSM-IV derived disorders are included in CSSD. While there are some changes in diagnostic criteria, there are concerns and limitations about the new classification needed to be more discussed before implementation. Functional somatic disturbance, the counterpart of converion disorder in DSM-IV, can be highly dependet on the developmental level of children. However, the role of developmental level needs to be considered.

Impact of pretreatment with antidepressants on the efficacy of duloxetine in terms of mood symptoms and functioning: an analysis of 15 pooled major depressive disorder studies.

PubMed

Barros, Bruno R; Schacht, Alexander; Happich, Michael; Televantou, Foula; Berggren, Lovisa; Walker, Daniel J; Dueñas, Hector J

2014-01-01

This post hoc analysis aimed to determine whether patients with major depressive disorder (MDD) in duloxetine trials who were antidepressant naive or who were previously exposed to antidepressants exhibited differences in efficacy and functioning. Data were pooled from 15 double-blind, placebo- and/or active-controlled duloxetine trials of adult patients with MDD conducted by Eli Lilly and Company. The individual studies took place between March 2000 and November 2009. Data were analyzed using 4 pretreatment subgroups: first-episode never treated, multiple-episode never treated, treated previously only with selective serotonin reuptake inhibitors (SSRIs), and previously treated with antidepressants other than just SSRIs. Measures included the 17-item Hamilton Depression Rating Scale (HDRS-17) total and somatic symptom subscale scores, Montgomery-Asberg Depression Rating Scale (MADRS) total score, and Sheehan Disability Scale total score. Response rates (50% and 30%) were based on the HDRS-17 total score and remission rates on either the HDRS-17 or MADRS total score. Response and remission rates were significantly greater (P < .05 in 11 of 12 comparisons) for duloxetine versus placebo in the 4 subgroups. A trend of greater response and remission occurred for first-episode versus multiple-episode patients; both groups were generally higher than the antidepressant-treated groups. Mean changes in efficacy measures were mostly significantly greater (P < .05 in 13 of 16 comparisons) for duloxetine versus placebo within each pretreatment subgroup, with some (P < .05 in 2 of 24 comparisons) significant interaction effects between subgroups on HDRS-17 total and somatic symptoms scores. Duloxetine was generally superior to placebo on response and remission rates and in mean change on efficacy measures. Response and remission rates were numerically greater for first-episode versus multiple-episode and drug-treated patients. Mean change differences on efficacy measures among the 4 subgroups were inconsistent. Duloxetine showed a similar therapeutic effect independent of episode frequency and antidepressant pretreatment.

Health related quality of life in patients with congestive heart failure: comparison with other chronic diseases and relation to functional variables

PubMed Central

Juenger, J; Schellberg, D; Kraemer, S; Haunstetter, A; Zugck, C; Herzog, W; Haass, M

2002-01-01

Objective: To assess health related quality of life of patients with congestive heart failure; to compare their quality of life with the previously characterised general population and in those with other chronic diseases; and to correlate the different aspects of quality of life with relevant somatic variables. Setting: University hospital. Patients and design: A German version of the generic quality of life measure (SF-36) containing eight dimensions was administered to 205 patients with congestive heart failure and systolic dysfunction. Cardiopulmonary evaluation included assessment of New York Heart Association (NYHA) functional class, left ventricular ejection fraction, peak oxygen uptake, and the distance covered during a standardised six minute walk test. Results: Quality of life significantly decreased with NYHA functional class (linear trend: p < 0.0001). In NYHA class III, the scores of five of the eight quality of life domains were reduced to around one third of those in the general population. The pattern of reduction was different in patients with chronic hepatitis C and major depression, and similar in patients on chronic haemodialysis. Multiple regression analysis showed that only the NYHA functional class was consistently and closely associated with all quality of life scales. The six minute walk test and peak oxygen uptake added to the explanation of the variance in only one of the eight quality of life domains (physical functioning). Left ventricular ejection fraction, duration of disease, and age showed no clear association with quality of life. Conclusions: In congestive heart failure, quality of life decreases as NYHA functional class worsens. Though NYHA functional class was the most dominant predictor among the somatic variables studied, the major determinants of reduced quality of life remain unknown. PMID:11847161

Health related quality of life in patients with congestive heart failure: comparison with other chronic diseases and relation to functional variables.

PubMed

Juenger, J; Schellberg, D; Kraemer, S; Haunstetter, A; Zugck, C; Herzog, W; Haass, M

2002-03-01

To assess health related quality of life of patients with congestive heart failure; to compare their quality of life with the previously characterised general population and in those with other chronic diseases; and to correlate the different aspects of quality of life with relevant somatic variables. University hospital. A German version of the generic quality of life measure (SF-36) containing eight dimensions was administered to 205 patients with congestive heart failure and systolic dysfunction. Cardiopulmonary evaluation included assessment of New York Heart Association (NYHA) functional class, left ventricular ejection fraction, peak oxygen uptake, and the distance covered during a standardised six minute walk test. Quality of life significantly decreased with NYHA functional class (linear trend: p < 0.0001). In NYHA class III, the scores of five of the eight quality of life domains were reduced to around one third of those in the general population. The pattern of reduction was different in patients with chronic hepatitis C and major depression, and similar in patients on chronic haemodialysis. Multiple regression analysis showed that only the NYHA functional class was consistently and closely associated with all quality of life scales. The six minute walk test and peak oxygen uptake added to the explanation of the variance in only one of the eight quality of life domains (physical functioning). Left ventricular ejection fraction, duration of disease, and age showed no clear association with quality of life. In congestive heart failure, quality of life decreases as NYHA functional class worsens. Though NYHA functional class was the most dominant predictor among the somatic variables studied, the major determinants of reduced quality of life remain unknown.

Integrated analysis of germline and somatic variants in ovarian cancer.

PubMed

Kanchi, Krishna L; Johnson, Kimberly J; Lu, Charles; McLellan, Michael D; Leiserson, Mark D M; Wendl, Michael C; Zhang, Qunyuan; Koboldt, Daniel C; Xie, Mingchao; Kandoth, Cyriac; McMichael, Joshua F; Wyczalkowski, Matthew A; Larson, David E; Schmidt, Heather K; Miller, Christopher A; Fulton, Robert S; Spellman, Paul T; Mardis, Elaine R; Druley, Todd E; Graubert, Timothy A; Goodfellow, Paul J; Raphael, Benjamin J; Wilson, Richard K; Ding, Li

2014-01-01

We report the first large-scale exome-wide analysis of the combined germline-somatic landscape in ovarian cancer. Here we analyse germline and somatic alterations in 429 ovarian carcinoma cases and 557 controls. We identify 3,635 high confidence, rare truncation and 22,953 missense variants with predicted functional impact. We find germline truncation variants and large deletions across Fanconi pathway genes in 20% of cases. Enrichment of rare truncations is shown in BRCA1, BRCA2 and PALB2. In addition, we observe germline truncation variants in genes not previously associated with ovarian cancer susceptibility (NF1, MAP3K4, CDKN2B and MLL3). Evidence for loss of heterozygosity was found in 100 and 76% of cases with germline BRCA1 and BRCA2 truncations, respectively. Germline-somatic interaction analysis combined with extensive bioinformatics annotation identifies 222 candidate functional germline truncation and missense variants, including two pathogenic BRCA1 and 1 TP53 deleterious variants. Finally, integrated analyses of germline and somatic variants identify significantly altered pathways, including the Fanconi, MAPK and MLL pathways.

ExScalibur: A High-Performance Cloud-Enabled Suite for Whole Exome Germline and Somatic Mutation Identification.

PubMed

Bao, Riyue; Hernandez, Kyle; Huang, Lei; Kang, Wenjun; Bartom, Elizabeth; Onel, Kenan; Volchenboum, Samuel; Andrade, Jorge

2015-01-01

Whole exome sequencing has facilitated the discovery of causal genetic variants associated with human diseases at deep coverage and low cost. In particular, the detection of somatic mutations from tumor/normal pairs has provided insights into the cancer genome. Although there is an abundance of publicly-available software for the detection of germline and somatic variants, concordance is generally limited among variant callers and alignment algorithms. Successful integration of variants detected by multiple methods requires in-depth knowledge of the software, access to high-performance computing resources, and advanced programming techniques. We present ExScalibur, a set of fully automated, highly scalable and modulated pipelines for whole exome data analysis. The suite integrates multiple alignment and variant calling algorithms for the accurate detection of germline and somatic mutations with close to 99% sensitivity and specificity. ExScalibur implements streamlined execution of analytical modules, real-time monitoring of pipeline progress, robust handling of errors and intuitive documentation that allows for increased reproducibility and sharing of results and workflows. It runs on local computers, high-performance computing clusters and cloud environments. In addition, we provide a data analysis report utility to facilitate visualization of the results that offers interactive exploration of quality control files, read alignment and variant calls, assisting downstream customization of potential disease-causing mutations. ExScalibur is open-source and is also available as a public image on Amazon cloud.

Clinical Presentation of Acute Gastroenteritis in Children With Functional Abdominal Pain Disorders.

PubMed

Saps, Miguel; Mintjens, Stijn; Pusatcioglu, Cenk K; Cohen, Daniel M; Sternberg, Petra

2017-08-01

Visceral hypersensitivity and abnormal coping are common in children with functional abdominal pain disorders (FAPDs). Thus, it would be expected that children with visceral hypersensitivity would report more pain if their gut is acutely inflamed. The aim of the study was to compare clinical symptoms and somatization of children with and without FAPDs at time of an episode of acute gastroenteritis. Seventy children with acute gastroenteritis and their parents completed the Rome III Diagnostic Questionnaire for Pediatric Functional GI Disorders and the Children's Somatization Inventory. Twenty-one percent of children were diagnosed with an FAPD. Children with FAPDs showed significantly more nongastrointestinal somatic symptoms than children without FAPDs. There were no significant differences in abdominal pain, nausea, vomiting, or school absenteeism between both groups at time of consultation.

Does contextual unemployment matter for health status across the life course? A longitudinal multilevel study exploring the link between neighbourhood unemployment and functional somatic symptoms.

PubMed

Brydsten, Anna; Gustafsson, Per E; Hammarström, Anne; San Sebastian, Miguel

2017-01-01

This study examines whether neighbourhood unemployment is related to functional somatic symptoms, independently of the individual employment, across the life course and at four specific life course periods (age 16, 21, 30 and 42). Self-reported questioner data was used from a 26-year prospective Swedish cohort (n=1010) with complementary neighbourhood register data. A longitudinal and a set of age-specific cross-sectional hierarchal linear regressions was carried out. The results suggest that living in a neighbourhood with high unemployment has implications for residents' level of functional somatic symptoms, regardless of their own unemployment across time, particularly at age 30. Copyright © 2016 The Authors. Published by Elsevier Ltd.. All rights reserved.

Multiple independent second-site mutations in two siblings with somatic mosaicism for Wiskott-Aldrich syndrome.

PubMed

Boztug, K; Germeshausen, M; Avedillo Díez, I; Gulacsy, V; Diestelhorst, J; Ballmaier, M; Welte, K; Maródi, L; Chernyshova, Li; Klein, C

2008-07-01

Wiskott-Aldrich syndrome (WAS) is an X-linked primary immunodeficiency disorder associated with microthrombocytopenia, eczema, autoimmunity and predisposition to malignant lymphoma. Although rare, few cases of somatic mosaicism have been published in WAS patients to date. We here report on two Ukrainian siblings who were referred to us at the age of 3 and 4 years, respectively. Both patients suffered from severe WAS caused by a nonsense mutation in exon 1 of the WAS gene. In both siblings, flow cytometric analysis revealed the presence of Wiskott-Aldrich syndrome protein (WASp)-positive and WASp-negative cell populations among T and B lymphocytes as well as natural killer (NK) cells. In contrast to previously described cases of revertant mosaicism in WAS, molecular analyses in both children showed that the WASp-positive T cells, B cells, and NK cells carried multiple different second-site mutations, resulting in different missense mutations. To our knowledge, this is the first report describing somatic mosaicism in WAS patients caused by several independent second-site mutations in the WAS gene.

New Insight Into the Biology, Risk Stratification, and Targeted Treatment of Myelodysplastic Syndromes.

PubMed

Haider, Mintallah; Duncavage, Eric J; Afaneh, Khalid F; Bejar, Rafael; List, Alan F

2017-01-01

In myelodysplastic syndromes (MDS), somatic mutations occur in five major categories: RNA splicing, DNA methylation, activated cell signaling, myeloid transcription factors, and chromatin modifiers. Although many MDS cases harbor more than one somatic mutation, in general, there is mutual exclusivity of mutated genes within a class. In addition to the prognostic significance of individual somatic mutations, more somatic mutations in MDS have been associated with poor prognosis. Prognostic assessment remains a critical component of the personalization of care for patient with MDS because treatment is highly risk adapted. Multiple methods for risk stratification are available with the revised International Prognostic Scoring System (IPSS-R), currently considered the gold standard. Increasing access to myeloid gene panels and greater evidence for the diagnostic and predictive value of somatic mutations will soon make sequencing part of the standard evaluation of patients with MDS. In the absence of formal guidelines for their prognostic use, well-validated mutations can still refine estimates of risk made with the IPSS-R. Not only are somatic gene mutations advantageous in understanding the biology of MDS and prognosis, they also offer potential as biomarkers and targets for the treatment of patients with MDS. Examples include deletion 5q, spliceosome complex gene mutations, and TP53 mutations.

Resolving rates of mutation in the brain using single-neuron genomics

PubMed Central

Evrony, Gilad D; Lee, Eunjung; Park, Peter J; Walsh, Christopher A

2016-01-01

Whether somatic mutations contribute functional diversity to brain cells is a long-standing question. Single-neuron genomics enables direct measurement of somatic mutation rates in human brain and promises to answer this question. A recent study (Upton et al., 2015) reported high rates of somatic LINE-1 element (L1) retrotransposition in the hippocampus and cerebral cortex that would have major implications for normal brain function, and suggested that these events preferentially impact genes important for neuronal function. We identify aspects of the single-cell sequencing approach, bioinformatic analysis, and validation methods that led to thousands of artifacts being interpreted as somatic mutation events. Our reanalysis supports a mutation frequency of approximately 0.2 events per cell, which is about fifty-fold lower than reported, confirming that L1 elements mobilize in some human neurons but indicating that L1 mosaicism is not ubiquitous. Through consideration of the challenges identified, we provide a foundation and framework for designing single-cell genomics studies. DOI: http://dx.doi.org/10.7554/eLife.12966.001 PMID:26901440

Sexual Victimization and Somatic Complaints in Pregnancy: Examination of Depression as a Mediator.

PubMed

Littleton, Heather

2015-01-01

Research suggests that women with histories of sexual victimization are more likely to experience somatic complaints in pregnancy. However, prior studies have been limited by homogenous samples, have primarily only examined the relationship of childhood sexual abuse (CSA) to somatic complaints, and have not examined potential mechanisms explaining this association. Thus, the current study examined the relationship between lifetime sexual victimization history and somatic complaints in pregnancy in an ethnically diverse sample of pregnant women. Additionally, depressive symptoms were examined as a mediator of the sexual victimization-somatic complaints relationship. Women were recruited from the waiting room of a university-affiliated obstetrics-gynecology clinic to complete a study of psychological health and negative sexual experiences. The 407 currently pregnant participants who completed measures of their sexual victimization history, depressive symptoms, and somatic complaints were primarily African American (53.6%), low to middle income (75.4%), and reported an unplanned pregnancy (72%). A total of 27.7% of women had a history of CSA and/or adolescent/adult sexual assault. Mediation analyses using bootstrapping supported depression as a significant mediator of the relationship between sexual victimization and somatic complaints, with a medium-sized effect (κ(2) = .09). Having a history of sexual victimization is associated with risk for poor mental and physical health during pregnancy. There are likely multiple mechanisms explaining the association between sexual victimization and somatic complaints in pregnancy, which should be investigated in future research. Copyright © 2015 Jacobs Institute of Women's Health. Published by Elsevier Inc. All rights reserved.

The impact of the duration of an untreated episode on improvement of depression and somatic symptoms

PubMed Central

Hung, Ching-I; Yu, Nan-Wen; Liu, Chia-Yih; Wu, Kuan-Yi; Yang, Ching-Hui

2015-01-01

Purpose The aim of this study was to investigate the impact of the duration of an untreated episode (DUE) on the improvement of depression and somatic symptoms among patients with major depressive disorder (MDD), after the patients had received 4 weeks of pharmacotherapy. Methods In this open-label study, there were 155 participants with MDD who were treated daily with 75 mg of venlafaxine for 4 weeks. DUE was defined as the interval between the onset of the index major depressive episode and the start of pharmacotherapy. The Depression and Somatic Symptoms Scale (DSSS), composed of the depression subscale (DS) and the somatic subscale (SS), was used. The SS included the pain subscale (PS) and the nonpain somatic subscale (NPSS). Multiple linear regressions were used to test the impacts of DUE on the improvement percentages (IPs) of depression and somatic symptoms. Results Eighty-five subjects completed the 4-week treatment. The IPs of the DS, SS, and NPSS were significantly negatively correlated with DUE. A shorter DUE was related to higher IPs. DUE was an independent factor, predicting the IPs of the DS, SS, and NPSS. DUE <1 month was the most powerful time-point to predict the IPs of the DS, SS, and NPSS. However, DUE was unable to predict the IP of the PS at all time-points. Conclusion A shorter DUE might be one of the factors related to greater improvement of depression and somatic symptoms. DUE should be considered as an important factor when investigating the prognosis of depression and somatic symptoms. PMID:26346571

The impact of the duration of an untreated episode on improvement of depression and somatic symptoms.

PubMed

Hung, Ching-I; Yu, Nan-Wen; Liu, Chia-Yih; Wu, Kuan-Yi; Yang, Ching-Hui

2015-01-01

The aim of this study was to investigate the impact of the duration of an untreated episode (DUE) on the improvement of depression and somatic symptoms among patients with major depressive disorder (MDD), after the patients had received 4 weeks of pharmacotherapy. In this open-label study, there were 155 participants with MDD who were treated daily with 75 mg of venlafaxine for 4 weeks. DUE was defined as the interval between the onset of the index major depressive episode and the start of pharmacotherapy. The Depression and Somatic Symptoms Scale (DSSS), composed of the depression subscale (DS) and the somatic subscale (SS), was used. The SS included the pain subscale (PS) and the nonpain somatic subscale (NPSS). Multiple linear regressions were used to test the impacts of DUE on the improvement percentages (IPs) of depression and somatic symptoms. Eighty-five subjects completed the 4-week treatment. The IPs of the DS, SS, and NPSS were significantly negatively correlated with DUE. A shorter DUE was related to higher IPs. DUE was an independent factor, predicting the IPs of the DS, SS, and NPSS. DUE <1 month was the most powerful time-point to predict the IPs of the DS, SS, and NPSS. However, DUE was unable to predict the IP of the PS at all time-points. A shorter DUE might be one of the factors related to greater improvement of depression and somatic symptoms. DUE should be considered as an important factor when investigating the prognosis of depression and somatic symptoms.

The evolution of multiple isotypic IgM heavy chain genes in the shark.

PubMed

Lee, Victor; Huang, Jing Li; Lui, Ming Fai; Malecek, Karolina; Ohta, Yuko; Mooers, Arne; Hsu, Ellen

2008-06-01

The IgM H chain gene organization of cartilaginous fishes consists of 15-200 miniloci, each with a few gene segments (V(H)-D1-D2-J(H)) and one C gene. This is a gene arrangement ancestral to the complex IgH locus that exists in all other vertebrate classes. To understand the molecular evolution of this system, we studied the nurse shark, which has relatively fewer loci, and characterized the IgH isotypes for organization, functionality, and the somatic diversification mechanisms that act upon them. Gene numbers differ slightly between individuals ( approximately 15), but five active IgM subclasses are always present. Each gene undergoes rearrangement that is strictly confined within the minilocus; in B cells there is no interaction between adjacent loci located > or =120 kb apart. Without combinatorial events, the shark IgM H chain repertoire is based on junctional diversity and, subsequently, somatic hypermutation. We suggest that the significant contribution by junctional diversification reflects the selected novelty introduced by RAG in the early vertebrate ancestor, whereas combinatorial diversity coevolved with the complex translocon organization. Moreover, unlike other cartilaginous fishes, there are no germline-joined VDJ at any nurse shark mu locus, and we suggest that such genes, when functional, are species-specific and may have specialized roles. With an entire complement of IgM genes available for the first time, phylogenetic analyses were performed to examine how the multiple Ig loci evolved. We found that all domains changed at comparable rates, but V(H) appears to be under strong positive selection for increased amino acid sequence diversity, and surprisingly, so does Cmicro2.

Analyses of spontaneous pink mutant events in the stamen hairs of Tradescantia clone BNL 4430 cultivated in a nutrient solution circulating growth chamber.

PubMed

Ichikawa, S; Wushur, S

2000-12-20

In order to obtain more fundamental data on Tradescantia clone BNL 4430, one of the most suitable testers for environmental mutagens, the occurrences of spontaneous somatic pink mutations in the stamen hairs were scored for 52 weeks from 12 December 1998 to 10 December 1999, cultivating the young inflorescence-bearing shoots with roots in a nutrient solution circulating (NSC) growth chamber. The environmental conditions in the chamber were 22.0+/-0.5 degrees C during the 16h day with the light intensity of 7.5klx from white fluorescent tubes, and 20.0+/-0.5 degrees C at night. During the scoring period, 697,443 stamen hairs with an average cell number of 25.36 were observed and 2642 pink mutant events (PMEs) were detected. The overall spontaneous mutation frequency was 1.56+/-0.03 PMEs per 10(4) hair-cell divisions, and the frequency was significantly lower in May, July and August and significantly higher in November and December. By analyzing the sectoring patterns of 1856 PMEs (70.25% of PMEs detected), the most of 172 cases of multiple (two to five) pink sectors observed in the same hairs (scored as 232 PMEs for calculating mutation frequency) were found to be the results of events involving somatic recombinations occurred in single cells or cell lineages, rather than those of two or more independent somatic mutations occurred in different cells. This finding clearly shows the significance of somatic recombinations in producing such multiple sectors (382 sectors in total) which occupied 19.0% of the 2006 pink sectors in total analyzed. Somatic recombinations were considered to be playing a significant role also in producing single PMEs in the stamen hairs.

Anxiety and Depression Are Risk Factors Rather than Consequences of Functional Somatic Symptoms in a General Population of Adolescents: The Trails Study

ERIC Educational Resources Information Center

Janssens, Karin A. M.; Rosmalen, Judith G. M.; Ormel, Johan; van Oort, Floor V. A.; Oldehinkel, Albertine J.

2010-01-01

Background: It is well known that functional somatic symptoms (FSS) are associated with anxiety and depression. However, evidence is lacking about how they are related to FSS. The aim of this study was to clarify these relationships and examine whether anxiety and depression are distinctly related to FSS. We hypothesized that anxiety contributes…

Unique Features of Fish Immune Repertoires: Particularities of Adaptive Immunity Within the Largest Group of Vertebrates

PubMed Central

Sunyer, Oriol J.

2016-01-01

Fishes (i.e., teleost fishes) are the largest group of vertebrates. Although their immune system is based on the fundamental receptors, pathways, and cell types found in all groups of vertebrates, fishes show a diversity of particular features that challenge some classical concepts of immunology. In this chapter, we discuss the particularities of fish immune repertoires from a comparative perspective. We examine how allelic exclusion can be achieved when multiple Ig loci are present, how isotypic diversity and functional specificity impact clonal complexity, how loss of the MHC class II molecules affects the cooperation between T and B cells, and how deep sequencing technologies bring new insights about somatic hypermutation in the absence of germinal centers. The unique coexistence of two distinct B-cell lineages respectively specialized in systemic and mucosal responses is also discussed. Finally, we try to show that the diverse adaptations of immune repertoires in teleosts can help in understanding how somatic adaptive mechanisms of immunity evolved in parallel in different lineages across vertebrates. PMID:26537384

Stress and Arousal Symptoms in Individuals and Groups - Persian Gulf War Symptoms as a Paradigm.

DTIC Science & Technology

1999-09-01

Symptoms." Psychological Medicine, 1991:21: 1029-1045, quotation from pp. 1040-1041. 18Kellner R., "Functional Somatic Symptoms and Hypochondriasis ...quasi-specific for future patterns of research into the somatic and other consequences of combat stress, deployment stress and other stresses of...psychiatric folklore. Much of the earlier research into the somatic consequences of stress and indeed into medicine as a whole, was correlational in

The modulation of visceral functions by somatic afferent activity.

PubMed

Sato, A; Schmidt, R F

1987-01-01

We began by briefly reviewing the historical background of neurophysiological studies of the somato-autonomic reflexes and then discussed recent studies on somatic-visceral reflexes in combination with autonomic efferent nerve activity and effector organ responses. Most of the studies that have advanced our knowledge in this area have been carried out on anesthetized animals, thus eliminating emotional factors. We would like to emphasize again that the functions of many, or perhaps all visceral organs can be modulated by somato-sympathetic or somato-parasympathetic reflex activity induced by a appropriate somatic afferent stimulation in anesthetized animals. As mentioned previously, some autonomic nervous outflow, e.g. the adrenal sympathetic nerve activity, is involved in the control of hormonal secretion. John F. Fulton wrote in his famous textbook "Physiology of the Nervous System" (1949) that the posterior pituitary neurosecretion system (i.e. for oxytocin and vasopressin) could be considered a part of the parasympathetic nervous system. In the study of body homeostasis and environmental adaptation it would seem very important to further analyze the contribution of somatic afferent input to the autonomic nervous and hormonal regulation of visceral organ activity. Also, some immunological functions have been found to be influenced by autonomic nerves or hormones (e.g. adrenal cortical hormone and catecholamines). Finally, we must take into account, as we have briefly discussed, that visceral functions can be modulated by somatic afferent input via various degrees of integration of autonomic nerves, hormones, and immunological processes. We trust that such research will be expanded to higher species of mammals, and that ultimately this knowledge of somato-visceral reflexes obtained in the physiological laboratory will become clinically useful in influencing visceral functions.

Expression of M6 and M7 lysin in Mytilus edulis is not restricted to sperm, but occurs also in oocytes and somatic tissue of males and females.

PubMed

Heß, Anne-Katrin; Bartel, Manuela; Roth, Karina; Messerschmidt, Katrin; Heilmann, Katja; Kenchington, Ellen; Micheel, Burkhard; Stuckas, Heiko

2012-08-01

Sperm proteins of marine sessile invertebrates have been extensively studied to understand the molecular basis of reproductive isolation. Apart from molecules such as bindin of sea urchins or lysin of abalone species, the acrosomal protein M7 lysin of Mytilus edulis has been analyzed. M7 lysin was found to be under positive selection, but mechanisms driving the evolution of this protein are not fully understood. To explore functional aspects, this study investigated the protein expression pattern of M7 and M6 lysin in gametes and somatic tissue of male and female M. edulis. The study employs a previously published monoclonal antibody (G26-AG8) to investigate M6 and M7 lysin protein expression, and explores expression of both genes. It is shown that these proteins and their encoding genes are expressed in gametes and somatic tissue of both sexes. This is in contrast to sea urchin bindin and abalone lysin, in which gene expression is strictly limited to males. Although future studies need to clarify the functional importance of both acrosomal proteins in male and female somatic tissue, new insights into the evolution of sperm proteins in marine sessile invertebrates are possible. This is because proteins with male-specific expression (bindin, lysin) might evolve differently than proteins with expression in both sexes (M6/M7 lysin), and the putative function of both proteins in females opens the possibility that the evolution of M6/M7 lysin is under sexual antagonistic selection, for example, mutations beneficial to the acrosomal function that are less beneficial the function in somatic tissue of females. Copyright © 2012 Wiley Periodicals, Inc.

Interoceptive Dysfunction: Toward An Integrated Framework for Understanding Somatic and Affective Disturbance in Depression

PubMed Central

Harshaw, Christopher

2014-01-01

Depression is characterized by disturbed sleep and eating, a variety of other, nonspecific somatic symptoms, and significant somatic comorbidities. Why there is such close association between cognitive and somatic dysfunction in depression is nonetheless poorly understood. An explosion of research in the area of interoception—the perception and interpretation of bodily signals—over the last decade nonetheless holds promise for illuminating what have until now been obscure links between the social, cognitive-affective, and somatic features of depression. This paper reviews rapidly accumulating evidence that both somatic signaling and interoception are frequently altered in depression. This includes comparative studies showing vagus-mediated effects on depression-like behaviors in rodent models as well as studies in humans indicating both dysfunction in the neural substrates for interoception (e.g., vagus, insula, anterior cingulate cortex) and reduced sensitivity to bodily stimuli in depression. An integrative framework for organizing and interpreting this evidence is put forward which incorporates (a) multiple potential pathways to interoceptive dysfunction; (b) interaction with individual, gender, and cultural differences in interoception; and (c) a developmental psychobiological systems perspective, emphasizing likely differential susceptibility to somatic and interoceptive dysfunction across the lifespan. Combined with current theory and evidence, it is suggested that core symptoms of depression (e.g., anhedonia, social deficits) may be products of disturbed interoceptive-exteroceptive integration. More research is nonetheless needed to fully elucidate the relationship between mind, body, and social context in depression. PMID:25365763

Depression, Anxiety and Somatization in Women with War Missing Family Members

PubMed Central

Baraković, Devla; Avdibegović, Esmina; Sinanović, Osman

2013-01-01

Introduction: During the war circumstances, women and children are exposed to multiple traumatic experiences, one of which is an violent disappearance of a family member. Goal: The aim of this research was to establish the presence of symptoms of depression, anxiety and somatization in women in Bosnia and Herzegovina who have sought their war missing family members for 15 to 18 years. Subjects and Methods: The research was based on a sample of 120 women with war missing family member and 40 women without a war missing family member as a control group. For assessment of depression, anxiety and symptoms of somatization the self-rating Beck Depression Inventory (BDI), Hamilton Anxiety Rating Scale (HAM-A), Somatic Symptoms Index (SSI) questionnaire and a general questionnaire on the sociodemographic data and data on war missing family members were used. Results: A significantly higher intensity of symptoms of depression (p<0.001), anxiety (p<0.001) and somatization (p = 0.013) was present in women with, in comparison to women without a missing family member. In comparison of the kinship with the missing family members, statistically significantly higher intensity of symptoms of depression, anxiety and somatization was in women with a missing child (p<0.001) in comparison to other missing family members. Conclusion: A prolonged period of seeking, waiting and uncertainty of what happened in the war with the missing family member presents for those women a prolonged suffering manifested through depression, anxiety and symptoms of somatization. PMID:24167436

Efficient regeneration of sorghum, Sorghum bicolor (L.) Moench, from shoot-tip explant.

PubMed

Syamala, D; Devi, Prathibha

2003-12-01

Novel protocols for production of multiple shoot-tip clumps and somatic embryos of Sorghum bicolor (L.) Moench were developed with long-term goal of crop improvement through genetic transformation. Multiple shoot-tip clumps were developed in vitro from shoot-tip explant of one-week old seedling, cultured on MS medium containing only BA (0.5, 1 or 2 mg/l) or both BA (1 or 2 mg/l) and 2,4-D (0.5 mg/l) with bi-weekly subculture. Somatic embryos were directly produced on the enlarged dome shaped growing structures that developed from the shoot-tips of one-week old seedling explants (without any callus formation) when cultured on MS medium supplemented with both 2,4-D (0.5 mg/l) and BA (0.5 mg/l). However, the supplementation of MS medium with only 2,4-D (0.5 mg/l) induced compact callus without any plantlet regeneration. Each multiple shoot-clump was capable of regenerating more than 80 shoots via an intensive differentiation of both axillary and adventitious shoot buds, the somatic embryos were capable of 90% germination, plant conversion and regeneration. The regenerated shoots could be efficiently rooted on MS medium containing indole-3-butyric acid (IBA 1 mg/l). The plants were successfully transplanted to glasshouse and grown to maturity with a survival rate of 98%. Morphogenetic response of the explants was found to be genotypically independent.

Simultaneous Identification of Multiple Driver Pathways in Cancer

PubMed Central

Leiserson, Mark D. M.; Blokh, Dima

2013-01-01

Distinguishing the somatic mutations responsible for cancer (driver mutations) from random, passenger mutations is a key challenge in cancer genomics. Driver mutations generally target cellular signaling and regulatory pathways consisting of multiple genes. This heterogeneity complicates the identification of driver mutations by their recurrence across samples, as different combinations of mutations in driver pathways are observed in different samples. We introduce the Multi-Dendrix algorithm for the simultaneous identification of multiple driver pathways de novo in somatic mutation data from a cohort of cancer samples. The algorithm relies on two combinatorial properties of mutations in a driver pathway: high coverage and mutual exclusivity. We derive an integer linear program that finds set of mutations exhibiting these properties. We apply Multi-Dendrix to somatic mutations from glioblastoma, breast cancer, and lung cancer samples. Multi-Dendrix identifies sets of mutations in genes that overlap with known pathways – including Rb, p53, PI(3)K, and cell cycle pathways – and also novel sets of mutually exclusive mutations, including mutations in several transcription factors or other genes involved in transcriptional regulation. These sets are discovered directly from mutation data with no prior knowledge of pathways or gene interactions. We show that Multi-Dendrix outperforms other algorithms for identifying combinations of mutations and is also orders of magnitude faster on genome-scale data. Software available at: http://compbio.cs.brown.edu/software. PMID:23717195

Pathogen Trojan Horse Delivers Bioactive Host Protein to Alter Maize Anther Cell Behavior in Situ.

PubMed

van der Linde, Karina; Timofejeva, Ljudmilla; Egger, Rachel L; Ilau, Birger; Hammond, Reza; Teng, Chong; Meyers, Blake C; Doehlemann, Gunther; Walbot, Virginia

2018-03-01

Small proteins are crucial signals during development, host defense, and physiology. The highly spatiotemporal restricted functions of signaling proteins remain challenging to study in planta. The several month span required to assess transgene expression, particularly in flowers, combined with the uncertainties from transgene position effects and ubiquitous or overexpression, makes monitoring of spatiotemporally restricted signaling proteins lengthy and difficult. This situation could be rectified with a transient assay in which protein deployment is tightly controlled spatially and temporally in planta to assess protein functions, timing, and cellular targets as well as to facilitate rapid mutagenesis to define functional protein domains. In maize ( Zea mays ), secreted ZmMAC1 (MULTIPLE ARCHESPORIAL CELLS1) was proposed to trigger somatic niche formation during anther development by participating in a ligand-receptor module. Inspired by Homer's Trojan horse myth, we engineered a protein delivery system that exploits the secretory capabilities of the maize smut fungus Ustilago maydis , to allow protein delivery to individual cells in certain cell layers at precise time points. Pathogen-supplied ZmMAC1 cell-autonomously corrected both somatic cell division and differentiation defects in mutant Zm mac1-1 anthers. These results suggest that exploiting host-pathogen interactions may become a generally useful method for targeting host proteins to cell and tissue types to clarify cellular autonomy and to analyze steps in cell responses. © 2018 American Society of Plant Biologists. All rights reserved.

Structure of the germline genome of Tetrahymena thermophila and relationship to the massively rearranged somatic genome

PubMed Central

Hamilton, Eileen P; Kapusta, Aurélie; Huvos, Piroska E; Bidwell, Shelby L; Zafar, Nikhat; Tang, Haibao; Hadjithomas, Michalis; Krishnakumar, Vivek; Badger, Jonathan H; Caler, Elisabet V; Russ, Carsten; Zeng, Qiandong; Fan, Lin; Levin, Joshua Z; Shea, Terrance; Young, Sarah K; Hegarty, Ryan; Daza, Riza; Gujja, Sharvari; Wortman, Jennifer R; Birren, Bruce W; Nusbaum, Chad; Thomas, Jainy; Carey, Clayton M; Pritham, Ellen J; Feschotte, Cédric; Noto, Tomoko; Mochizuki, Kazufumi; Papazyan, Romeo; Taverna, Sean D; Dear, Paul H; Cassidy-Hanley, Donna M; Xiong, Jie; Miao, Wei; Orias, Eduardo; Coyne, Robert S

2016-01-01

The germline genome of the binucleated ciliate Tetrahymena thermophila undergoes programmed chromosome breakage and massive DNA elimination to generate the somatic genome. Here, we present a complete sequence assembly of the germline genome and analyze multiple features of its structure and its relationship to the somatic genome, shedding light on the mechanisms of genome rearrangement as well as the evolutionary history of this remarkable germline/soma differentiation. Our results strengthen the notion that a complex, dynamic, and ongoing interplay between mobile DNA elements and the host genome have shaped Tetrahymena chromosome structure, locally and globally. Non-standard outcomes of rearrangement events, including the generation of short-lived somatic chromosomes and excision of DNA interrupting protein-coding regions, may represent novel forms of developmental gene regulation. We also compare Tetrahymena’s germline/soma differentiation to that of other characterized ciliates, illustrating the wide diversity of adaptations that have occurred within this phylum. DOI: http://dx.doi.org/10.7554/eLife.19090.001 PMID:27892853

Producing primate embryonic stem cells by somatic cell nuclear transfer.

PubMed

Byrne, J A; Pedersen, D A; Clepper, L L; Nelson, M; Sanger, W G; Gokhale, S; Wolf, D P; Mitalipov, S M

2007-11-22

Derivation of embryonic stem (ES) cells genetically identical to a patient by somatic cell nuclear transfer (SCNT) holds the potential to cure or alleviate the symptoms of many degenerative diseases while circumventing concerns regarding rejection by the host immune system. However, the concept has only been achieved in the mouse, whereas inefficient reprogramming and poor embryonic development characterizes the results obtained in primates. Here, we used a modified SCNT approach to produce rhesus macaque blastocysts from adult skin fibroblasts, and successfully isolated two ES cell lines from these embryos. DNA analysis confirmed that nuclear DNA was identical to donor somatic cells and that mitochondrial DNA originated from oocytes. Both cell lines exhibited normal ES cell morphology, expressed key stem-cell markers, were transcriptionally similar to control ES cells and differentiated into multiple cell types in vitro and in vivo. Our results represent successful nuclear reprogramming of adult somatic cells into pluripotent ES cells and demonstrate proof-of-concept for therapeutic cloning in primates.

Stress and Resilience in Functional Somatic Syndromes – A Structural Equation Modeling Approach

PubMed Central

Fischer, Susanne; Lemmer, Gunnar; Gollwitzer, Mario; Nater, Urs M.

2014-01-01

Background Stress has been suggested to play a role in the development and perpetuation of functional somatic syndromes. The mechanisms of how this might occur are not clear. Purpose We propose a multi-dimensional stress model which posits that childhood trauma increases adult stress reactivity (i.e., an individual's tendency to respond strongly to stressors) and reduces resilience (e.g., the belief in one's competence). This in turn facilitates the manifestation of functional somatic syndromes via chronic stress. We tested this model cross-sectionally and prospectively. Methods Young adults participated in a web survey at two time points. Structural equation modeling was used to test our model. The final sample consisted of 3′054 participants, and 429 of these participated in the follow-up survey. Results Our proposed model fit the data in the cross-sectional (χ2(21)  = 48.808, p<.001, CFI  = .995, TLI  = .992, RMSEA  = .021, 90% CI [.013.029]) and prospective analyses (χ2(21)  = 32.675, p<.05, CFI  = .982, TLI  = .969, RMSEA  = .036, 90% CI [.001.059]). Discussion Our findings have several clinical implications, suggesting a role for stress management training in the prevention and treatment of functional somatic syndromes. PMID:25396736

Targeting mitochondrial function and proteostasis to mitigate dynapenia.

PubMed

Musci, Robert V; Hamilton, Karyn L; Miller, Benjamin F

2018-01-01

Traditionally, interventions to treat skeletal muscle aging have largely targeted sarcopenia-the age-related loss of skeletal muscle mass. Dynapenia refers to the age-related loss in skeletal muscle function due to factors outside of muscle mass, which helps to inform treatment strategies for aging skeletal muscle. There is evidence that mechanisms to maintain protein homeostasis and proteostasis, deteriorate with age. One key mechanism to maintain proteostasis is protein turnover, which is an energetically costly process. When there is a mismatch between cellular energy demands and energy provision, inelastic processes related to metabolism are maintained, but there is competition for the remaining energy between the elastic processes of somatic maintenance and growth. With aging, mitochondrial dysfunction reduces ATP generation capacity, constraining the instantaneous supply of energy, thus compromising growth and somatic maintenance processes. Further, with age the need for somatic maintenance increases because of the accumulation of protein damage. In this review, we highlight the significant role mitochondria have in maintaining skeletal muscle proteostasis through increased energy provision, protein turnover, and substrate flux. In addition, we provide evidence that improving mitochondrial function could promote a cellular environment that is conducive to somatic maintenance, and consequently for mitigating dynapenia. Finally, we highlight interventions, such as aerobic exercise, that could be used to improve mitochondrial function and improve outcomes related to dynapenia.

When does hardship matter for health? Neighborhood and individual disadvantages and functional somatic symptoms from adolescence to mid-life in The Northern Swedish Cohort.

PubMed

Gustafsson, Per E; San Sebastian, Miguel

2014-01-01

A large body of research has shown that health is influenced by disadvantaged living conditions, including both personal and neighborhood conditions. Little is however known to what degree the health impact of different forms of disadvantage differ along the life course. The present study aims to examine when, during the life course, neighborhood and individual disadvantages relate to functional somatic symptoms. Participants (n = 992) came from The Northern Swedish Cohort and followed from age 16, 21, 30 until 42 years. Functional somatic symptoms, socioeconomic disadvantage, and social and material adversity were measured through questionnaires and linked to register data on neighborhood disadvantage. Data was analyzed with longitudinal and cross-sectional multilevel models. Results showed that neighborhood disadvantage, social and material adversity and gender all contributed independently to overall levels of symptoms across the life course. Cross-sectional analyses also suggested that the impact of disadvantage differed between life course periods; neighborhood disadvantage was most important in young adulthood, and the relative importance of material versus social adversity increased as participants grew older. In summary, the study suggests that disadvantages from different contextual sources may affect functional somatic health across the life course, but also through life course specific patterns.

ExScalibur: A High-Performance Cloud-Enabled Suite for Whole Exome Germline and Somatic Mutation Identification

PubMed Central

Huang, Lei; Kang, Wenjun; Bartom, Elizabeth; Onel, Kenan; Volchenboum, Samuel; Andrade, Jorge

2015-01-01

Whole exome sequencing has facilitated the discovery of causal genetic variants associated with human diseases at deep coverage and low cost. In particular, the detection of somatic mutations from tumor/normal pairs has provided insights into the cancer genome. Although there is an abundance of publicly-available software for the detection of germline and somatic variants, concordance is generally limited among variant callers and alignment algorithms. Successful integration of variants detected by multiple methods requires in-depth knowledge of the software, access to high-performance computing resources, and advanced programming techniques. We present ExScalibur, a set of fully automated, highly scalable and modulated pipelines for whole exome data analysis. The suite integrates multiple alignment and variant calling algorithms for the accurate detection of germline and somatic mutations with close to 99% sensitivity and specificity. ExScalibur implements streamlined execution of analytical modules, real-time monitoring of pipeline progress, robust handling of errors and intuitive documentation that allows for increased reproducibility and sharing of results and workflows. It runs on local computers, high-performance computing clusters and cloud environments. In addition, we provide a data analysis report utility to facilitate visualization of the results that offers interactive exploration of quality control files, read alignment and variant calls, assisting downstream customization of potential disease-causing mutations. ExScalibur is open-source and is also available as a public image on Amazon cloud. PMID:26271043

Influence of Competitive-Anxiety on Heart Rate Variability in Swimmers.

PubMed

Fortes, Leonardo S; da Costa, Bruna D V; Paes, Pedro P; do Nascimento Júnior, José R A; Fiorese, Lenamar; Ferreira, Maria E C

2017-12-01

The aim of this study was to analyze the relationship between competitive anxiety and heart rate variability (HRV) in swimming athletes. A total of 66 volunteers (41 male and 27 female) who swam the 400-m freestyle in the Brazilian Swimming Championships participated. Thirty minutes before the 400-m freestyle event, the athletes answered the Competitive Anxiety Inventory (CSAI-2R) questionnaire, then underwent anthropometric (body weight, height, and skinfold thickness) and HRV measurements. Then, at a second meeting, held 3 h after the 400-m freestyle event, the athletes returned to the evaluation room for HRV measurement (Polar ® RS800cx, Kempele, Finland). Multiple linear regression was used to evaluate the relationship between competitive anxiety and HRV. The multiple linear regression was performed in three blocks (block 1: cognitive anxiety, block 2: somatic anxiety, and block 3: self-confidence), adopting the forward model. The results indicated a significant association between cognitive anxiety (p = 0.001) and HRV. An increased magnitude of the association was observed when somatic anxiety was inserted in the model (p = 0.001). In contrast, self-confidence showed, which was inserted in block 3, no relationship with HRV (p = 0.27). It was concluded that cognitive and somatic anxieties were associated with the HRV of swimmers. Athletes with a high magnitude of cognitive and/or somatic anxiety demonstrated more significant autonomic nervous system disturbance. Practically, psychological interventions are needed to improve anxiety states that are specific to perform well, and to improve HRV.

Stable transformation via particle bombardment in two different soybean regeneration systems.

PubMed

Sato, S; Newell, C; Kolacz, K; Tredo, L; Finer, J; Hinchee, M

1993-05-01

The Biolistics(®) particle delivery system for the transformation of soybean (Glycine max L. Merr.) was evaluated in two different regeneration systems. The first system was multiple shoot proliferation from shoot tips obtained from immature zygotic embryos of the cultivar Williams 82, and the second was somatic embryogenesis from a long term proliferative suspension culture of the cultivar Fayette. Bombardment of shoot tips with tungsten particles, coated with precipitated DNA containing the gene for β-glucuronidase (GUS), produced GUS-positive sectors in 30% of the regenerated shoots. However, none of the regenerants which developed into plants continued to produce GUS positive tissue. Bombardment of embryogenic suspension cultures produced GUS positive globular somatic embryos which proliferated into GUS positive somatic embryos and plants. An average of 4 independent transgenic lines were generated per bombarded flask of an embryogenic suspension. Particle bombardment delivered particles into the first two cell layers of either shoot tips or somatic embryos. Histological analysis indicated that shoot organogenesis appeared to involve more than the first two superficial cell layers of a shoot tip, while somatic embryo proliferation occurred from the first cell layer of existing somatic embryos. The different transformation results obtained with these two systems appeared to be directly related to differences in the cell types which were responsible for regeneration and their accessibility to particle penetration.

Anxious Depression and early changes in the HAMD-17 anxiety-somatization factor items and antidepressant treatment outcome

PubMed Central

Farabaugh, Amy H.; Bitran, Stella; Witte, Janet; Alpert, Jonathan; Chuzi, Sarah; Clain, Alisabet J.; Baer, Lee; Fava, Maurizio; McGrath, Patrick J.; Dording, Christina; Mischoulon, David; Papakostas, George I

2010-01-01

Objective To assess the relationship between early changes in anxiety/somatization symptoms and treatment outcome among MDD subjects during a 12-week trial of fluoxetine. We also examined the relationship between anxious depression and treatment response. Methods 510 MDD patients received 12 weeks of fluoxetine with flexible dosing (target dosages: 10 mg/day (week 1), 20 mg/day (weeks 2–4), 40 mg/day (weeks 4–8), and 60 mg/day (weeks 5–12)). We assessed the relationship between early changes in HAMD-17- anxiety/somatization factor items and depressive remission, as well as whether anxious depression at baseline predicted remission at study endpoint. . Baseline HAMD-17 scores were considered as covariates and the Bonferroni correction (p ≤ .008) was used for multiple comparisons. Results Adjusting for baseline HAMD-17 scores, patients who experienced greater early improvement in somatic symptoms (gastrointestinal) were significantly more likely to attain remission (HAMD-17 < 8) at endpoint than those without early improvement (p = .006). Early changes in the remaining items did not predict remission, nor did anxious depression at baseline. Conclusions Among the anxiety/somatization factor items, only early changes in somatic symptoms (gastrointestinal) predicted remission. Future studies are warranted to further investigate this relationship, as well as that between anxious depression and treatment outcome. PMID:20400905

Bottlenecks in bog pine multiplication by somatic embryogenesis and their visualization with the environmental scanning electron microscope.

PubMed

Vlašínová, Helena; Neděla, Vilem; Đorđević, Biljana; Havel, Ladislav

2017-07-01

Somatic embryogenesis (SE) is an important biotechnological technique used for the propagation of many pine species in vitro. However, in bog pine, one of the most endangered tree species in the Czech Republic, limitations were observed, which negatively influenced the development and further germination of somatic embryos. Although initiation frequency was very low-0.95 %, all obtained cell lines were subjected to maturation. The best responding cell line (BC1) was used and subjected to six different variants of the maturation media. The media on which the highest number of early-precotyledonary/cotyledonary somatic embryos was formed was supplemented with 121 μM abscisic acid (ABA) and with 6 % maltose. In the end of maturation experiments, different abnormalities in formation of somatic embryos were observed. For visualization and identification of abnormalities in meristem development during proliferation and maturation processes, the environmental scanning electron microscope was used. In comparison to the classical light microscope, the non-commercial environmental scanning electron microscope AQUASEM II has been found as a very useful tool for the quick recognition of apical meristem disruption and abnormal development. To our knowledge, this is the first report discussing somatic embryogenesis in bog pine. Based on this observation, the cultivation procedure could be enhanced and the method for SE of bog pine optimized.

[Treatment of functional somatic syndrome with abdominal pain].

PubMed

Abe, Tetsuya; Kanbara, Kenji; Mizuno, Yasuyuki; Fukunaga, Mikihiko

2009-09-01

Functional somatic syndrome (FSS) with abdominal pain include functional gastrointestinal disorder, chronic pancreatitis, chronic pelvic pain syndrome, which generally contain autonomic dysfunction. Regarding the treatment of FSS, it is important to know about FSS for a therapist at first. Secondly, the therapist should find out physical dysfunction of patients positively, and confirm objectively the hypotheses about both peripheral and central pathophysiological mechanisms as much as possible. Heart rate variability is an easy method, and useful to assess autonomic function. After grasping the patient's explanatory model about the illness, the therapist showes the most acceptable treatment for the patient at last.

Landscape of somatic mutations in 560 breast cancer whole-genome sequences

DOE PAGES

Nik-Zainal, Serena; Davies, Helen; Staaf, Johan; ...

2016-05-02

Here, we analysed whole-genome sequences of 560 breast cancers to advance understanding of the driver mutations conferring clonal advantage and the mutational processes generating somatic mutations. We found that 93 protein-coding cancer genes carried probable driver mutations. Some non-coding regions exhibited high mutation frequencies, but most have distinctive structural features probably causing elevated mutation rates and do not contain driver mutations. Mutational signature analysis was extended to genome rearrangements and revealed twelve base substitution and six rearrangement signatures. Three rearrangement signatures, characterized by tandem duplications or deletions, appear associated with defective homologous-recombination-based DNA repair: one with deficient BRCA1 function, anothermore » with deficient BRCA1 or BRCA2 function, the cause of the third is unknown. This analysis of all classes of somatic mutation across exons, introns and intergenic regions highlights the repertoire of cancer genes and mutational processes operating, and progresses towards a comprehensive account of the somatic genetic basis of breast cancer.« less

Landscape of somatic mutations in 560 breast cancer whole-genome sequences

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

Nik-Zainal, Serena; Davies, Helen; Staaf, Johan

Here, we analysed whole-genome sequences of 560 breast cancers to advance understanding of the driver mutations conferring clonal advantage and the mutational processes generating somatic mutations. We found that 93 protein-coding cancer genes carried probable driver mutations. Some non-coding regions exhibited high mutation frequencies, but most have distinctive structural features probably causing elevated mutation rates and do not contain driver mutations. Mutational signature analysis was extended to genome rearrangements and revealed twelve base substitution and six rearrangement signatures. Three rearrangement signatures, characterized by tandem duplications or deletions, appear associated with defective homologous-recombination-based DNA repair: one with deficient BRCA1 function, anothermore » with deficient BRCA1 or BRCA2 function, the cause of the third is unknown. This analysis of all classes of somatic mutation across exons, introns and intergenic regions highlights the repertoire of cancer genes and mutational processes operating, and progresses towards a comprehensive account of the somatic genetic basis of breast cancer.« less

Comorbidity in Migraine with Functional Somatic Syndromes, Psychiatric Disorders and Inflammatory Diseases: A Matter of Central Sensitization?

PubMed

Grassini, Simone; Nordin, Steven

2017-01-01

To approach the questions as to why migraine appears to be associated with functional somatic syndromes (FSSs) and whether central sensitization may be an underlying mechanism, the present study investigated (a) comorbidity with diagnoses of three FSSs, three psychiatric disorders, and three inflammatory diseases, (b) degree of mental health problems (stress, burnout, anxiety, depression and somatization), and (c) prevalence of ten cognitive/affective and nine airway symptoms in persons with migraine in the general population. From a randomized and stratified Swedish adult sample, questionnaire data were analyzed from 151 individuals with a diagnosis of migraine and 3,255 without migraine. The results showed (a) significant comorbidity in migraine with all FSSs, psychiatric disorders and inflammatory diseases, (b) significantly elevated scores on stress, burnout, anxiety, depression, and somatization, and (c) relatively high prevalence rates on almost all symptoms. Taken together, the results motivate future study of central sensitization as a mechanism underlying migraine.

Landscape of somatic mutations in 560 breast cancer whole genome sequences

PubMed Central

Nik-Zainal, Serena; Davies, Helen; Staaf, Johan; Ramakrishna, Manasa; Glodzik, Dominik; Zou, Xueqing; Martincorena, Inigo; Alexandrov, Ludmil B.; Martin, Sancha; Wedge, David C.; Van Loo, Peter; Ju, Young Seok; Smid, Marcel; Brinkman, Arie B; Morganella, Sandro; Aure, Miriam R.; Lingjærde, Ole Christian; Langerød, Anita; Ringnér, Markus; Ahn, Sung-Min; Boyault, Sandrine; Brock, Jane E.; Broeks, Annegien; Butler, Adam; Desmedt, Christine; Dirix, Luc; Dronov, Serge; Fatima, Aquila; Foekens, John A.; Gerstung, Moritz; Hooijer, Gerrit KJ; Jang, Se Jin; Jones, David R.; Kim, Hyung-Yong; King, Tari A.; Krishnamurthy, Savitri; Lee, Hee Jin; Lee, Jeong-Yeon; Li, Yilong; McLaren, Stuart; Menzies, Andrew; Mustonen, Ville; O’Meara, Sarah; Pauporté, Iris; Pivot, Xavier; Purdie, Colin A.; Raine, Keiran; Ramakrishnan, Kamna; Rodríguez-González, F. Germán; Romieu, Gilles; Sieuwerts, Anieta M.; Simpson, Peter T; Shepherd, Rebecca; Stebbings, Lucy; Stefansson, Olafur A; Teague, Jon; Tommasi, Stefania; Treilleux, Isabelle; Van den Eynden, Gert G.; Vermeulen, Peter; Vincent-Salomon, Anne; Yates, Lucy; Caldas, Carlos; van’t Veer, Laura; Tutt, Andrew; Knappskog, Stian; Tan, Benita Kiat Tee; Jonkers, Jos; Borg, Åke; Ueno, Naoto T; Sotiriou, Christos; Viari, Alain; Futreal, P. Andrew; Campbell, Peter J; Span, Paul N.; Van Laere, Steven; Lakhani, Sunil R; Eyfjord, Jorunn E.; Thompson, Alastair M.; Birney, Ewan; Stunnenberg, Hendrik G; van de Vijver, Marc J; Martens, John W.M.; Børresen-Dale, Anne-Lise; Richardson, Andrea L.; Kong, Gu; Thomas, Gilles; Stratton, Michael R.

2016-01-01

We analysed whole genome sequences of 560 breast cancers to advance understanding of the driver mutations conferring clonal advantage and the mutational processes generating somatic mutations. 93 protein-coding cancer genes carried likely driver mutations. Some non-coding regions exhibited high mutation frequencies but most have distinctive structural features probably causing elevated mutation rates and do not harbour driver mutations. Mutational signature analysis was extended to genome rearrangements and revealed 12 base substitution and six rearrangement signatures. Three rearrangement signatures, characterised by tandem duplications or deletions, appear associated with defective homologous recombination based DNA repair: one with deficient BRCA1 function; another with deficient BRCA1 or BRCA2 function; the cause of the third is unknown. This analysis of all classes of somatic mutation across exons, introns and intergenic regions highlights the repertoire of cancer genes and mutational processes operative, and progresses towards a comprehensive account of the somatic genetic basis of breast cancer. PMID:27135926

Quality of life and neurotic disorders in general healthcare.

PubMed

Herrman, Helen; Chopra, Prem

2009-01-01

To review recent findings on the relationship between neurotic disorders (specifically depression, anxiety and somatization) and function and quality of life (QoL) in patients with complex clinical presentations, and to consider the clinical and public health implications. The high prevalence of comorbid depression and anxiety among patients with general medical disorders is well known. The impact of the comorbidity on function in these patients is documented extensively. The study of their QoL is an emerging area of work, though its interpretation is controversial. The impact of somatization on function and QoL is less well studied. Recent findings emphasize the value of a common measure for QoL across health conditions. Depression, anxiety and somatization are a significant burden in the general population and failure to recognize and manage these problems in general healthcare contributes to delayed recovery. A holistic approach to symptom, disability and QoL assessment, done in awareness of possible measurement redundancy, is likely to assist better recognition and management of these conditions. Further research is needed on the effects on QoL of depression and anxiety in patients with general medical disorders and early detection and treatment of somatization.

Somatization in the conceptualization of sickle cell disease.

PubMed

Wellington, Chanté; Edwards, Christopher L; McNeil, Janice; Wood, Mary; Crisp, Benjamin; Feliu, Miriam; Byrd, Goldie; McDougald, Camela; Edwards, Lekisha; Whitfield, Keith E

2010-11-01

The unpredictable nature of sickle cell disease (SCD) and its social and environmental consequences can produce an unhealthy and almost exclusive focus on physical functioning. At the upper range of this focus on health concerns is somatization. In the current study, using 156 adult patients (55.13% female, 86) with SCD, mean age 35.59 +/- 12.73, we explored the relationship of somatization to pain. We found somatization to be predictive of pain severity and current pain intensity as well as a range of averaged indices of pain over time (p < .0001). We further found somatization to be predictive of a range of negative psychological experiences to include depression, anxiety, and hostility (p < .0001). We interpret these data to suggest that patients with SCD who have a propensity to focus exclusively on their health or are more sensitive to minor changes in their health status (somatization) may also be more likely to report greater concerns about their health and higher ratings of pain.

Integration of Genomic, Biologic, and Chemical Approaches to Target p53 Loss and Gain-of-Function in Triple Negative Breast Cancer

DTIC Science & Technology

2014-09-01

in this renewal: p53 triple negative breast cancer subtypes gene expression somatic cell genetics CRISPR /Cas 3. OVERALL PROJECT SUMMARY...to the efficacy of the synthetic lethality screen. In addition, we have optimized the use of CRISPR /Cas, a novel somatic cell recombination...completing this stage of the research within the upcoming Year 2 of the award period. Figure 1. CRISPR /Cas-mediated in vitro somatic cell

Substance-related disorders and somatic symptoms: how should clinicians understand the associations?

PubMed

Yoshimasu, Kouichi

2012-12-01

There are five major patterns which explain the associations between somatic symptoms and substance-related disorders (SRD) in patients without organic disorders. They are withdrawal somatic symptoms, somatic symptoms related to co-morbid mental disorders, those related to co-morbid infectious diseases, functional intractable somatic symptoms (including somatoform disorders), and symptoms associated with intoxication. Those somatic symptoms that occur according to those five patterns might overlap each other, making it difficult for physicians to precisely grasp the associations between somatic symptoms and SRD. This results in a very complicated formation of various kinds of symptoms (syndrome). Furthermore, the clinical and social features of those patterns of associations differ between legal and illicit substances users. It should also be noted that such somatic symptoms associated with SRD may be affected by social factors such as cultural backgrounds or legal restrictions on such substances. Those factors differ according to each country, area, or community whose cultural backgrounds are somewhat specific. In those areas, psychosocial factors such as stigmas, prejudices, or feeling ashamed of one's mental disorder (including SRD) also differ. Thus, it is important to take into account the effects of social or psychosocial backgrounds when evaluating and studying the associations between somatic symptoms and SRD. When clinicians confront patients with somatic symptoms and suspected SRD, they should presume which association pattern is the most significant problem for the patients, based on those psychosocial and biological information obtained from the patients themselves and their surroundings. This procedure might give an opportunity to clinicians for elucidating complicated associations between somatic complaints and SRD.

Survival of ovarian somatic cells during sex change in the protogynous wrasse, Halichoeres trimaculatus.

PubMed

Nozu, Ryo; Horiguchi, Ryo; Murata, Ryosuke; Kobayashi, Yasuhisa; Nakamura, Masaru

2013-02-01

The three-spot wrasse (Halichoeres trimaculatus), which inhabits the coral reefs of Okinawa, changes sex from female to male. Sex change in this species is controlled by a social system. Oocytes disappear completely from the ovary, and male germ cells and somatic cells comprising testicular tissue arise a new during the sex change process. However, little is known of the fate and origin of the gonadal tissue-forming cells during sex change. In particular, the fate of ovarian somatic cells has not been determined, although the ovarian tissue regresses histologically. To approach this question, we analyzed apoptosis and cell proliferation in the sex-changing gonads. Unexpectedly, we found that few apoptotic somatic cells were present during sex change, suggesting that ovarian somatic cells might survive during the regression of the ovarian tissue. On the other hand, cell proliferation was detected in many granulosa cells surrounding the degenerating oocytes, a few epithelial cells covering ovigerous lamella and a few somatic cells associated with gonial germ cells at an early stage of sex change. Then, we found that proliferative ovarian somatic cells remained in the gonads late in the sex change process. Based on these results, we concluded that some functional somatic cells of the ovary are reused as testicular somatic cells during the gonadal sex change in the three-spot wrasse.

The relationship between early changes in the HAMD-17 anxiety/somatization factor items and treatment outcome among depressed outpatients.

PubMed

Farabaugh, Amy; Mischoulon, David; Fava, Maurizio; Wu, Shirley L; Mascarini, Alessandra; Tossani, Eliana; Alpert, Jonathan E

2005-03-01

The 17-item Hamilton Rating Scale for Depression (HAMD-17) Anxiety/Somatization factor includes six items: Anxiety (psychic), Anxiety (somatic), Somatic Symptoms (gastrointestinal), Somatic Symptoms (general), Hypochondriasis and Insight. This study examines the relationship between early changes (defined as those observed between baseline and week 1) in these HAMD-17 Anxiety/Somatization Factor items and treatment outcome among major depressive disorder (MDD) patients who participated in a study comparing the antidepressant efficacy of a standardized extract of hypericum with both placebo and fluoxetine. Following a 1-week, single-blind washout, patients with MDD diagnosed by the Structured Clinical Interview for DSM-IV (SCID) were randomized to 12 weeks of double-blind treatment with hypericum extract (900 mg/day), fluoxetine (20 mg/day) or placebo. The relationship between early changes in HAMD-17 anxiety/somatization factor items and treatment outcome was assessed separately for patients who received study treatment (hypericum or fluoxetine) versus placebo with a logistic regression method. One hundred and thirty-five patients (female 57%, mean age=37.3+/-11.0 years; mean baseline HAMD-17=19.7+/-3.2 years) were randomized to double-blind treatment and were included in the intent-to-treat (ITT) analyses. After adjusting for baseline HAMD-17 scores and for multiple comparisons with the Bonferroni correction, patients who remitted (HAMD-17 score <8) after study treatment had significantly greater early improvement in Somatic Symptoms (General) scores than non-remitters. No other significant differences in early changes were noted for the remaining items between remitters versus non-remitters who received active treatment. For patients treated with placebo, early change was not predictive of remission for any of the items after Bonferroni correction. In conclusion, the presence of early improvement on the HAMD-17 item concerning fatigue and general somatic symptoms is significantly predictive of achieving remission at endpoint with active study treatment but not with placebo.

Correlations between sexual dysfunction, depression, anxiety, and somatic symptoms among patients with major depressive disorder.

PubMed

Lin, Chiao-Fan; Juang, Yeong-Yuh; Wen, Jung-Kwang; Liu, Chia-Yih; Hung, Ching-I

2012-01-01

The purpose of this study was to investigate the degree of correlation between sexual dysfunction and depression, anxiety, and somatic symptoms among patients with major depressive disorder (MDD) and to identify the dimension most predictive of sexual dysfunction. One-hundred and thirty-five outpatients with MDD were enrolled and were treated with open-label venlafaxine 75 mg daily for one month. The Arizona Sexual Experience Scale-Chinese Version (ASEX-CV), Depression and Somatic Symptoms Scale (DSSS), Hamilton Depression Rating Scale, and Hospital Anxiety and Depression Scale (HADS) were administered at baseline and at one-month follow-up and the improvement percentage (IP) of each scale posttreatment was calculated. Multiple linear regression was used to determine the dimension most predictive of the total ASEX-CV score. Seventy subjects (20 men, 50 women) completed the one-month pharmacotherapy and the four scales. The depression subscale of the HADS was most strongly correlated with the ASEX-CV scale and was the only subscale to independently predict the total ASEX-CV score at the two points. However, the somatic subscale of the DSSS was not correlated with any ASEX-CV item. At the endpoint, depression, anxiety, and somatic symptoms were significantly improved (IP 48.5% to 26.0%); however, very little improvement was observed in the total ASEX-CV score (IP -1.6%). The severity of sexual dysfunction among patients with MDD was most correlated with the severity of the depressive dimension, but not the severity of the somatic dimension. Further studies are indicated to explore the relationships between sexual dysfunction, depression, anxiety, and somatic symptoms.

Characterization of the multiple resistance traits of somatic hybrids between Solanum cardiophyllum Lindl. and two commercial potato cultivars.

PubMed

Thieme, Ramona; Rakosy-Tican, Elena; Nachtigall, Marion; Schubert, Jörg; Hammann, Thilo; Antonova, Olga; Gavrilenko, Tatjana; Heimbach, Udo; Thieme, Thomas

2010-10-01

Interspecific somatic hybrids between commercial cultivars of potato Solanum tuberosum L. Agave and Delikat and the wild diploid species Solanum cardiophyllum Lindl. (cph) were produced by protoplast electrofusion. The hybrid nature of the regenerated plants was confirmed by flow cytometry, simple sequence repeat (SSR), amplified fragment length polymorphism (AFLP), microsatellite-anchored fragment length polymorphism (MFLP) markers and morphological analysis. Somatic hybrids were assessed for their resistance to Colorado potato beetle (CPB) using a laboratory bioassay, to Potato virus Y (PVY) by mechanical inoculation and field trials, and foliage blight in a greenhouse and by field trials. Twenty-four and 26 somatic hybrids of cph + cv. Agave or cph + cv. Delikat, respectively, showed no symptoms of infection with PVY, of which 3 and 12, respectively, were also resistant to foliage blight. One hybrid of cph + Agave performed best in CPB and PVY resistance tests. Of the somatic hybrids that were evaluated for their morphology and tuber yield in the field for 3 years, four did not differ significantly in tuber yield from the parental and standard cultivars. Progeny of hybrids was obtained by pollinating them with pollen from a cultivar, selfing or cross-pollination. The results confirm that protoplast electrofusion can be used to transfer the CPB, PVY and late blight resistance of cph into somatic hybrids. These resistant somatic hybrids can be used in pre-breeding studies, molecular characterization and for increasing the genetic diversity available for potato breeding by marker-assisted combinatorial introgression into the potato gene pool.

Somatic INK4a-ARF locus mutations: a significant mechanism of gene inactivation in squamous cell carcinomas of the head and neck.

PubMed

Poi, M J; Yen, T; Li, J; Song, H; Lang, J C; Schuller, D E; Pearl, D K; Casto, B C; Tsai, M D; Weghorst, C M

2001-01-01

The INK4a-ARF locus is located on human chromosome 9p21 and is known to encode two functionally distinct tumor-suppressor genes. The p16(INK4a) (p16) tumor-suppressor gene product is a negative regulator of cyclin-dependent kinases 4 and 6, which in turn positively regulate progression of mammalian cells through the cell cycle. The p14(ARF) tumor-suppressor gene product specifically interacts with human double minute 2, leading to the subsequent stabilization of p53 and G(1) arrest. Previous investigations analyzing the p16 gene in squamous cell carcinomas of the head and neck (SCCHNs) have suggested the predominate inactivating events to be homozygous gene deletions and hypermethylation of the p16 promoter. Somatic mutational inactivation of p16 has been reported to be low (0-10%, with a combined incidence of 25 of 279, or 9%) and to play only a minor role in the development of SCCHN. The present study examined whether this particular mechanism of INK4a/ARF inactivation, specifically somatic mutation, has been underestimated in SCCHN by determining the mutational status of the p16 and p14(ARF) genes in 100 primary SCCHNs with the use of polymerase chain reaction technology and a highly sensitive, nonradioactive modification of single-stranded conformational polymorphism (SSCP) analysis termed "cold" SSCP. Exons 1alpha, 1beta, and 2 of INK4a/ARF were amplified using intron-based primers or a combination of intron- and exon-based primers. A total of 27 SCCHNs (27%) exhibited sequence alterations in this locus, 22 (22%) of which were somatic sequence alterations and five (5%) of which were a single polymorphism in codon 148. Of the 22 somatic alterations, 20 (91%) directly or indirectly involved exon 2, and two (9%) were located within exon 1alpha. No mutations were found in exon 1beta. All 22 somatic mutations would be expected to yield altered p16 proteins, but only 15 of them should affect p14(ARF) proteins. Specific somatic alterations included microdeletions or insertions (nine of 22, 41%), a microrearrangement (one of 22, 5%), and single nucleotide substitutions (12 of 22, 56%). In addition, we analyzed the functional characteristics of seven unique mutant p16 proteins identified in this study by assessing their ability to inhibit cyclin-dependent kinase 4 activity. Six of the seven mutant proteins tested exhibited reduced function compared with wild-type p16, ranging from minor decreases of function (twofold to eightfold) in four samples to total loss of function (29- to 38-fold decrease) in two other samples. Overall, somatic mutation of the INK4a/ARF tumor suppressor locus, resulting in functionally deficient p16 and possibly p14(ARF) proteins, seems to be a prevalent event in the development of SCCHN. Mol. Carcinog. 30:26-36, 2001. Copyright 2001 Wiley-Liss, Inc.

Release of somatic embryogenic potential from excised zygotic embryos of carrot and maintenance of proembryonic cultures in hormone-free medium.

PubMed

Smith, D L; Krikorian, A D

1989-01-01

Excised zygotic embryos, mericarps ("seeds") and hypocotyls of seedlings of cultivated carrot Daucus carota cv. Scarlet Nantes were evaluated for their ability to generate somatic embryos on a semisolid hormone-free nutrient medium. Neither intact zygotic embryos nor hypocotyls ever produced somatic embryos. However, mericarps and broken zygotic embryos were excellent sources for somatic embryo production (response levels as high as 86%). Somatic embryo formation was highest from cotyledons, but was also observed on isolated hypocotyls and root tips of mature zygotic embryos. On media containing unreduced nitrogen, somatic embryo formation led to the generation of vigorous cultures comprised entirely of somatic embryos at various stages of development which in turn proliferated still other somatic embryos. However, a medium was devised which when 1-5 mM NH4+ was the sole nitrogen source, led only to a proliferation of globular proembryos. Sustained subculturing of these proembryos at 2-3 week intervals enabled establishment of highly uniform cultures in which no further development into more mature stages of embryonic development occurred. These have been maintained, without decline, as morphogenetically competent proembryonic globules for over ten months. A basal medium containing from 1-5 mM NH4+ as the sole nitrogen source appears not to be inductive to somatic proembryo formation. Instead, such a medium is best thought of as permissive to the expression of embryogenically determined cells within zygotic embryos. By excising and breaking or wounding zygotic embryos, constituent cells are probably released from positional or chemical restraints and thus are able to express their innate embryogenic potential. Once a proembryonic culture is established, this medium containing 1-5 mM NH4+ as the sole nitrogen source provides a nonpermissive environment to the development and growth of later embryonic stages, but it does allow the continued formation and multiplication of globular somatic proembryos. The sequence of events leading from excised broken zygotic embryos to the formation of somatic embryos and the maintenance of somatic proembryos are demonstrated by scanning electron microscopy and histological preparations. Germination levels from intact zygotic embryos on media with varying levels and ratios of unreduced vs. reduced inorganic nitrogen were determined as well and provided baseline or control data on the type of response obtained from nonwounded material.

Release of somatic embryogenic potential from excised zygotic embryos of carrot and maintenance of proembryonic cultures in hormone-free medium

NASA Technical Reports Server (NTRS)

Smith, D. L.; Krikorian, A. D.

1989-01-01

Excised zygotic embryos, mericarps ("seeds") and hypocotyls of seedlings of cultivated carrot Daucus carota cv. Scarlet Nantes were evaluated for their ability to generate somatic embryos on a semisolid hormone-free nutrient medium. Neither intact zygotic embryos nor hypocotyls ever produced somatic embryos. However, mericarps and broken zygotic embryos were excellent sources for somatic embryo production (response levels as high as 86%). Somatic embryo formation was highest from cotyledons, but was also observed on isolated hypocotyls and root tips of mature zygotic embryos. On media containing unreduced nitrogen, somatic embryo formation led to the generation of vigorous cultures comprised entirely of somatic embryos at various stages of development which in turn proliferated still other somatic embryos. However, a medium was devised which when 1-5 mM NH4+ was the sole nitrogen source, led only to a proliferation of globular proembryos. Sustained subculturing of these proembryos at 2-3 week intervals enabled establishment of highly uniform cultures in which no further development into more mature stages of embryonic development occurred. These have been maintained, without decline, as morphogenetically competent proembryonic globules for over ten months. A basal medium containing from 1-5 mM NH4+ as the sole nitrogen source appears not to be inductive to somatic proembryo formation. Instead, such a medium is best thought of as permissive to the expression of embryogenically determined cells within zygotic embryos. By excising and breaking or wounding zygotic embryos, constituent cells are probably released from positional or chemical restraints and thus are able to express their innate embryogenic potential. Once a proembryonic culture is established, this medium containing 1-5 mM NH4+ as the sole nitrogen source provides a nonpermissive environment to the development and growth of later embryonic stages, but it does allow the continued formation and multiplication of globular somatic proembryos. The sequence of events leading from excised broken zygotic embryos to the formation of somatic embryos and the maintenance of somatic proembryos are demonstrated by scanning electron microscopy and histological preparations. Germination levels from intact zygotic embryos on media with varying levels and ratios of unreduced vs. reduced inorganic nitrogen were determined as well and provided baseline or control data on the type of response obtained from nonwounded material.

Coordinate Regulation of Stem Cell Competition by Slit-Robo and JAK-STAT Signaling in the Drosophila Testis

PubMed Central

Stine, Rachel R.; Greenspan, Leah J.; Ramachandran, Kapil V.; Matunis, Erika L.

2014-01-01

Stem cells in tissues reside in and receive signals from local microenvironments called niches. Understanding how multiple signals within niches integrate to control stem cell function is challenging. The Drosophila testis stem cell niche consists of somatic hub cells that maintain both germline stem cells and somatic cyst stem cells (CySCs). Here, we show a role for the axon guidance pathway Slit-Roundabout (Robo) in the testis niche. The ligand Slit is expressed specifically in hub cells while its receptor, Roundabout 2 (Robo2), is required in CySCs in order for them to compete for occupancy in the niche. CySCs also require the Slit-Robo effector Abelson tyrosine kinase (Abl) to prevent over-adhesion of CySCs to the niche, and CySCs mutant for Abl outcompete wild type CySCs for niche occupancy. Both Robo2 and Abl phenotypes can be rescued through modulation of adherens junction components, suggesting that the two work together to balance CySC adhesion levels. Interestingly, expression of Robo2 requires JAK-STAT signaling, an important maintenance pathway for both germline and cyst stem cells in the testis. Our work indicates that Slit-Robo signaling affects stem cell function downstream of the JAK-STAT pathway by controlling the ability of stem cells to compete for occupancy in their niche. PMID:25375180

A practical approach to fibromyalgia.

PubMed Central

Cymet, Tyler Childs

2003-01-01

Fibromyalgia is the name given to a collection of symptoms with no clear physiologic cause, The constellation of symptoms are clearly recognizable as a distinct pathologic entity. The diagnosis is made through clinical observations made by the examiner. Differential diagnosis must include other somatic syndromes as well as disease entities like hepatitis, hypothyroidism, diabetes mellitus, electrolyte imbalance, multiple sclerosis, and cancer. Diagnostic criteria are given as guidelines for the diagnosis, not as absolute requirements. Treatment of this condition remains individualized and relies heavily on having a therapeutic relationship with a provider. Treatment of this syndrome needs to be looked at as an ongoing process. Goal oriented treatment aimed at maintaining specific functions can be directed at helping a patient get restorative sleep, alleviating the somatic pains that ail the patient, keeping a person productive, regulating schedules or through goal oriented agreements made with the patient. Since this syndrome is chronic and may effect all areas of a persons functioning the family and social support system of the person being treated need to be evaluated. Patients often seek alternative medical treatments for this problem including diet therapy, acupuncture, and herbal therapy. Treatment must involve more than just the symptoms presented and the patient can only be treated successfully if they are willing to work at changing their own perceptions, and ways of relating to stressors in their world. PMID:12749618

The RING finger/B-box factor TAM-1 and a retinoblastoma-like protein LIN-35 modulate context-dependent gene silencing in Caenorhabditis elegans.

PubMed

Hsieh, J; Liu, J; Kostas, S A; Chang, C; Sternberg, P W; Fire, A

1999-11-15

Context-dependent gene silencing is used by many organisms to stably modulate gene activity for large chromosomal regions. We have used tandem array transgenes as a model substrate in a screen for Caenorhabditis elegans mutants that affect context-dependent gene silencing in somatic tissues. This screen yielded multiple alleles of a previously uncharacterized gene, designated tam-1 (for tandem-array-modifier). Loss-of-function mutations in tam-1 led to a dramatic reduction in the activity of numerous highly repeated transgenes. These effects were apparently context dependent, as nonrepetitive transgenes retained activity in a tam-1 mutant background. In addition to the dramatic alterations in transgene activity, tam-1 mutants showed modest alterations in expression of a subset of endogenous cellular genes. These effects include genetic interactions that place tam-1 into a group called the class B synMuv genes (for a Synthetic Multivulva phenotype); this family plays a negative role in the regulation of RAS pathway activity in C. elegans. Loss-of-function mutants in other members of the class-B synMuv family, including lin-35, which encodes a protein similar to the tumor suppressor Rb, exhibit a hypersilencing in somatic transgenes similar to that of tam-1 mutants. Molecular analysis reveals that tam-1 encodes a broadly expressed nuclear protein with RING finger and B-box motifs.

Repeated variate stress in male rats induces increased voiding frequency, somatic sensitivity, and urinary bladder nerve growth factor expression

PubMed Central

Merrill, Liana; Malley, Susan

2013-01-01

Stress exacerbates symptoms of functional lower urinary tract disorders including interstitial cystitis (IC)/bladder pain syndrome (BPS) and overactive bladder (OAB) in humans, but mechanisms contributing to symptom worsening are unknown. These studies address stress-induced changes in the structure and function of the micturition reflex using an animal model of stress in male rats. Rats were exposed to 7 days of repeated variate stress (RVS). Target organ (urinary bladder, thymus, adrenal gland) tissues were collected and weighed following RVS. Evans blue (EB) concentration and histamine, myeloperoxidase (MPO), nerve growth factor (NGF), brain-derived neurotropic factor (BDNF), and CXCL12 protein content (ELISA) were measured in the urinary bladder, and somatic sensitivity of the hindpaw and pelvic regions was determined following RVS. Bladder function was evaluated using continuous, open outlet intravesical infusion of saline in conscious rats. Increases in body weight gain were significantly (P ≤ 0.01) attenuated by day 5 of RVS, and adrenal weight was significantly (P ≤ 0.05) increased. Histamine, MPO, NGF, and CXCL12 protein expression was significantly (P ≤ 0.01) increased in the urinary bladder after RVS. Somatic sensitivity of the hindpaw and pelvic regions was significantly (P ≤ 0.01) increased at all monofilament forces tested (0.1–4 g) after RVS. Intercontraction interval, infused volume, and void volume were significantly (P ≤ 0.01) decreased after RVS. These studies demonstrate increased voiding frequency, histamine, MPO, NGF, and CXCL12 bladder content and somatic sensitivity after RVS suggesting an inflammatory component to stress-induced changes in bladder function and somatic sensitivity. PMID:23657640

Somatic Symptoms in Traumatized Children and Adolescents

ERIC Educational Resources Information Center

Kugler, Brittany B.; Bloom, Marlene; Kaercher, Lauren B.; Truax, Tatyana V.; Storch, Eric A.

2012-01-01

Childhood exposure to trauma has been associated with increased rates of somatic symptoms (SS), which may contribute to diminished daily functioning. One hundred and sixty-one children residing at a residential treatment home who had experienced neglect and/or abuse were administered the Trauma Symptom Checklist for Children (TSCC), the…

Acculturation, Stressors, and Somatization Patterns among Students from Extreme South Texas.

ERIC Educational Resources Information Center

Montgomery, Gary T.

1992-01-01

Cervantes and Castro's model proposes that acculturation level functions both as external stressor and internal mediator influencing one's appraisal of environmental stressors and somatic/health outcomes. The model was supported by surveys of headache causes, severity, symptoms, and coping strategies among 844 Mexican-American high school and…

Expression and functional analysis of menin in a multiple endocrine neoplasia type 1 (MEN1) patient with somatic loss of heterozygosity in chromosome 11q13 and unidentified germline mutation of the MEN1 gene.

PubMed

Naito, Junko; Kaji, Hiroshi; Sowa, Hideaki; Kitazawa, Riko; Kitazawa, Sohei; Tsukada, Toshihiko; Hendy, Geoffrey N; Sugimoto, Toshitsugu; Chihara, Kazuo

2006-06-01

In some patients with multiple endocrine neoplasia type 1 (MEN1) it is not possible to identify a germline mutation in the MEN1 gene. We sought to document the loss of expression and function of the MEN1 gene product, menin, in the tumors of such a patient. The proband is an elderly female patient with primary hyperparathyroidism, pancreatic islet tumor, and breast cancer. Her son has primary hyperparathyroidism. No germline MEN1 mutation was identified in the proband or her son. However, loss of heterozygosity at the MEN1 locus and complete lack of menin expression were demonstrated in the proband's tumor tissue. The proband's cultured parathyroid cells lacked the normal reduction in proliferation and parathyroid hormone secretion in response to transforming growth factor- beta. This assessment provided insight into the molecular pathogenesis of the patient and provides evidence for a critical requirement for menin in the antiproliferative action of transforming growth factor-beta.

In-vitro morphogenesis of corn (Zea mays L.) : I. Differentiation of multiple shoot clumps and somatic embryos from shoot tips.

PubMed

Zhong, H; Srinivasan, C; Sticklen, M B

1992-07-01

In-vitro methods have been developed to regenerate clumps of multiple shoots and somatic embryos at high frequency from shoot tips of aseptically-grown seedlings as well as from shoot apices of precociously-germinated immature zygotic embryos of corn (Zea mays L.). About 500 shoots were produced from a shoot tip after eight weeks of culture (primary culture and one subculture of four weeks) in darkness on Murashige and Skoog basal medium (MS) supplemented with 500 mg/L casein hydrolysate (CH) and 9 μM N(6)-benzyladenine (BA). In this medium, shoots formed in shoot tips as tightly packed "multiple shoot clumps" (MSC), which were composed of some axillary shoots and many adventitious shoots. When the shoot tips were cultured on MS medium containing 500 mg/L CH, 9 μM BA and 2.25 μM 2,4-dichlorophenoxyacetic acid (2,4-D), most of the shoots in the clumps were adventitious in origin. Similar shoot tips cultured on MS medium containing 500 mg/L CH, 4.5 μM BA and 2.25 μM 2,4-D regenerated many somatic embryos within eight weeks of culture. Somatic embryos were produced either directly from the shoot apical meristems or from calli derived from the shoots apices. Both the MSC and the embryos produced normal shoots on MS medium containing 2.25 μM BA and 1.8 μM indole-3-butyric acid (IBA). These shoots were rooted on MS medium containing 3.6 μM IBA, and fertile corn plants were grown in the greenhouse. The sweet-corn genotype, Honey N Pearl, was used for the experiments described above, but shoot-tip cultures from all of 19 other corn genotypes tested also formed MSC on MS medium containing 500 mg/L CH and 9 μM BA.

Somatic mutations in salivary duct carcinoma and potential therapeutic targets

PubMed Central

Smith, Joel A.; Clarke, Angus J.; Luk, Peter P.; Selinger, Christina I.; Mahon, Kate L.; Kraitsek, Spiridoula; Palme, Carsten; Boyer, Michael J.; Dinger, Marcel E.; Cowley, Mark J.; O’Toole, Sandra A.

2017-01-01

Background Salivary duct carcinomas (SDCa) are rare highly aggressive malignancies. Most patients die from distant metastatic disease within three years of diagnosis. There are limited therapeutic options for disseminated disease. Results 11 cases showed androgen receptor expression and 6 cases showed HER2 amplification. 6 Somatic mutations with additional available targeted therapies were identified: EGFR (p.G721A: Gefitinib), PDGFRA (p.H845Y: Imatinib and Crenolanib), PIK3CA (p.H1047R: Everolimus), ERBB2 (p.V842I: Lapatinib), HRAS (p.Q61R: Selumetinib) and KIT (p.T670I: Sorafenib). Furthermore, alterations in PTEN, PIK3CA and HRAS that alter response to androgen deprivation therapy and HER2 inhibition were also seen. Materials and Methods Somatic mutation analysis was performed on DNA extracted from 15 archival cases of SDCa using the targeted Illumina TruSeq Amplicon Cancer Panel. Potential targetable genetic alterations were identified using extensive literature and international somatic mutation database (COSMIC, KEGG) search. Immunohistochemistry for androgen receptor and immunohistochemistry and fluorescent in situ hybridization for HER2 were also performed. Conclusions SDCa show multiple somatic mutations, some that are amenable to pharmacologic manipulation and others that confer resistance to treatments currently under investigation. These findings emphasize the need to develop testing and treatment strategies for SDCa. PMID:29100278

Physical "phantasies" and family functions: overcoming the mind/body dualism in somatization.

PubMed

Redekop, F; Stuart, S; Mertens, C

1999-01-01

In this article, we examine some of the ways in which family therapists have conceptualized the experience of illness of unexplained physical origin. We argue that opinions about the etiology of somatic symptoms should not be the primary focus of therapeutic work with people who share the prototypical characteristics of what has been defined as "somatization disorder." We suggest that current research in neurobiology can expand the linguistic resources of clinicians and help them avoid perpetuating unhelpful dichotomies between the mind and the body.

Cloned cows with short telomeres deliver healthy offspring with normal-length telomeres.

PubMed

Miyashita, Norikazu; Kubo, Yasuaki; Yonai, Miharu; Kaneyama, Kanako; Saito, Norio; Sawai, Ken; Minamihashi, Akira; Suzuki, Toshiyuki; Kojima, Toshiyuki; Nagai, Takashi

2011-10-01

Dolly, the first mammal cloned from a somatic cell, had shorter telomeres than age-matched controls and died at an early age because of disease. To investigate longevity and lifetime performance in cloned animals, we produced cloned cows with short telomeres using oviductal epithelial cells as donor cells. At 5 years of age, despite the presence of short telomeres, all cloned cows delivered multiple healthy offspring following artificial insemination with conventionally processed spermatozoa from noncloned bulls, and their milk production was comparable to that of donor cows. Moreover, this study revealed that the offspring had normal-length telomeres in their leukocytes and major organs. Thus, cloned animals have normal functional germ lines, and therefore germ line function can completely restore telomere lengths in clone gametes by telomerase activity, resulting in healthy offspring with normal-length telomeres.

Somatic mosaicism of androgen receptor CAG repeats in colorectal carcinoma epithelial cells from men.

PubMed

Di Fabio, Francesco; Alvarado, Carlos; Gologan, Adrian; Youssef, Emad; Voda, Linda; Mitmaker, Elliot; Beitel, Lenore K; Gordon, Philip H; Trifiro, Mark

2009-06-01

The X-linked human androgen receptor gene (AR) contains an exonic polymorphic trinucleotide CAG. The length of this encoded CAG tract inversely affects AR transcriptional activity. Colorectal carcinoma is known to express the androgen receptor, but data on somatic CAG repeat lengths variations in malignant and normal epithelial cells are still sporadic. Using laser capture microdissection (LCM), epithelial cells from colorectal carcinoma and normal-appearing mucosa were collected from the fresh tissue of eight consecutive male patients undergoing surgery (mean age, 70 y; range, 54-82). DNA isolated from each LCM sample underwent subsequent PCR and DNA sequencing to precisely determine AR CAG repeat lengths and the presence of microsatellite instability (MSI). Different AR CAG repeat lengths were observed in colorectal carcinoma (ranging from 0 to 36 CAG repeats), mainly in the form of multiple shorter repeat lengths. This genetic heterogeneity (somatic mosaicism) was also found in normal-appearing colorectal mucosa. Half of the carcinoma cases examined tended to have a higher number of AR CAG repeat lengths with a wider range of repeat size variation compared to normal mucosa. MSI carcinomas tended to have longer median AR CAG repeat lengths (n = 17) compared to microsatellite stable carcinomas (n = 14), although the difference was not significant (P = 0.31, Mann-Whitney test). Multiple unique somatic mutations of the AR CAG repeats occur in colorectal mucosa and in carcinoma, predominantly resulting in shorter alleles. Colorectal epithelial cells carrying AR alleles with shorter CAG repeat lengths may be more androgen-sensitive and therefore have a growth advantage.

Factors Associated with Suicidal Ideation and Quality of Life in Adolescents from Puerto Rico with Type 1 Diabetes.

PubMed

Guerrero-Ramírez, Grace; Cumba-Avilés, Eduardo

2018-03-01

People with type 1 diabetes (T1D) may experience significant changes in their daily routines due to this condition, which frequently results in depressive symptoms and the deterioration of their quality of life. We examined the factors associated with suicidal ideation (SI) and diabetes-related quality of life (DRQOL) in adolescents (aged 12 to 17) with T1D. The sample consisted of 51 youths (29 girls) recruited during a treatment study for depression. They completed the Diabetes Quality of Life for Youth questionnaire, the Suicidal Ideation Questionnaire Junior, and other measures that explore emotional, cognitive, somatic, behavioral, and relational aspects. Their caregivers completed the Barriers to Adherence Questionnaire and the Somatic Complaints subscale of the Child Behavior Checklist, among other measures. We used correlation and multiple linear regression analyses to identify the factors associated with the dependent variables. The variables associated with SI were depression, somatic complaints, perceived family emotional support, self care for diabetes, self-deprecation, helplessness, and hopelessness, among others. In a multiple regression analysis, the first 3 accounted for 46% of the variance. Those related to DRQOL included cognitive alterations, barriers to adherence, perceived family emotional support, self-efficacy for diabetes and for depression, helplessness, anxiety, and self-deprecation, among others. The first 4 accounted for 61% of the variance. Our findings highlight the impact of emotional, cognitive, somatic, behavioral, and relational aspects on the quality of mental health and the DRQOL of youth with T1D, as well as their pertinence for the development of psychosocial interventions for this population.

Sperm quality assays: How good are they? The horse perspective.

PubMed

Love, Charles C

2018-04-22

Sperm quality assays have increased in number in the last 10 years. Most of these assays are flow cytometry based in application and are modified from assays that have been developed to measure somatic cell function. The goal of any sperm quality assay should be to advance the clinicians/researchers understanding of sperm cell function and the relationship to fertility. While these assays appear to measure somatic cell-like functions in sperm there tends to be little understanding how the results of these assays relate to fertility. Copyright © 2018. Published by Elsevier B.V.

Overlapping SETBP1 gain-of-function mutations in Schinzel-Giedion syndrome and hematologic malignancies

PubMed Central

Steehouwer, Marloes; Gilissen, Christian; Graham, Sarah A.; Hoover-Fong, Julie; Telegrafi, Aida B.; Destree, Anne; Smigiel, Robert; Lambie, Lindsday A.; Kayserili, Hülya; Altunoglu, Umut; Lapi, Elisabetta; Uzielli, Maria Luisa; Aracena, Mariana; Nur, Banu G.; Mihci, Ercan; Moreira, Lilia M. A.; Borges Ferreira, Viviane; Horovitz, Dafne D. G.; da Rocha, Katia M.; Jezela-Stanek, Aleksandra; Brooks, Alice S.; Reutter, Heiko; Cohen, Julie S.; Fatemi, Ali; Smitka, Martin; Grebe, Theresa A.; Di Donato, Nataliya; Deshpande, Charu; Vandersteen, Anthony; Marques Lourenço, Charles; Dufke, Andreas; Rossier, Eva; Andre, Gwenaelle; Baumer, Alessandra; Spencer, Careni; McGaughran, Julie; Franke, Lude; Veltman, Joris A.; De Vries, Bert B. A.; Schinzel, Albert; Fisher, Simon E.; Hoischen, Alexander

2017-01-01

Schinzel-Giedion syndrome (SGS) is a rare developmental disorder characterized by multiple malformations, severe neurological alterations and increased risk of malignancy. SGS is caused by de novo germline mutations clustering to a 12bp hotspot in exon 4 of SETBP1. Mutations in this hotspot disrupt a degron, a signal for the regulation of protein degradation, and lead to the accumulation of SETBP1 protein. Overlapping SETBP1 hotspot mutations have been observed recurrently as somatic events in leukemia. We collected clinical information of 47 SGS patients (including 26 novel cases) with germline SETBP1 mutations and of four individuals with a milder phenotype caused by de novo germline mutations adjacent to the SETBP1 hotspot. Different mutations within and around the SETBP1 hotspot have varying effects on SETBP1 stability and protein levels in vitro and in in silico modeling. Substitutions in SETBP1 residue I871 result in a weak increase in protein levels and mutations affecting this residue are significantly more frequent in SGS than in leukemia. On the other hand, substitutions in residue D868 lead to the largest increase in protein levels. Individuals with germline mutations affecting D868 have enhanced cell proliferation in vitro and higher incidence of cancer compared to patients with other germline SETBP1 mutations. Our findings substantiate that, despite their overlap, somatic SETBP1 mutations driving malignancy are more disruptive to the degron than germline SETBP1 mutations causing SGS. Additionally, this suggests that the functional threshold for the development of cancer driven by the disruption of the SETBP1 degron is higher than for the alteration in prenatal development in SGS. Drawing on previous studies of somatic SETBP1 mutations in leukemia, our results reveal a genotype-phenotype correlation in germline SETBP1 mutations spanning a molecular, cellular and clinical phenotype. PMID:28346496

Impact of Pretreatment With Antidepressants on the Efficacy of Duloxetine in Terms of Mood Symptoms and Functioning: An Analysis of 15 Pooled Major Depressive Disorder Studies

PubMed Central

Barros, Bruno R.; Schacht, Alexander; Happich, Michael; Televantou, Foula; Berggren, Lovisa; Walker, Daniel J.

2014-01-01

Objective: This post hoc analysis aimed to determine whether patients with major depressive disorder (MDD) in duloxetine trials who were antidepressant naive or who were previously exposed to antidepressants exhibited differences in efficacy and functioning. Method: Data were pooled from 15 double-blind, placebo- and/or active-controlled duloxetine trials of adult patients with MDD conducted by Eli Lilly and Company. The individual studies took place between March 2000 and November 2009. Data were analyzed using 4 pretreatment subgroups: first-episode never treated, multiple-episode never treated, treated previously only with selective serotonin reuptake inhibitors (SSRIs), and previously treated with antidepressants other than just SSRIs. Measures included the 17-item Hamilton Depression Rating Scale (HDRS-17) total and somatic symptom subscale scores, Montgomery-Asberg Depression Rating Scale (MADRS) total score, and Sheehan Disability Scale total score. Response rates (50% and 30%) were based on the HDRS-17 total score and remission rates on either the HDRS-17 or MADRS total score. Results: Response and remission rates were significantly greater (P < .05 in 11 of 12 comparisons) for duloxetine versus placebo in the 4 subgroups. A trend of greater response and remission occurred for first-episode versus multiple-episode patients; both groups were generally higher than the antidepressant-treated groups. Mean changes in efficacy measures were mostly significantly greater (P < .05 in 13 of 16 comparisons) for duloxetine versus placebo within each pretreatment subgroup, with some (P < .05 in 2 of 24 comparisons) significant interaction effects between subgroups on HDRS-17 total and somatic symptoms scores. Conclusions: Duloxetine was generally superior to placebo on response and remission rates and in mean change on efficacy measures. Response and remission rates were numerically greater for first-episode versus multiple-episode and drug-treated patients. Mean change differences on efficacy measures among the 4 subgroups were inconsistent. Duloxetine showed a similar therapeutic effect independent of episode frequency and antidepressant pretreatment. PMID:25667808

Somatic and vicarious pain are represented by dissociable multivariate brain patterns

PubMed Central

Krishnan, Anjali; Woo, Choong-Wan; Chang, Luke J; Ruzic, Luka; Gu, Xiaosi; López-Solà, Marina; Jackson, Philip L; Pujol, Jesús; Fan, Jin; Wager, Tor D

2016-01-01

Understanding how humans represent others’ pain is critical for understanding pro-social behavior. ‘Shared experience’ theories propose common brain representations for somatic and vicarious pain, but other evidence suggests that specialized circuits are required to experience others’ suffering. Combining functional neuroimaging with multivariate pattern analyses, we identified dissociable patterns that predicted somatic (high versus low: 100%) and vicarious (high versus low: 100%) pain intensity in out-of-sample individuals. Critically, each pattern was at chance in predicting the other experience, demonstrating separate modifiability of both patterns. Somatotopy (upper versus lower limb: 93% accuracy for both conditions) was also distinct, located in somatosensory versus mentalizing-related circuits for somatic and vicarious pain, respectively. Two additional studies demonstrated the generalizability of the somatic pain pattern (which was originally developed on thermal pain) to mechanical and electrical pain, and also demonstrated the replicability of the somatic/vicarious dissociation. These findings suggest possible mechanisms underlying limitations in feeling others’ pain, and present new, more specific, brain targets for studying pain empathy. DOI: http://dx.doi.org/10.7554/eLife.15166.001 PMID:27296895

The subcellular distribution of T-type Ca2+ channels in interneurons of the lateral geniculate nucleus.

PubMed

Allken, Vaneeda; Chepkoech, Joy-Loi; Einevoll, Gaute T; Halnes, Geir

2014-01-01

Inhibitory interneurons (INs) in the lateral geniculate nucleus (LGN) provide both axonal and dendritic GABA output to thalamocortical relay cells (TCs). Distal parts of the IN dendrites often enter into complex arrangements known as triadic synapses, where the IN dendrite plays a dual role as postsynaptic to retinal input and presynaptic to TC dendrites. Dendritic GABA release can be triggered by retinal input, in a highly localized process that is functionally isolated from the soma, but can also be triggered by somatically elicited Ca(2+)-spikes and possibly by backpropagating action potentials. Ca(2+)-spikes in INs are predominantly mediated by T-type Ca(2+)-channels (T-channels). Due to the complex nature of the dendritic signalling, the function of the IN is likely to depend critically on how T-channels are distributed over the somatodendritic membrane (T-distribution). To study the relationship between the T-distribution and several IN response properties, we here run a series of simulations where we vary the T-distribution in a multicompartmental IN model with a realistic morphology. We find that the somatic response to somatic current injection is facilitated by a high T-channel density in the soma-region. Conversely, a high T-channel density in the distal dendritic region is found to facilitate dendritic signalling in both the outward direction (increases the response in distal dendrites to somatic input) and the inward direction (the soma responds stronger to distal synaptic input). The real T-distribution is likely to reflect a compromise between several neural functions, involving somatic response patterns and dendritic signalling.

The Subcellular Distribution of T-Type Ca2+ Channels in Interneurons of the Lateral Geniculate Nucleus

PubMed Central

Allken, Vaneeda; Chepkoech, Joy-Loi; Einevoll, Gaute T.; Halnes, Geir

2014-01-01

Inhibitory interneurons (INs) in the lateral geniculate nucleus (LGN) provide both axonal and dendritic GABA output to thalamocortical relay cells (TCs). Distal parts of the IN dendrites often enter into complex arrangements known as triadic synapses, where the IN dendrite plays a dual role as postsynaptic to retinal input and presynaptic to TC dendrites. Dendritic GABA release can be triggered by retinal input, in a highly localized process that is functionally isolated from the soma, but can also be triggered by somatically elicited Ca2+-spikes and possibly by backpropagating action potentials. Ca2+-spikes in INs are predominantly mediated by T-type Ca2+-channels (T-channels). Due to the complex nature of the dendritic signalling, the function of the IN is likely to depend critically on how T-channels are distributed over the somatodendritic membrane (T-distribution). To study the relationship between the T-distribution and several IN response properties, we here run a series of simulations where we vary the T-distribution in a multicompartmental IN model with a realistic morphology. We find that the somatic response to somatic current injection is facilitated by a high T-channel density in the soma-region. Conversely, a high T-channel density in the distal dendritic region is found to facilitate dendritic signalling in both the outward direction (increases the response in distal dendrites to somatic input) and the inward direction (the soma responds stronger to distal synaptic input). The real T-distribution is likely to reflect a compromise between several neural functions, involving somatic response patterns and dendritic signalling. PMID:25268996

PTT analysis of polyps from FAP patients reveals a great majority of APC truncating mutations

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

Luijt, R.B. van der; Khan, P.M.; Tops, C.M.J.

The adenomatous polyposis coli (APC) gene plays an important role in colorectal carcinogenesis. Germline APC mutations are associated with familial adenomatous polyposis (FAP), an autosomal dominantly inherited predisposition to colorectal cancer, characterized by the development of numerous adenomatous polyps in the large intestine. In order to investigate whether somatic inactivation of the remaining APC allele is necessary for adenoma formation, we collected multiple adenomatous polyps from individual FAP patients and investigated the presence of somatic mutations in the APC gene. The analysis of somatic APC mutations in these tumor samples was performed using a rapid and sensitive assay, called themore » protein truncation test (PTT). Chain-terminating somatic APC mutations were detected in the great majority of the tumor samples investigated. As expected, these mutations were mainly located in the mutation cluster region (MCR) in exon 15. Our results confirm that somatic mutation of the second APC allele is required for adenoma formation in FAP. Interestingly, in the polyps investigated in our study, the second APC allele is somatically inactivated through point mutation leading to a stop codon rather than by loss of heterozygosity. The observation that somatic second hits in APC are required for tumor development in FAP is in apparent accordance with the Knudson hypothesis for classical tumor suppressor genes. However, it is yet unknown whether chain-terminating APC mutations lead to a truncated protein exerting a dominant-negative effect or whether these mutations result in a null allele. Further investigation of this important issue will hopefully provide a better understanding of the mechanism of action of the mutated APC alleles in colorectal carcinogenesis.« less

Somatic Symptoms in Children and Adolescents with Anxiety Disorders

ERIC Educational Resources Information Center

Ginsburg, Golda S.; Riddle, Mark A.; Davies, Mark

2006-01-01

Objective: To evaluate the prevalence of somatic symptoms (SSs) in children and adolescents with anxiety disorders; the relationship between SSs and anxiety severity, impairment, and child global functioning; and the impact of fluvoxamine (FLV) versus pill placebo (PBO) on reducing SSs. Method: As part of a double-blind, placebo-controlled trial,…

Germline activating MTOR mutation arising through gonadal mosaicism in two brothers with megalencephaly and neurodevelopmental abnormalities.

PubMed

Mroske, Cameron; Rasmussen, Kristen; Shinde, Deepali N; Huether, Robert; Powis, Zoe; Lu, Hsiao-Mei; Baxter, Ruth M; McPherson, Elizabeth; Tang, Sha

2015-11-05

In humans, Mammalian Target of Rapamycin (MTOR) encodes a 300 kDa serine/ threonine protein kinase that is ubiquitously expressed, particularly at high levels in brain. MTOR functions as an integrator of multiple cellular processes, and in so doing either directly or indirectly regulates the phosphorylation of at least 800 proteins. While somatic MTOR mutations have been recognized in tumors for many years, and more recently in hemimegalencephaly, germline MTOR mutations have rarely been described. We report the successful application of family-trio Diagnostic Exome Sequencing (DES) to identify the underlying molecular etiology in two brothers with multiple neurological and developmental lesions, and for whom previous testing was non-diagnostic. The affected brothers, who were 6 and 23 years of age at the time of DES, presented symptoms including but not limited to mild Autism Spectrum Disorder (ASD), megalencephaly, gross motor skill delay, cryptorchidism and bilateral iris coloboma. Importantly, we determined that each affected brother harbored the MTOR missense alteration p.E1799K (c.5395G>A). This exact variant has been previously identified in multiple independent human somatic cancer samples and has been shown to result in increased MTOR activation. Further, recent independent reports describe two unrelated families in whom p.E1799K co-segregated with megalencephaly and intellectual disability (ID); in both cases, p.E1799K was shown to have originated due to germline mosaicism. In the case of the family reported herein, the absence of p.E1799K in genomic DNA extracted from the blood of either parent suggests that this alteration most likely arose due to gonadal mosaicism. Further, the p.E1799K variant exerts its effect by a gain-of-function (GOF), autosomal dominant mechanism. Herein, we describe the use of DES to uncover an activating MTOR missense alteration of gonadal mosaic origin that is likely to be the causative mutation in two brothers who present multiple neurological and developmental abnormalities. Our report brings the total number of families who harbor MTOR p.E1799K in association with megalencephaly and ID to three. In each case, evidence suggests that p.E1799K arose in the affected individuals due to gonadal mosaicism. Thus, MTOR p.E1799K can now be classified as a pathogenic GOF mutation that causes megalencephaly and cognitive impairment in humans.

Somatic NLRP3 mosaicism in Muckle-Wells syndrome. A genetic mechanism shared by different phenotypes of cryopyrin-associated periodic syndromes.

PubMed

Nakagawa, Kenji; Gonzalez-Roca, Eva; Souto, Alejandro; Kawai, Toshinao; Umebayashi, Hiroaki; Campistol, Josep María; Cañellas, Jeronima; Takei, Syuji; Kobayashi, Norimoto; Callejas-Rubio, Jose Luis; Ortego-Centeno, Norberto; Ruiz-Ortiz, Estíbaliz; Rius, Fina; Anton, Jordi; Iglesias, Estibaliz; Jimenez-Treviño, Santiago; Vargas, Carmen; Fernandez-Martin, Julian; Calvo, Inmaculada; Hernández-Rodríguez, José; Mendez, María; Dordal, María Teresa; Basagaña, Maria; Bujan, Segundo; Yashiro, Masato; Kubota, Tetsuo; Koike, Ryuji; Akuta, Naoko; Shimoyama, Kumiko; Iwata, Naomi; Saito, Megumu K; Ohara, Osamu; Kambe, Naotomo; Yasumi, Takahiro; Izawa, Kazushi; Kawai, Tomoki; Heike, Toshio; Yagüe, Jordi; Nishikomori, Ryuta; Aróstegui, Juan I

2015-03-01

: Familial cold autoinflammatory syndrome, Muckle-Wells syndrome (MWS), and chronic, infantile, neurological, cutaneous and articular (CINCA) syndrome are dominantly inherited autoinflammatory diseases associated to gain-of-function NLRP3 mutations and included in the cryopyrin-associated periodic syndromes (CAPS). A variable degree of somatic NLRP3 mosaicism has been detected in ≈35% of patients with CINCA. However, no data are currently available regarding the relevance of this mechanism in other CAPS phenotypes. To evaluate somatic NLRP3 mosaicism as the disease-causing mechanism in patients with clinical CAPS phenotypes other than CINCA and NLRP3 mutation-negative. NLRP3 analyses were performed by Sanger sequencing and by massively parallel sequencing. Apoptosis-associated Speck-like protein containing a CARD (ASC)-dependent nuclear factor kappa-light chain-enhancer of activated B cells (NF-κB) activation and transfection-induced THP-1 cell death assays determined the functional consequences of the detected variants. A variable degree (5.5-34.9%) of somatic NLRP3 mosaicism was detected in 12.5% of enrolled patients, all of them with a MWS phenotype. Six different missense variants, three novel (p.D303A, p.K355T and p.L411F), were identified. Bioinformatics and functional analyses confirmed that they were disease-causing, gain-of-function NLRP3 mutations. All patients treated with anti-interleukin1 drugs showed long-lasting positive responses. We herein show somatic NLRP3 mosaicism underlying MWS, probably representing a shared genetic mechanism in CAPS not restricted to CINCA syndrome. The data here described allowed definitive diagnoses of these patients, which had serious implications for gaining access to anti-interleukin 1 treatments under legal indication and for genetic counselling. The detection of somatic mosaicism is difficult when using conventional methods. Potential candidates should benefit from the use of modern genetic tools. Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://group.bmj.com/group/rights-licensing/permissions.

Big Five personality traits and medically unexplained symptoms in later life.

PubMed

van Dijk, S D M; Hanssen, D; Naarding, P; Lucassen, P; Comijs, H; Oude Voshaar, R

2016-10-01

Personality dysfunction has been postulated as the most clinically salient problem of persons suffering from medically unexplained symptoms (MUS) but empirical studies are scarce. This study aims to compare the personality profile of older patients suffering from MUS with two comparison groups and a control group. Ninety-six older patients with MUS were compared with 153 frequent attenders in primary care suffering from medically explained symptoms (MES), 255 patients with a past-month depressive disorder (DSM-IV-TR), and a control group of 125 older persons. The Big Five personality domains (NEO-Five-Factor Inventory) were compared between groups by multiple ANCOVAs adjusted for age, sex, education, partner status and cognitive functioning. Linear regression analyses were applied to examine the association between health anxiety (Whitley Index) and somatization (Brief Symptom Inventory). The four groups differed with respect to neuroticism (P<0.001), extraversion (P<0.001), and agreeableness (P=0.045). Post hoc analyses, showed that MUS patients compared to controls scored higher on neuroticism and agreeableness, and compared to depressed patients lower on neuroticism and higher on extraversion as well agreeableness. Interestingly, MUS and MES patients had a similar personality profile. Health anxiety and somatization were associated with a higher level of neuroticism and a lower level of extraversion and conscientiousness, irrespective whether the physical symptom was explained or not. Older patients with MUS have a specific personality profile, comparable to MES patients. Health anxiety and somatization may be better indicators of psychopathology than whether a physical symptom is medically explained or not. Copyright © 2016 Elsevier Masson SAS. All rights reserved.

DNA Methylation Profiling of Embryonic Stem Cell Differentiation into the Three Germ Layers

PubMed Central

Isagawa, Takayuki; Nagae, Genta; Shiraki, Nobuaki; Fujita, Takanori; Sato, Noriko; Ishikawa, Shumpei; Kume, Shoen; Aburatani, Hiroyuki

2011-01-01

Embryogenesis is tightly regulated by multiple levels of epigenetic regulation such as DNA methylation, histone modification, and chromatin remodeling. DNA methylation patterns are erased in primordial germ cells and in the interval immediately following fertilization. Subsequent developmental reprogramming occurs by de novo methylation and demethylation. Variance in DNA methylation patterns between different cell types is not well understood. Here, using methylated DNA immunoprecipitation and tiling array technology, we have comprehensively analyzed DNA methylation patterns at proximal promoter regions in mouse embryonic stem (ES) cells, ES cell-derived early germ layers (ectoderm, endoderm and mesoderm) and four adult tissues (brain, liver, skeletal muscle and sperm). Most of the methylated regions are methylated across all three germ layers and in the three adult somatic tissues. This commonly methylated gene set is enriched in germ cell-associated genes that are generally transcriptionally inactive in somatic cells. We also compared DNA methylation patterns by global mapping of histone H3 lysine 4/27 trimethylation, and found that gain of DNA methylation correlates with loss of histone H3 lysine 4 trimethylation. Our combined findings indicate that differentiation of ES cells into the three germ layers is accompanied by an increased number of commonly methylated DNA regions and that these tissue-specific alterations in methylation occur for only a small number of genes. DNA methylation at the proximal promoter regions of commonly methylated genes thus appears to be an irreversible mark which functions to fix somatic lineage by repressing the transcription of germ cell-specific genes. PMID:22016810

The personality trait of neuroticism is strongly associated with long-term morbidity in testicular cancer survivors.

PubMed

Grov, Ellen Karine; Fosså, Sophie D; Bremnes, Roy M; Dahl, Olav; Klepp, Olbjørn; Wist, Erik; Dahl, Alv A

2009-01-01

Neuroticism is a personality trait expressing nervousness and insecurity. Associations between neuroticism and morbidity in long-term cancer survivors have hardly been explored. The aim of this study was to explore associations between neuroticism and somatic and mental morbidity and lifestyle issues in long-term survivors of testicular cancer (TCSs). All Norwegian TCSs treated between 1980 and 1994 (n = 1 814) were invited to this cross-sectional study. Among them 1 428 (79% response rate) delivered valid data. Neuroticism was self-rated on an abridged version of the Eysenck Personality Inventory. Information was collected by mailed questionnaires. The associations of neuroticism and self-reported variables were tested with multivariate logistic regression analyses. Neuroticism was significantly associated with presence of somatic complaints, reduced physical function, neurotoxic side-effects (tinnitus, hearing impairment, peripheral neuropathy, and Raynaud's Phenomenon), self-esteem, concerns about not being able to father children, sexual problems, hazardous alcohol use, daily use of medication, use of sedatives and hypnotics, recent visits to a general practitioner, and seeing a psychologist/ psychiatrist after ended cancer treatment. Poor self-rated health, higher number of negative life events, economical problems and problems getting loans granted showed significant associations with neuroticism. Neuroticism in TCSs at long-term follow-up is significantly associated with somatic and mental morbidities, and several aspects of unhealthy lifestyle. High levels of neuroticism should be considered in TCSs expressing multiple complaints and concerns at follow-up consultations. Assessment of neuroticism may be clinically important in order to offer appropriate interventions to prevent and manage morbidity in TCSs.

DNA methylation profiling of embryonic stem cell differentiation into the three germ layers.

PubMed

Isagawa, Takayuki; Nagae, Genta; Shiraki, Nobuaki; Fujita, Takanori; Sato, Noriko; Ishikawa, Shumpei; Kume, Shoen; Aburatani, Hiroyuki

2011-01-01

Embryogenesis is tightly regulated by multiple levels of epigenetic regulation such as DNA methylation, histone modification, and chromatin remodeling. DNA methylation patterns are erased in primordial germ cells and in the interval immediately following fertilization. Subsequent developmental reprogramming occurs by de novo methylation and demethylation. Variance in DNA methylation patterns between different cell types is not well understood. Here, using methylated DNA immunoprecipitation and tiling array technology, we have comprehensively analyzed DNA methylation patterns at proximal promoter regions in mouse embryonic stem (ES) cells, ES cell-derived early germ layers (ectoderm, endoderm and mesoderm) and four adult tissues (brain, liver, skeletal muscle and sperm). Most of the methylated regions are methylated across all three germ layers and in the three adult somatic tissues. This commonly methylated gene set is enriched in germ cell-associated genes that are generally transcriptionally inactive in somatic cells. We also compared DNA methylation patterns by global mapping of histone H3 lysine 4/27 trimethylation, and found that gain of DNA methylation correlates with loss of histone H3 lysine 4 trimethylation. Our combined findings indicate that differentiation of ES cells into the three germ layers is accompanied by an increased number of commonly methylated DNA regions and that these tissue-specific alterations in methylation occur for only a small number of genes. DNA methylation at the proximal promoter regions of commonly methylated genes thus appears to be an irreversible mark which functions to fix somatic lineage by repressing the transcription of germ cell-specific genes.

Whole-exome sequencing identifies novel MPL and JAK2 mutations in triple-negative myeloproliferative neoplasms

PubMed Central

Milosevic Feenstra, Jelena D.; Nivarthi, Harini; Gisslinger, Heinz; Leroy, Emilie; Rumi, Elisa; Chachoua, Ilyas; Bagienski, Klaudia; Kubesova, Blanka; Pietra, Daniela; Gisslinger, Bettina; Milanesi, Chiara; Jäger, Roland; Chen, Doris; Berg, Tiina; Schalling, Martin; Schuster, Michael; Bock, Christoph; Constantinescu, Stefan N.; Cazzola, Mario

2016-01-01

Essential thrombocythemia (ET) and primary myelofibrosis (PMF) are chronic diseases characterized by clonal hematopoiesis and hyperproliferation of terminally differentiated myeloid cells. The disease is driven by somatic mutations in exon 9 of CALR or exon 10 of MPL or JAK2-V617F in >90% of the cases, whereas the remaining cases are termed “triple negative.” We aimed to identify the disease-causing mutations in the triple-negative cases of ET and PMF by applying whole-exome sequencing (WES) on paired tumor and control samples from 8 patients. We found evidence of clonal hematopoiesis in 5 of 8 studied cases based on clonality analysis and presence of somatic genetic aberrations. WES identified somatic mutations in 3 of 8 cases. We did not detect any novel recurrent somatic mutations. In 3 patients with clonal hematopoiesis analyzed by WES, we identified a somatic MPL-S204P, a germline MPL-V285E mutation, and a germline JAK2-G571S variant. We performed Sanger sequencing of the entire coding region of MPL in 62, and of JAK2 in 49 additional triple-negative cases of ET or PMF. New somatic (T119I, S204F, E230G, Y591D) and 1 germline (R321W) MPL mutation were detected. All of the identified MPL mutations were gain-of-function when analyzed in functional assays. JAK2 variants were identified in 5 of 57 triple-negative cases analyzed by WES and Sanger sequencing combined. We could demonstrate that JAK2-V625F and JAK2-F556V are gain-of-function mutations. Our results suggest that triple-negative cases of ET and PMF do not represent a homogenous disease entity. Cases with polyclonal hematopoiesis might represent hereditary disorders. PMID:26423830

Whole-exome sequencing identifies novel MPL and JAK2 mutations in triple-negative myeloproliferative neoplasms.

PubMed

Milosevic Feenstra, Jelena D; Nivarthi, Harini; Gisslinger, Heinz; Leroy, Emilie; Rumi, Elisa; Chachoua, Ilyas; Bagienski, Klaudia; Kubesova, Blanka; Pietra, Daniela; Gisslinger, Bettina; Milanesi, Chiara; Jäger, Roland; Chen, Doris; Berg, Tiina; Schalling, Martin; Schuster, Michael; Bock, Christoph; Constantinescu, Stefan N; Cazzola, Mario; Kralovics, Robert

2016-01-21

Essential thrombocythemia (ET) and primary myelofibrosis (PMF) are chronic diseases characterized by clonal hematopoiesis and hyperproliferation of terminally differentiated myeloid cells. The disease is driven by somatic mutations in exon 9 of CALR or exon 10 of MPL or JAK2-V617F in >90% of the cases, whereas the remaining cases are termed "triple negative." We aimed to identify the disease-causing mutations in the triple-negative cases of ET and PMF by applying whole-exome sequencing (WES) on paired tumor and control samples from 8 patients. We found evidence of clonal hematopoiesis in 5 of 8 studied cases based on clonality analysis and presence of somatic genetic aberrations. WES identified somatic mutations in 3 of 8 cases. We did not detect any novel recurrent somatic mutations. In 3 patients with clonal hematopoiesis analyzed by WES, we identified a somatic MPL-S204P, a germline MPL-V285E mutation, and a germline JAK2-G571S variant. We performed Sanger sequencing of the entire coding region of MPL in 62, and of JAK2 in 49 additional triple-negative cases of ET or PMF. New somatic (T119I, S204F, E230G, Y591D) and 1 germline (R321W) MPL mutation were detected. All of the identified MPL mutations were gain-of-function when analyzed in functional assays. JAK2 variants were identified in 5 of 57 triple-negative cases analyzed by WES and Sanger sequencing combined. We could demonstrate that JAK2-V625F and JAK2-F556V are gain-of-function mutations. Our results suggest that triple-negative cases of ET and PMF do not represent a homogenous disease entity. Cases with polyclonal hematopoiesis might represent hereditary disorders. © 2016 by The American Society of Hematology.

IPS multicentric study: Functional somatic symptoms in depression

PubMed Central

Grover, Sandeep; Avasthi, Ajit; Kalita, Kamal; Dalal, P. K.; Rao, G. P.; Chadda, R. K.; Lakdawala, Bhavesh; Bang, Govind; Chakraborty, Kaustav; Kumar, Sudhir; Singh, P. K.; Kathuria, Puneet; Thirunavukarasu, M; Sharma, P. S. V. N.; Harish, T.; Shah, Nilesh; Deka, Kamla

2013-01-01

Background: As a pilot project, Indian Psychiatric Society conducted the first multicentric study involving diverse settings from teaching institutions in public and private sectors and even privately run psychiatric clinics. Aim of the Study: To study the typology of functional somatic complaints (FSC) in patients with first episode depression. Materials and Methods: A total of 741 patients from 16 centers across the country participated in the study. They were assessed on Bradford Somatic Symptom inventory for FSC, Beck Depression Inventory for severity of depression, and Comprehensive Psychopathological Rating Scale- anxiety index (CPRS-AI) for anxiety symptoms. Results: The mean age of the study sample was 38.23 years (SD-11.52). There was equal gender distribution (male - 49.8% vs. females 50.2%). Majority of the patients were married (74.5%), Hindus (57%), and from nuclear family (68.2%). A little over half of the patients were from urban background (52.9%). The mean duration of illness at the time of assessment was 25.55 months. Most of the patients (77%) had more than 10 FSCs, with 39.7% having more than 20 FSCs as assessed on Bradford Somatic Inventory. The more common FSC as assessed on Bradford Somatic Inventory were lack of energy (weakness) much of the time (76.2%), severe headache (74%) and feeling tired when not working (71%), pain in legs (64%), aware of palpitations (59.5%), head feeling heavy (59.4%), aches and pains all over the body (55.5%), mouth or throat getting dry (55.2%), pain or tension in neck and shoulder (54%), head feeling hot or burning (54%), and darkness or mist in front of the eyes (49.1%). The prevalence and typology of FSCs is to a certain extent influenced by the sociodemographic variables and severity of depression. Conclusion: Functional somatic symptoms are highly prevalent in Indian depressed patients and hence deserve more attention while diagnosing depression in Indian setting. PMID:23441051

Innexin2 gap junctions in somatic support cells are required for cyst formation and for egg chamber formation in Drosophila.

PubMed

Mukai, Masanori; Kato, Hirotaka; Hira, Seiji; Nakamura, Katsuhiro; Kita, Hiroaki; Kobayashi, Satoru

2011-01-01

Germ cells require intimate associations with surrounding somatic cells during gametogenesis. During oogenesis, gap junctions mediate communication between germ cells and somatic support cells. However, the molecular mechanisms by which gap junctions regulate the developmental processes during oogenesis are poorly understood. We have identified a female sterile allele of innexin2 (inx2), which encodes a gap junction protein in Drosophila. In females bearing this inx2 allele, cyst formation and egg chamber formation are impaired. In wild-type germaria, Inx2 is strongly expressed in escort cells and follicle cells, both of which make close contact with germline cells. We show that inx2 function in germarial somatic cells is required for the survival of early germ cells and promotes cyst formation, probably downstream of EGFR pathway, and that inx2 function in follicle cells promotes egg chamber formation through the regulation of DE-cadherin and Bazooka (Baz) at the boundary between germ cells and follicle cells. Furthermore, genetic experiments demonstrate that inx2 interacts with the zero population growth (zpg) gene, which encodes a germline-specific gap junction protein. These results indicate a multifunctional role for Inx2 gap junctions in somatic support cells in the regulation of early germ cell survival, cyst formation and egg chamber formation. Inx2 gap junctions may mediate the transfer of nutrients and signal molecules between germ cells and somatic support cells, as well as play a role in the regulation of cell adhesion. Copyright © 2011 Elsevier Ireland Ltd. All rights reserved.

A greater number of somatic pain sites is associated with poor mental health in adolescents: a cross-sectional study

PubMed Central

2013-01-01

Background Identifying indicators of poor mental health during adolescence is a significant public health issue. Previous studies which suggested an association between the number of somatic pains and depression have mainly focused on adults or have employed samples with a narrow age range. To date, results from previous studies have been inconsistent regarding the association between somatic pain and academic impairment. Therefore, the main aims of the present study were to 1) investigate the association between the number of somatic pain sites and poor mental health using a community sample of adolescents aged 12 to 18 years and employing a simple method of assessment, and 2) examine the association between the number of somatic pain sites and perceived academic impairment. Methods Data analysis was conducted using a large cross-sectional survey of adolescents in grades 7 to 12. The one-month prevalence rates for three sites of somatic pain including head, neck and shoulders, and abdomen were examined. Poor mental health was evaluated using the General Health Questionnaire, and perceived academic impairment was measured using a self-report questionnaire. Results A total of 18,104 adolescents participated in the survey. A greater number of pain sites was associated with poor mental health, and this association was consistent across age and gender. There was no difference in effect on mental health between any of the pain sites. Although there was an association between the number of somatic pain sites and perceived academic impairment, the results suggested that the association was mediated by poor mental health. Conclusions Simple reporting methods for assessing the number of pain sites may be a feasible indicator of poor mental health in adolescents. Professionals working with adolescents should consider the possibility of poor mental health, especially when students report multiple somatic pains. PMID:23327684

Discovery and prioritization of somatic mutations in diffuse large B-cell lymphoma (DLBCL) by whole-exome sequencing

PubMed Central

Lohr, Jens G.; Stojanov, Petar; Lawrence, Michael S.; Auclair, Daniel; Chapuy, Bjoern; Sougnez, Carrie; Cruz-Gordillo, Peter; Knoechel, Birgit; Asmann, Yan W.; Slager, Susan L.; Novak, Anne J.; Dogan, Ahmet; Ansell, Stephen M.; Zou, Lihua; Gould, Joshua; Saksena, Gordon; Stransky, Nicolas; Rangel-Escareño, Claudia; Fernandez-Lopez, Juan Carlos; Hidalgo-Miranda, Alfredo; Melendez-Zajgla, Jorge; Hernández-Lemus, Enrique; Schwarz-Cruz y Celis, Angela; Imaz-Rosshandler, Ivan; Ojesina, Akinyemi I.; Jung, Joonil; Pedamallu, Chandra S.; Lander, Eric S.; Habermann, Thomas M.; Cerhan, James R.; Shipp, Margaret A.; Getz, Gad; Golub, Todd R.

2012-01-01

To gain insight into the genomic basis of diffuse large B-cell lymphoma (DLBCL), we performed massively parallel whole-exome sequencing of 55 primary tumor samples from patients with DLBCL and matched normal tissue. We identified recurrent mutations in genes that are well known to be functionally relevant in DLBCL, including MYD88, CARD11, EZH2, and CREBBP. We also identified somatic mutations in genes for which a functional role in DLBCL has not been previously suspected. These genes include MEF2B, MLL2, BTG1, GNA13, ACTB, P2RY8, PCLO, and TNFRSF14. Further, we show that BCL2 mutations commonly occur in patients with BCL2/IgH rearrangements as a result of somatic hypermutation normally occurring at the IgH locus. The BCL2 point mutations are primarily synonymous, and likely caused by activation-induced cytidine deaminase–mediated somatic hypermutation, as shown by comprehensive analysis of enrichment of mutations in WRCY target motifs. Those nonsynonymous mutations that are observed tend to be found outside of the functionally important BH domains of the protein, suggesting that strong negative selection against BCL2 loss-of-function mutations is at play. Last, by using an algorithm designed to identify likely functionally relevant but infrequent mutations, we identify KRAS, BRAF, and NOTCH1 as likely drivers of DLBCL pathogenesis in some patients. Our data provide an unbiased view of the landscape of mutations in DLBCL, and this in turn may point toward new therapeutic strategies for the disease. PMID:22343534

Histological and transcript analyses of intact somatic embryos in an elite maize (Zea mays L.) inbred line Y423.

PubMed

Liu, Beibei; Su, Shengzhong; Wu, Ying; Li, Ying; Shan, Xiaohui; Li, Shipeng; Liu, Hongkui; Dong, Haixiao; Ding, Meiqi; Han, Junyou; Yuan, Yaping

2015-07-01

Intact somatic embryos were obtained from an elite maize inbred line Y423, bred in our laboratory. Using 13-day immature embryos after self-pollination as explants, and after 4-5 times subculture, a large number of somatic embryos were detected on the surface of the embryonic calli on the medium. The intact somatic embryos were transferred into the differential medium, where the plantlets regenerated with shoots and roots forming simultaneously. Histological analysis and scanning electron micrographs confirmed the different developmental stages of somatic embryogenesis, including globular-shaped embryo, pear-shaped embryo, scutiform embryo, and mature embryo. cDNA-amplified fragment length polymorphism (cDNA-AFLP) was used for comparative transcript profiling between embryogenic and non-embryogenic calli of a new elite maize inbred line Y423 during somatic embryogenesis. Differentially expressed genes were cloned and sequenced. Gene Ontology analysis of 117 candidate genes indicated their involvement in cellular component, biological process and molecular function. Nine of the candidate genes were selected. The changes in their expression levels during embryo induction and regeneration were analyzed in detail using quantitative real-time PCR. Two full-length cDNA sequences, encoding ZmSUF4 (suppressor of fir 4-like protein) and ZmDRP3A (dynamin-related protein), were cloned successfully from intact somatic embryos of the elite inbred maize line Y423. Here, a procedure for maize plant regeneration from somatic embryos is described. Additionally, the possible roles of some of these genes during the somatic embryogenesis has been discussed. This study is a systematic analysis of the cellular and molecular mechanism during the formation of intact somatic embryos in maize. Copyright © 2015 Elsevier Masson SAS. All rights reserved.

Sun exposure causes somatic second-hit mutations and angiofibroma development in tuberous sclerosis complex

PubMed Central

Tyburczy, Magdalena E.; Wang, Ji-an; Li, Shaowei; Thangapazham, Rajesh; Chekaluk, Yvonne; Moss, Joel; Kwiatkowski, David J.; Darling, Thomas N.

2014-01-01

Tuberous sclerosis complex (TSC) is characterized by the formation of tumors in multiple organs and is caused by germline mutation in one of two tumor suppressor genes, TSC1 and TSC2. As for other tumor suppressor gene syndromes, the mechanism of somatic second-hit events in TSC tumors is unknown. We grew fibroblast-like cells from 29 TSC skin tumors from 22 TSC subjects and identified germline and second-hit mutations in TSC1/TSC2 using next-generation sequencing. Eighteen of 22 (82%) subjects had a mutation identified, and 8 of the 18 (44%) subjects were mosaic with mutant allele frequencies of 0 to 19% in normal tissue DNA. Multiple tumors were available from four patients, and in each case, second-hit mutations in TSC2 were distinct indicating they arose independently. Most remarkably, 7 (50%) of the 14 somatic point mutations were CC>TT ultraviolet ‘signature’ mutations, never seen as a TSC germline mutation. These occurred exclusively in facial angiofibroma tumors from sun-exposed sites. These results implicate UV-induced DNA damage as a cause of second-hit mutations and development of TSC facial angiofibromas and suggest that measures to limit UV exposure in TSC children and adults should reduce the frequency and severity of these lesions. PMID:24271014

Visual and somatic sensory feedback of brain activity for intuitive surgical robot manipulation.

PubMed

Miura, Satoshi; Matsumoto, Yuya; Kobayashi, Yo; Kawamura, Kazuya; Nakashima, Yasutaka; Fujie, Masakatsu G

2015-01-01

This paper presents a method to evaluate the hand-eye coordination of the master-slave surgical robot by measuring the activation of the intraparietal sulcus in users brain activity during controlling virtual manipulation. The objective is to examine the changes in activity of the intraparietal sulcus when the user's visual or somatic feedback is passed through or intercepted. The hypothesis is that the intraparietal sulcus activates significantly when both the visual and somatic sense pass feedback, but deactivates when either visual or somatic is intercepted. The brain activity of three subjects was measured by the functional near-infrared spectroscopic-topography brain imaging while they used a hand controller to move a virtual arm of a surgical simulator. The experiment was performed several times with three conditions: (i) the user controlled the virtual arm naturally under both visual and somatic feedback passed, (ii) the user moved with closed eyes under only somatic feedback passed, (iii) the user only gazed at the screen under only visual feedback passed. Brain activity showed significantly better control of the virtual arm naturally (p<;0.05) when compared with moving with closed eyes or only gazing among all participants. In conclusion, the brain can activate according to visual and somatic sensory feedback agreement.

How well do parental and peer relationships in adolescence predict health in adulthood?

PubMed

Landstedt, Evelina; Hammarström, Anne; Winefield, Helen

2015-07-01

Although health effects of social relationships are well-researched, long-term health consequences of adolescent family as well as peer relationships are poorly understood. The aim of the study was to explore the prospective importance of parental and peer social relationships in adolescence on internalising and functional somatic symptoms in adulthood. Data were drawn from four waves of the Northern Swedish Cohort Study, response rate 94.3%, N=1001. Outcome variables were internalising and functional somatic symptoms at the ages of 21, 30 and 42. Relationship variables at age 16 were poor parental contact and three indicators of poor peer relationships. Associations were assessed in multivariate ordinal logistic regressions with adjustment for confounders and baseline health. Results show that the main relationships-related predictors of adult internalising symptoms were self-rated poor peer relationships in terms of spending time alone during after-school hours and poor parental relationship. Functional somatic symptoms on the other hand were most strongly associated with poor parental contact and not being happy with classmates at age 16. The quality of parental and peer relationships in adolescence predicts adult mental and functional somatic health as much as 26 years later, even when accounting for confounders and adolescent symptomatology. This study extends past research by exploring how both adolescent parental and peer relationships (self-reported as well as teacher reported) predict adult self-reported health. © 2015 the Nordic Societies of Public Health.

Cloning crops in a CELSS via tissue culture: Prospects and problems

NASA Technical Reports Server (NTRS)

Carman, John G.; Hess, J. Richard

1990-01-01

Micropropagation is currently used to clone fruits, nuts, and vegetables and involves controlling the outgrowth in vitro of basal, axillary, or adventitious buds. Following clonal multiplication, shoots are divided and rooted. This process has greatly reduced space and energy requirements in greenhouses and field nurseries and has increased multiplication rates by greater than 20 fold for some vegetatively propagated crops and breeding lines. Cereal and legume crops can also be cloned by tissue culture through somatic embryogenesis. Somatic embryos can be used to produce 'synthetic seed', which can tolerate desiccation and germinate upon rehydration. Synthetic seed of hybrid wheat, rice, soybean and other crops could be produced in a controlled ecological life support system. Thus, yield advantages of hybreds over inbreds (10 to 20 percent) could be exploited without having to provide additional facilities and energy for parental-line and hybrid seed nurseries.

Somatic and germinal cells' interrelationship in the course of seminiferous tubule maturation in man.

PubMed

Kula, K; Romer, T E; Wlodarczyk, W P

1980-02-01

Certain successive phases of seminiferous tubule maturation were observed in a transsection of a Leydig cell adenoma-bearing testis of a boy with precocious puberty. Massively accumulated Leydig cells may stimulate the maturation of Sertoli cells, as indicated by progressive replacement of Sertoli cell precursors by mature Sertoli cells at a distance closer to the adenoma. On the other hand, tubules less advanced in maturation contained a higher number of somatic cells than those more advanced in maturation. Leydig-cell-dependent maturation of Sertoli cells may be in competition with Certoli cell multiplication, or numerous undifferentiated somatic cells may undergo a natural elimination in the course of tubular maturation. An inverse relation between the number of Sertoli cell precursors and the number of meiotic spermatocytes suggests that quantitative reduction of Sertoli cell precursors may be important for the intratubular milieu necessary for the onset of the first meiosis in man.

Hexavalent chromium induces apoptosis in male somatic and spermatogonial stem cells via redox imbalance

PubMed Central

Das, Joydeep; Kang, Min-Hee; Kim, Eunsu; Kwon, Deug-Nam; Choi, Yun-Jung; Kim, Jin-Hoi

2015-01-01

Hexavalent chromium [Cr(VI)], an environmental toxicant, causes severe male reproductive abnormalities. However, the actual mechanisms of toxicity are not clearly understood and have not been studied in detail. The present in vitro study aimed to investigate the mechanism of reproductive toxicity of Cr(VI) in male somatic cells (mouse TM3 Leydig cells and TM4 Sertoli cells) and spermatogonial stem cells (SSCs) because damage to or dysfunction of these cells can directly affect spermatogenesis, resulting in male infertility. Cr(VI) by inducing oxidative stress was cytotoxic to both male somatic cells and SSCs in a dose-dependent manner, and induced mitochondria-dependent apoptosis. Although the mechanism of Cr(VI)-induced cytotoxicity was similar in both somatic cells, the differences in sensitivity of TM3 and TM4 cells to Cr(VI) could be attributed, at least in part, to cell-specific regulation of P-AKT1, P-ERK1/2, and P-P53 proteins. Cr(VI) affected the differentiation and self-renewal mechanisms of SSCs, disrupted steroidogenesis in TM3 cells, while in TM4 cells, the expression of tight junction signaling and cell receptor molecules was affected as well as the secretory functions were impaired. In conclusion, our results show that Cr(VI) is cytotoxic and impairs the physiological functions of male somatic cells and SSCs. PMID:26355036

The Somatic Appraisal Model of Affect: Paradigm for Educational Neuroscience and Neuropedagogy

ERIC Educational Resources Information Center

Patten, Kathryn E.

2011-01-01

This chapter presents emotion as a function of brain-body interaction, as a vital part of a multi-tiered phylogenetic set of neural mechanisms, evoked by both instinctive processes and learned appraisal systems, and argues to establish the primacy of emotion in relation to cognition. Primarily based on Damasio's somatic marker hypothesis, but also…

Transcriptional Noise and Somatic Mutations in the Aging Pancreas.

PubMed

Swisa, Avital; Kaestner, Klaus H; Dor, Yuval

2017-12-05

The underlying mechanisms and functional significance of pancreatic β cell heterogeneity are an intensive area of investigation. In a recent Cell paper, Enge and colleagues (2017) performed single-cell RNA sequencing of human pancreatic cells and concluded that with age, pancreatic cells become transcriptionally noisy and accumulate somatic mutations. Copyright © 2017. Published by Elsevier Inc.

Examination of the interrelations between the factors of PTSD, major depression, and generalized anxiety disorder in a heterogeneous trauma-exposed sample using DSM 5 criteria.

PubMed

Price, Matthew; van Stolk-Cooke, Katherine

2015-11-01

Exposure to traumatic events places individuals at high risk for multiple psychiatric disorders, including posttraumatic stress disorder (PTSD), major depressive disorder (MDD), and generalized anxiety disorder (GAD). The high rates of comorbidity among these conditions merit evaluation in order to improve diagnosis and treatment approaches. The current study evaluated the association between PTSD, MDD, and GAD factors as presented in the DSM 5. 602 trauma-exposed individuals who experienced an event that met Criterion A for the DSM 5 PTSD diagnosis were recruited through Amazon.com, Inc.'s Mechanical Turk (MTurk) to complete an assessment of the impact of stressful events on their lives. High interrelations were detected among the 4 PTSD factors, 2 MDD factors that corresponded to somatic and affective symptoms, and the single GAD factor. The affective factor of MDD was most strongly related to the emotional numbing factor of PTSD, whereas the somatic factor of MDD was most strongly related to the hyperarousal factor of PTSD. The GAD factor was most strongly related to the hyperarousal factor of PTSD, relative to the other PTSD factors. The strength of the interrelations between factors of the three disorders is largely a function of the overlap in symptoms and calls into question the uniqueness of negative affective symptoms of PTSD, MDD and GAD. Results suggest that improved understanding of the trauma reaction requires a focus on the unique presentation of each individual and assessment of multiple disorders. Copyright © 2015 Elsevier B.V. All rights reserved.

Do informal caregivers in mental illness feel more burdened? A comparative study of mental versus somatic illnesses.

PubMed

Hastrup, Lene H; Van Den Berg, Bernard; Gyrd-Hansen, Dorte

2011-08-01

This study investigates a possible added subjective burden among informal caregivers to care recipients with a mental illness or a combination of mental and somatic illnesses compared with caregivers to care recipients with a somatic illness. The study also investigates the subjective caregiver burden by caregivers' characteristics and objective burden. The association between subjective caregiver burden and socio-demographic factors, objective burden, and health-related quality of life was analyzed in a population of 865 Dutch informal caregivers, using multiple linear regression analysis. Controlling for other factors in the analysis, we found that caring for a recipient with mental illness or a combination of mental and somatic illness was associated with an extra subjective caregiver burden (measured by Caregiver Strain Index). Objective burden, in terms of more than 50 hours of care provision per week, less than three years of caregiving, or living together with the care recipients was associated with higher subjective caregiver burden. Other factors associated with higher subjective caregiver burden were being partners or a child of care recipient, having a paid job, a low health-related quality of life (EQ-5D), or having an illness. This study suggests that caregivers to care recipients with a mental and especially a combination of mental and somatic illnesses have a higher subjective caregiver burden compared with caregivers to care recipients with a somatic illness. Because the study is not representative of all caregivers, more research focusing on identifying and contacting informal caregivers is needed to confirm the result.

Genotoxicity testing of different types of beverages in the Drosophila wing Somatic Mutation And Recombination Test.

PubMed

Graf, U; Moraga, A A; Castro, R; Díaz Carrillo, E

1994-05-01

Five wines and one brandy of Spanish origin as well as three herbal teas and ordinary black tea were tested for genotoxicity in the wing Somatic Mutation And Recombination Test (SMART) which makes use of the two recessive wing cell markers multiple wing hairs (mwh) and flare (flr3) on the left arm of chromosome 3 of Drosophila melanogaster. 3-day-old larvae trans-heterozygous for these two markers were fed the beverages at different concentrations and for different feeding periods using Drosophila instant medium. Somatic mutations or mitotic recombinations induced in the cells of the wing imaginal discs give rise to mutant single or twin spots on the wing blade of the emerging adult flies showing either the mwh phenotype or/and the flr phenotype. One of the red wines showed a clear genotoxic activity that was not due to its ethanol content. Two herbal teas (Urtica dioica, Achillea millefolium) and black tea (Camellia sinensis) proved to be weakly genotoxic as well. Furthermore, it was shown that quercetin and rutin, two flavonols present in beverages of plant origin, also exhibited weak genotoxic activity in the somatic cells of Drosophila. These results demonstrate that Drosophila in vivo somatic assays can detect the genotoxicity of complex mixtures such as beverages. In particular, it is possible to administer these test materials in the same form as that in which they are normally consumed.

Micropropagation of Codiaeum variegatum (L.) Blume and regeneration induction via adventitious buds and somatic embryogenesis.

PubMed

Radice, Silvia

2010-01-01

Codiaeum variegatum (L) Blume cv. "Corazon de oro" and cv. "Norma" are successfully micropropagated when culture are initiated with explants taken from newly sprouted shoots. The establishment and multiplication steps are possible when 1 mg/L BA or 1 mg/L IAA and 3 mg/L 2iP are added to MS medium, according to the cultivar respectively selected.Adventive organogenesis and somatic embryogenesis are induced from leaf explants taken from in vitro buds of croton. On leaf-sectioned of "Corazon de oro" cultured in vitro, 1 mg/L BA stimulates continuous somatic embryos development and induces some shoots too. Replacing BA with 1 mg/L TDZ induces up to 100% bud regeneration in the same explants. On the other hand, leaf-sectioned of C. variegatum cv. Norma does not start somatic embryo differentiation if 1 mg/L TDZ is not added to the MS basal medium. Incipient callus is observed after 30 days of culture, and then, subculture to MS with 1 mg/L BA allows the same process to show on the "Corazon de oro" cultivar. Somatic embryos show growth arrest that is partially overcome by transfer to hormone-free basal medium with activated charcoal. Root induction is possible on basal medium plus 1 mg/L IBA. Plantlets in the greenhouse have variegated leaves true-to-type.

Nausea in Children With Functional Abdominal Pain Predicts Poor Health Outcomes in Young Adulthood.

PubMed

Russell, Alexandra C; Stone, Amanda L; Walker, Lynn S

2017-05-01

Nausea is common among children with functional abdominal pain (FAP). We evaluated the relation of nausea to short- and long-term morbidity in pediatric patients with FAP. We performed a prospective study of 871 children with FAP (age, 8-17 y) seen in a pediatric gastroenterology practice; follow-up data were collected from 392 of the patients at 8.7 ± 3.3 years later. Participants were defined as having significant nausea if they reported nausea "a lot" or "a whole lot" within the past 2 weeks. Validated questionnaires assessed abdominal pain, gastrointestinal and somatic symptoms, and depression. Baseline measures, anxiety, and the Rome III criteria were assessed in the follow-up evaluation. At baseline, 44.8% of the patients reported significant nausea. Those with nausea reported worse abdominal pain, gastrointestinal symptoms, somatic symptoms, and depression than those without nausea (P < .001 for all). When the children had reached young adulthood, those with nausea in childhood continued to have more severe gastrointestinal (P < .001) and somatic symptoms (P = .003) than patients without nausea in childhood, as well as higher levels of anxiety (P = .02) and depression (P = .02). In the follow-up evaluation, somatic symptoms, depression, and anxiety remained significant after controlling for baseline abdominal pain severity. Pediatric patients with FAP and nausea have more severe short- and long-term gastrointestinal and somatic symptoms than patients with FAP without nausea, as well as reductions in mental health and daily function. Pediatric patients with FAP and nausea therefore need intensive treatment and follow-up evaluation. Copyright © 2017 AGA Institute. Published by Elsevier Inc. All rights reserved.

[Functional somatization: a conceptual review].

PubMed

Fabião, Cristina; Fleming, Manuela; Barbosa, António

2011-01-01

The authors have brought together and analised texts about the history of the concept of hysteria. In these texts hysteria is fundamentally considered a disease of organic origin (of the womb), and, in the Middle Age, evidence of demonic possession. From the XVII century onwards, apart from the etiopathogenic concepts, also taken into consideration are aspects connected to the differential diagnosis with other similar entities and the therapy used each period. Even, in subsequent centuries, authors such as Syndenham, who consider hysteria to be a multidimensional entity, are rare. Empiricism has contributed to discoveries in biology and physiology, both general and of the nervous system itself, and given birth to the formulation of the Spinal Irritation Theory and Reflex Theory. These theories have led to strictly organic treatment of hysteria, in the same way that hysterectomies were performed to alleviate somatic symptoms connected to this disease. The introduction of hypnosis in medical practice, with Charcot in X1X century, allowed for the element of suggestion to be observed ( a non organic element) which accompanies the symptoms of hysteria. Two of his disciples, Janet and Freud, would define and isolate psychic mechanisms in the symptoms of hysteria: Dissociation of the consciousness (Janet) and Conversion (Freud). The last one developed a therapeutic method of a psychological nature for hysteria. The therapeutic implications and the pertinence of the distinction between unspecific somatization or functional (of somatic origin) somatization and somatization linked to disassociation mechanisms and conversion (psychic origin) are discussed as well as the evolution of international classification systems of somatization and the questions posed by the algorithms chosen for the cataloguing of symptoms. A revision of the relevant empirical studies about the association of somatization with depressive and anxiety disorders, within the general population, is made. The characteristics that permeate the clinical descriptions of somatoform disorders (whose validity criteria remain weak) and are not integrated within the diagnostic criteria for somatoform disorders are considered. We draw conclusions about the difficulties and consequences of the changes that some authors advocate in relation to the new classification system for somatoform syndromes.

Bone Morphogenetic Protein (BMP) signaling in animal reproductive system development and function.

PubMed

Lochab, Amaneet K; Extavour, Cassandra G

2017-07-15

In multicellular organisms, the specification, maintenance, and transmission of the germ cell lineage to subsequent generations are critical processes that ensure species survival. A number of studies suggest that the Bone Morphogenetic Protein (BMP) pathway plays multiple roles in this cell lineage. We wished to use a comparative framework to examine the role of BMP signaling in regulating these processes, to determine if patterns would emerge that might shed light on the evolution of molecular mechanisms that may play germ cell-specific or other reproductive roles across species. To this end, here we review evidence to date from the literature supporting a role for BMP signaling in reproductive processes across Metazoa. We focus on germ line-specific processes, and separately consider somatic reproductive processes. We find that from primordial germ cell (PGC) induction to maintenance of PGC identity and gametogenesis, BMP signaling regulates these processes throughout embryonic development and adult life in multiple deuterostome and protostome clades. In well-studied model organisms, functional genetic evidence suggests that BMP signaling is required in the germ line across all life stages, with the exception of PGC specification in species that do not use inductive signaling to induce germ cell formation. The current evidence is consistent with the hypothesis that BMP signaling is ancestral in bilaterian inductive PGC specification. While BMP4 appears to be the most broadly employed ligand for the reproductive processes considered herein, we also noted evidence for sex-specific usage of different BMP ligands. In gametogenesis, BMP6 and BMP15 seem to have roles restricted to oogenesis, while BMP8 is restricted to spermatogenesis. We hypothesize that a BMP-based mechanism may have been recruited early in metazoan evolution to specify the germ line, and was subsequently co-opted for use in other germ line-specific and somatic reproductive processes. We suggest that if future studies assessing the function of the BMP pathway across extant species were to include a reproductive focus, that we would be likely to find continued evidence in favor of an ancient association between BMP signaling and the reproductive cell lineage in animals. Copyright © 2017 Elsevier Inc. All rights reserved.

Factors Associated With Suicidal Ideation and Quality of Life in Adolescents from Puerto Rico With Type 1 Diabetes

PubMed Central

Guerrero-Ramírez, Grace; Cumba-Avilés, Eduardo

2018-01-01

Objective People with type 1 diabetes (T1D) may experience significant changes in their daily routines due to this condition, which frequently results in depressive symptoms and the deterioration of their quality of life. We examined the factors associated with suicidal ideation (SI) and diabetes-related quality of life (DRQOL) in adolescents (aged 12 to 17) with T1D. Methods The sample consisted of 51 youths (29 girls) recruited during a treatment study for depression. They completed the Diabetes Quality of Life for Youth questionnaire, the Suicidal Ideation Questionnaire-Junior, and other measures that explore emotional, cognitive, somatic, behavioral, and relational aspects. Their caregivers completed the Barriers to Adherence Questionnaire and the Somatic Complaints subscale of the Child Behavior Checklist, among other measures. We used correlation and multiple linear regression analyses to identify the factors associated with the dependent variables. Results The variables associated with SI were depression, somatic complaints, perceived family emotional support, self-care for diabetes, self-deprecation, helplessness, and hopelessness, among others. In a multiple regression analysis, the first 3 accounted for 46% of the variance. Those related to DRQOL included cognitive alterations, barriers to adherence, perceived family emotional support, self-efficacy for diabetes and for depression, helplessness, anxiety, and self-deprecation, among others. The first 4 accounted for 61% of the variance. Conclusion Our findings highlight the impact of emotional, cognitive, somatic, behavioral, and relational aspects on the quality of mental health and the DRQOL of youth with T1D, as well as their pertinence for the development of psychosocial interventions for this population. PMID:29547680

Mutations of RNA splicing factors in hematological malignancies.

PubMed

Shukla, Girish C; Singh, Jagjit

2017-11-28

Systematic large-scale cancer genomic studies have produced numerous significant findings. These studies have not only revealed new cancer-promoting genes, but they also have identified cancer-promoting functions of previously known "housekeeping" genes. These studies have identified numerous mutations in genes which play a fundamental role in nuclear precursor mRNA splicing. Somatic mutations and copy number variation in many of the splicing factors which participate in the formation of multiple spliceosomal complexes appear to play a role in many cancers and in particular in myelodysplastic syndromes (MDS). Mutated proteins seem to interfere with the recognition of the authentic splice sites (SS) leading to utilization of suboptimal alternative splicing sites generating aberrantly spliced mRNA isoforms. This short review is focusing on the function of the splice factors involved in the formation of splicing complexes and potential mechanisms which affect usage of the authentic splice site recognition. Copyright © 2017 Elsevier B.V. All rights reserved.

Functional genomic Landscape of Human Breast Cancer drivers, vulnerabilities, and resistance

PubMed Central

Marcotte, Richard; Sayad, Azin; Brown, Kevin R.; Sanchez-Garcia, Felix; Reimand, Jüri; Haider, Maliha; Virtanen, Carl; Bradner, James E.; Bader, Gary D.; Mills, Gordon B.; Pe’er, Dana; Moffat, Jason; Neel, Benjamin G.

2016-01-01

Summary Large-scale genomic studies have identified multiple somatic aberrations in breast cancer, including copy number alterations, and point mutations. Still, identifying causal variants and emergent vulnerabilities that arise as a consequence of genetic alterations remain major challenges. We performed whole genome shRNA “dropout screens” on 77 breast cancer cell lines. Using a hierarchical linear regression algorithm to score our screen results and integrate them with accompanying detailed genetic and proteomic information, we identify vulnerabilities in breast cancer, including candidate “drivers,” and reveal general functional genomic properties of cancer cells. Comparisons of gene essentiality with drug sensitivity data suggest potential resistance mechanisms, effects of existing anti-cancer drugs, and opportunities for combination therapy. Finally, we demonstrate the utility of this large dataset by identifying BRD4 as a potential target in luminal breast cancer, and PIK3CA mutations as a resistance determinant for BET-inhibitors. PMID:26771497

A Gene Gravity Model for the Evolution of Cancer Genomes: A Study of 3,000 Cancer Genomes across 9 Cancer Types.

PubMed

Cheng, Feixiong; Liu, Chuang; Lin, Chen-Ching; Zhao, Junfei; Jia, Peilin; Li, Wen-Hsiung; Zhao, Zhongming

2015-09-01

Cancer development and progression result from somatic evolution by an accumulation of genomic alterations. The effects of those alterations on the fitness of somatic cells lead to evolutionary adaptations such as increased cell proliferation, angiogenesis, and altered anticancer drug responses. However, there are few general mathematical models to quantitatively examine how perturbations of a single gene shape subsequent evolution of the cancer genome. In this study, we proposed the gene gravity model to study the evolution of cancer genomes by incorporating the genome-wide transcription and somatic mutation profiles of ~3,000 tumors across 9 cancer types from The Cancer Genome Atlas into a broad gene network. We found that somatic mutations of a cancer driver gene may drive cancer genome evolution by inducing mutations in other genes. This functional consequence is often generated by the combined effect of genetic and epigenetic (e.g., chromatin regulation) alterations. By quantifying cancer genome evolution using the gene gravity model, we identified six putative cancer genes (AHNAK, COL11A1, DDX3X, FAT4, STAG2, and SYNE1). The tumor genomes harboring the nonsynonymous somatic mutations in these genes had a higher mutation density at the genome level compared to the wild-type groups. Furthermore, we provided statistical evidence that hypermutation of cancer driver genes on inactive X chromosomes is a general feature in female cancer genomes. In summary, this study sheds light on the functional consequences and evolutionary characteristics of somatic mutations during tumorigenesis by propelling adaptive cancer genome evolution, which would provide new perspectives for cancer research and therapeutics.

A Gene Gravity Model for the Evolution of Cancer Genomes: A Study of 3,000 Cancer Genomes across 9 Cancer Types

PubMed Central

Lin, Chen-Ching; Zhao, Junfei; Jia, Peilin; Li, Wen-Hsiung; Zhao, Zhongming

2015-01-01

Cancer development and progression result from somatic evolution by an accumulation of genomic alterations. The effects of those alterations on the fitness of somatic cells lead to evolutionary adaptations such as increased cell proliferation, angiogenesis, and altered anticancer drug responses. However, there are few general mathematical models to quantitatively examine how perturbations of a single gene shape subsequent evolution of the cancer genome. In this study, we proposed the gene gravity model to study the evolution of cancer genomes by incorporating the genome-wide transcription and somatic mutation profiles of ~3,000 tumors across 9 cancer types from The Cancer Genome Atlas into a broad gene network. We found that somatic mutations of a cancer driver gene may drive cancer genome evolution by inducing mutations in other genes. This functional consequence is often generated by the combined effect of genetic and epigenetic (e.g., chromatin regulation) alterations. By quantifying cancer genome evolution using the gene gravity model, we identified six putative cancer genes (AHNAK, COL11A1, DDX3X, FAT4, STAG2, and SYNE1). The tumor genomes harboring the nonsynonymous somatic mutations in these genes had a higher mutation density at the genome level compared to the wild-type groups. Furthermore, we provided statistical evidence that hypermutation of cancer driver genes on inactive X chromosomes is a general feature in female cancer genomes. In summary, this study sheds light on the functional consequences and evolutionary characteristics of somatic mutations during tumorigenesis by propelling adaptive cancer genome evolution, which would provide new perspectives for cancer research and therapeutics. PMID:26352260

Spontaneous generation of germline characteristics in mouse fibrosarcoma cells

NASA Astrophysics Data System (ADS)

Ma, Zhan; Hu, Yao; Jiang, Guoying; Hou, Jun; Liu, Ruilai; Lu, Yuan; Liu, Chunfang

2012-10-01

Germline/embryonic-specific genes have been found to be activated in somatic tumors. In this study, we further showed that cells functioning as germline could be present in mouse fibrosarcoma cells (L929 cell line). Early germline-like cells spontaneously appeared in L929 cells and further differentiated into oocyte-like cells. These germline-like cells can, in turn, develop into blastocyst-like structures in vitro and cause teratocarcinomas in vivo, which is consistent with natural germ cells in function. Generation of germline-like cells from somatic tumors might provide a novel way to understand why somatic cancer cells have strong features of embryonic/germline development. It is thought that the germline traits of tumors are associated with the central characteristics of malignancy, such as immortalization, invasion, migration and immune evasion. Therefore, germline-like cells in tumors might provide potential targets to tumor biology, diagnosis and therapy.

Somatic and Functional Status of Boys from Various Social and Environmental Categories

ERIC Educational Resources Information Center

Domaradzki, Jaroslaw; Ignasiak, Zofia; Slawinska, Teresa

2009-01-01

Study aim: To assess the somatic and fitness status of adolescent boys from polluted industrial areas. Material and methods: A group of 313 boys aged 11-15 years from 5 villages located in the copper mine area in South-Western Poland were classified by the degree of lead and cadmium pollution (high--very high) and by parents' education…

Somatic mutations affect key pathways in lung adenocarcinoma

PubMed Central

Ding, Li; Getz, Gad; Wheeler, David A.; Mardis, Elaine R.; McLellan, Michael D.; Cibulskis, Kristian; Sougnez, Carrie; Greulich, Heidi; Muzny, Donna M.; Morgan, Margaret B.; Fulton, Lucinda; Fulton, Robert S.; Zhang, Qunyuan; Wendl, Michael C.; Lawrence, Michael S.; Larson, David E.; Chen, Ken; Dooling, David J.; Sabo, Aniko; Hawes, Alicia C.; Shen, Hua; Jhangiani, Shalini N.; Lewis, Lora R.; Hall, Otis; Zhu, Yiming; Mathew, Tittu; Ren, Yanru; Yao, Jiqiang; Scherer, Steven E.; Clerc, Kerstin; Metcalf, Ginger A.; Ng, Brian; Milosavljevic, Aleksandar; Gonzalez-Garay, Manuel L.; Osborne, John R.; Meyer, Rick; Shi, Xiaoqi; Tang, Yuzhu; Koboldt, Daniel C.; Lin, Ling; Abbott, Rachel; Miner, Tracie L.; Pohl, Craig; Fewell, Ginger; Haipek, Carrie; Schmidt, Heather; Dunford-Shore, Brian H.; Kraja, Aldi; Crosby, Seth D.; Sawyer, Christopher S.; Vickery, Tammi; Sander, Sacha; Robinson, Jody; Winckler, Wendy; Baldwin, Jennifer; Chirieac, Lucian R.; Dutt, Amit; Fennell, Tim; Hanna, Megan; Johnson, Bruce E.; Onofrio, Robert C.; Thomas, Roman K.; Tonon, Giovanni; Weir, Barbara A.; Zhao, Xiaojun; Ziaugra, Liuda; Zody, Michael C.; Giordano, Thomas; Orringer, Mark B.; Roth, Jack A.; Spitz, Margaret R.; Wistuba, Ignacio I.; Ozenberger, Bradley; Good, Peter J.; Chang, Andrew C.; Beer, David G.; Watson, Mark A.; Ladanyi, Marc; Broderick, Stephen; Yoshizawa, Akihiko; Travis, William D.; Pao, William; Province, Michael A.; Weinstock, George M.; Varmus, Harold E.; Gabriel, Stacey B.; Lander, Eric S.; Gibbs, Richard A.; Meyerson, Matthew; Wilson, Richard K.

2009-01-01

Determining the genetic basis of cancer requires comprehensive analyses of large collections of histopathologically well-classified primary tumours. Here we report the results of a collaborative study to discover somatic mutations in 188 human lung adenocarcinomas. DNA sequencing of 623 genes with known or potential relationships to cancer revealed more than 1,000 somatic mutations across the samples. Our analysis identified 26 genes that are mutated at significantly high frequencies and thus are probably involved in carcinogenesis. The frequently mutated genes include tyrosine kinases, among them the EGFR homologue ERBB4; multiple ephrin receptor genes, notably EPHA3; vascular endothelial growth factor receptor KDR; and NTRK genes. These data provide evidence of somatic mutations in primary lung adenocarcinoma for several tumour suppressor genes involved in other cancers—including NF1, APC, RB1 and ATM—and for sequence changes in PTPRD as well as the frequently deleted gene LRP1B. The observed mutational profiles correlate with clinical features, smoking status and DNA repair defects. These results are reinforced by data integration including single nucleotide polymorphism array and gene expression array. Our findings shed further light on several important signalling pathways involved in lung adenocarcinoma, and suggest new molecular targets for treatment. PMID:18948947

Germline and somatic polymerase ε and δ mutations define a new class of hypermutated colorectal and endometrial cancers

PubMed Central

Briggs, Sarah; Tomlinson, Ian

2013-01-01

Polymerases ϵ and δ are the main enzymes that replicate eukaryotic DNA. Accurate replication occurs through Watson–Crick base pairing and also through the action of the polymerases' exonuclease (proofreading) domains. We have recently shown that germline exonuclease domain mutations (EDMs) of POLE and POLD1 confer a high risk of multiple colorectal adenomas and carcinoma (CRC). POLD1 mutations also predispose to endometrial cancer (EC). These mutations are associated with high penetrance and dominant inheritance, although the phenotype can be variable. We have named the condition polymerase proofreading-associated polyposis (PPAP). Somatic POLE EDMs have also been found in sporadic CRCs and ECs, although very few somatic POLD1 EDMs have been detected. Both the germline and the somatic DNA polymerase EDMs cause an ‘ultramutated’, apparently microsatellite-stable, type of cancer, sometimes leading to over a million base substitutions per tumour. Here, we present the evidence for POLE and POLD1 as important contributors to the pathogenesis of CRC and EC, and highlight some of the key questions in this emerging field. Copyright © 2013 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd PMID:23447401

Neurofibromin Deficiency-Associated Transcriptional Dysregulation Suggests a Novel Therapy for Tibial Pseudoarthrosis in NF1

PubMed Central

Paria, Nandina; Cho, Tae-Joon; Choi, In Ho; Kamiya, Nobuhiro; Kayembe, Kay; Mao, Rong; Margraf, Rebecca L.; Obermosser, Gerlinde; Oxendine, Ila; Sant, David W.; Song, Mi Hyun; Stevenson, David A.; Viskochil, David H.; Wise, Carol A.; Kim, Harry K.W.; Rios, Jonathan J

2014-01-01

Neurofibromatosis type 1 (NF1) is an autosomal dominant disease caused by mutations in NF1. Among the earliest manifestations is tibial pseudoarthrosis and persistent nonunion after fracture. To further understand the pathogenesis of pseudoarthrosis and the underlying bone remodeling defect, pseudoarthrosis tissue and cells cultured from surgically resected pseudoarthrosis tissue from NF1 individuals were analyzed using whole-exome and whole-transcriptome sequencing as well as genomewide microarray analysis. Genomewide analysis identified multiple genetic mechanisms resulting in somatic bi-allelic NF1 inactivation; no other genes with recurring somatic mutations were identified. Gene expression profiling identified dysregulated pathways associated with neurofibromin deficiency, including phosphoinosital-3-kinase (PI3K) and mitogen-activated protein kinase (MAPK) signaling pathways. Unlike aggressive NF1-associated malignancies, tibial pseudoarthrosis tissue does not harbor a high frequency of somatic mutations in oncogenes or other tumor-suppressor genes, such as p53. However, gene expression profiling indicates pseudoarthrosis tissue has a tumor-promoting transcriptional pattern, despite lacking tumorigenic somatic mutations. Significant over-expression of specific cancer-associated genes in pseudoarthrosis highlights a potential for receptor tyrosine kinase inhibitors to target neurofibromin-deficient pseudoarthrosis and promote proper bone remodeling and fracture healing. PMID:24932921

What cost mitochondria? The maintenance of functional mitochondrial DNA within and across generations

PubMed Central

Aanen, Duur K.; Spelbrink, Johannes N.; Beekman, Madeleine

2014-01-01

The peculiar biology of mitochondrial DNA (mtDNA) potentially has detrimental consequences for organismal health and lifespan. Typically, eukaryotic cells contain multiple mitochondria, each with multiple mtDNA genomes. The high copy number of mtDNA implies that selection on mtDNA functionality is relaxed. Furthermore, because mtDNA replication is not strictly regulated, within-cell selection may favour mtDNA variants with a replication advantage, but a deleterious effect on cell fitness. The opportunities for selfish mtDNA mutations to spread are restricted by various organism-level adaptations, such as uniparental transmission, germline mtDNA bottlenecks, germline selection and, during somatic growth, regular alternation between fusion and fission of mitochondria. These mechanisms are all hypothesized to maintain functional mtDNA. However, the strength of selection for maintenance of functional mtDNA progressively declines with age, resulting in age-related diseases. Furthermore, organismal adaptations that most probably evolved to restrict the opportunities for selfish mtDNA create secondary problems. Owing to predominantly maternal mtDNA transmission, recombination among mtDNA from different individuals is highly restricted or absent, reducing the scope for repair. Moreover, maternal inheritance precludes selection against mtDNA variants with male-specific effects. We finish by discussing the consequences of life-history differences among taxa with respect to mtDNA evolution and make a case for the use of microorganisms to experimentally manipulate levels of selection. PMID:24864309

Hypochondriasis and somatization in college women: a personal projects analysis.

PubMed

Karoly, P; Lecci, L

1993-03-01

Although the descriptive features of hypochondriasis and somatization have been widely studied, the motivational correlates (goal representations) of individuals manifesting abnormal illness patterns have not been considered. The Personal Projects Analysis method (Little, 1983) was used to contrast the health and nonhealth goals of female undergraduates. Subjects selected 10 goals for evaluation along a series of dimensions. When health pursuits alone were examined, hypochondriasis on the Minnesota Multiphasic Personality Inventory was found to correlate directly with goal appraisal dimensions subsumed by an anxiety-absorption factor and inversely with dimensions characterizing rewardingness, thus suggesting a negativity of health goal construal. Somatizers also pursued more health-related projects than did nonsomatizers; nonhealth goal cognition did not relate as strongly to hypochondriasis. Finally, using discriminant function analysis, goal representations were shown to significantly and substantially differentiate somatizers from nonsomatizers.

Evaluating the impact of depression, anxiety & autonomic function on health related quality of life, vocational functioning and health care utilisation in acute coronary syndrome patients: the ADVENT study protocol

PubMed Central

2013-01-01

Background Depression and anxiety are highly prevalent and co-morbid in acute coronary syndrome patients. Somatic and cognitive subtypes of depression and anxiety in acute coronary syndrome have been shown to be associated with mortality although their association with patient outcomes is unknown, as are the mechanisms that underpin these associations. We are conducting a prospective cohort study which aims to examine in acute coronary syndrome patients: (1) the role of somatic subtypes of depression and anxiety as predictors of health related quality of life outcomes; (2) how somatic subtypes of depression and anxiety relate to long term vocational functioning and healthcare utilisation; and (3) the role of the autonomic nervous system assessed by heart rate variability as a moderator of these associations. Methods Patients are being screened after index admission for acute coronary syndrome at a single, high volume centre, MonashHeart, Monash Health, Victoria, Australia. The inclusion criterion is all patients aged > 21 years old and fluent in English admitted to MonashHeart, Monash Health with a diagnosis of acute coronary syndrome. The primary outcome is mean health related quality of life (Short Form-36) Physical and Mental Health Summary scores at 12 and 24 months in subtypes with somatic symptoms of depression and anxiety. Depressive domains are assessed by the Beck Depression Inventory II and the Cardiac Depression Scale. Anxiety is measured using the Speilberger State-Trait Anxiety Inventory and the Crown Crisp Phobic Anxiety questionnaire. Secondary outcomes include clinical variables, healthcare service utilisation and vocational functioning. Discussion This manuscript presents the protocol for a prospective cohort study which will investigate the role of somatic subtypes of depression and anxiety as predictors of health related quality of life, long-term vocational functioning and health service use, and the role of the autonomic nervous system in moderating these associations. Findings from the study have the potential to inform more effective pharmacological, psychological and behavioural interventions and better guide health policy on the use of health care resources. PMID:24237848

Involvement of chronic epipharyngitis in autoimmune (auto-inflammatory) syndrome induced by adjuvants (ASIA).

PubMed

Hotta, Osamu; Tanaka, Ayaki; Torigoe, Akira; Imai, Kazuaki; Ieiri, Norio

2017-02-01

The epipharynx is an immunologically active site even under normal conditions, and enhanced immunologic activation is prone to occur in response to an upper respiratory infection, air pollution, and possibly to vaccine adjuvants. Due to the potential link between the central nervous system and immune function, a relationship between epipharyngitis and autonomic nervous disturbance as well as autoimmune disease has been suggested. Various functional somatic symptoms have been described after human papillomavirus (HPV) vaccination, although a causal relationship has not been established. We examined the epipharynx in young women showing functional somatic symptoms following HPV vaccination. Surprisingly, despite having minimal symptoms involving the pharynx, all patients were found to have severe epipharyngitis. In addition, significant improvement in symptoms was seen in most patients who underwent epipharyngeal treatment. Thus, we speculate that the chronic epipharyngitis potentially caused by the vaccine adjuvant may be involved in the pathogenesis of functional somatic syndrome (FSS) post-HPV vaccination. Further, we suggest that epipharyngeal treatment may be effective for various types of FSS regardless of the initial cause, as well as for some autoimmune diseases, and that this may be an important direction in future research.

Somatization is associated with worse outcome in a chiropractic patient population with neck pain and low back pain.

PubMed

Ailliet, L; Rubinstein, S M; Knol, D; van Tulder, M W; de Vet, H C W

2016-02-01

To determine if psychosocial factors are associated with outcome in patients with neck pain or low back pain. In a prospective, multi-center chiropractic practice-based cohort study in Belgium and The Netherlands, 917 patients, of which 326 with neck pain and 591 with low back pain, completed self-administered questionnaires at baseline, following the second visit, and at 1, 3, 6 and 12 months. Psychosocial factors assessed at baseline were: distress, depression, anxiety and somatization via the Four Dimensional Symptom Questionnaire, patient's beliefs regarding the effect of physical activity and work on their complaint via the Fear Avoidance Beliefs Questionnaire, and social support via the Feij social support scale. Primary outcome measures were perceived recovery, pain intensity, and functional status which was measured with the Neck Disability Index and Oswestry Disability Index. A univariable regression analysis to estimate the relation between each psychological variable and outcome was followed by a multivariable multilevel regression analysis. There were no differences in baseline patient characteristics between the patient population from Belgium and the Netherlands. Somatization scores are consistently associated with perceived recovery, functional status and pain for both neck pain and low-back pain. Depression was associated with poorer functioning in patients with LBP. There was a small association between fear and function and pain for patients with neck pain or low-back pain. Somatization was the only variable consistently found to be associated with diminished perceived recovery, higher degree of neck or low back disability, and increased neck or low back pain. Copyright © 2015 Elsevier Ltd. All rights reserved.

Fecal Incontinence in Adolescents Is Associated With Child Abuse, Somatization, and Poor Health-related Quality of Life.

PubMed

Rajindrajith, Shaman; Devanarayana, Niranga Manjuri; Benninga, Marc Alexander

2016-05-01

The aim of this study was to evaluate the association between fecal incontinence (FI), child abuse, somatization, and health-related quality of life (HRQoL) in adolescents. Adolescents (ages 13-18 years) were selected from 4 semi-urban schools in the Gampaha district, Sri Lanka. A validated, self-administered questionnaire was used for data collection. FI was defined as at least 1 episode of leakage of feces per month. A total of 1807 adolescents were analyzed (boys 973 [53.8%], mean age 14.4 years, standard deviation [SD] 1.4 years). A total of 47 (2.6%) had FI. Prevalence of sexual abuse (17% vs 2.3% in controls, P < 0.0001), emotional abuse (40.4% vs 22.7%, P < 0.0001), and physical abuse (51% vs 24.3%, P < 0.0001) was significantly higher in children with FI. Adolescents with FI had higher mean somatization scores [mean 20.1, (SD 14.5) vs mean 9.3, (SD 9.2)] compared with those without FI (P < 0.0001). Those with FI also had lower HRQoL scores for physical functioning, social functioning, emotional functioning domains, and performances at school, together with a lower overall HRQoL score compared with those without FI (74.6 vs 87.1, P < 0.0001). There is a significant association between FI and physical, sexual, and emotional abuse. They also have a higher somatization score and a poor HRQoL score in physical, emotional, social, and school functioning domains compared with those without FI.

[In vitro regeneration and applications using vegetable cell and tissue culture].

PubMed

Jordán, M

1990-10-01

Plant cells by means of their totipotency and aided by in vitro culture techniques can be induced to perform morphogenesis leading to somatic embryoids and massive clonal multiplication; microspores or pollen can be triggered to recover haploid plants, then characters expressed via haploidy can be selected and fixed. Protoplasts from different species can lead to recombinations. We report here work done on Carica pubescens, where somatic embryoids were obtained from cells; in Prunus avium androgenesis leading to pollen calli was triggered, while plants were recovered from Nicotiana tabacum anthers. Fusion products were obtained using C. pubescens and C. papaya protoplasts, leading up to calli and shoots.

Diagnosing Depression in Chronic Pain Patients: DSM-IV Major Depressive Disorder vs. Beck Depression Inventory (BDI).

PubMed

Knaster, Peter; Estlander, Ann-Mari; Karlsson, Hasse; Kaprio, Jaakko; Kalso, Eija

2016-01-01

Diagnosing depression in chronic pain is challenging due to overlapping somatic symptoms. In questionnaires, such as the Beck Depression Inventory (BDI), responses may be influenced more by pain than by the severity of depression. In addition, previous studies have suggested that symptoms of negative self-image, a key element in depression, are uncommon in chronic pain-related depression. The object of this study is to assess the relationship of the somatic and cognitive-emotional items of BDI with the diagnosis of depression, pain intensity, and disability. One hundred consecutive chronic pain patients completed the Structured Clinical Interview for DSM Disorders (SCID) for the diagnosis of major depressive disorder (MDD) according to DSM-IV. Two subscales of BDI (negative view of self and somatic-physical function) were created according to the factor model presented by Morley. In the regression analysis, the somatic-physical function factor associated with MDD, while the negative view of self factor did not. Patients with MDD had higher scores in several of the BDI items when analysed separately. Insomnia and weight loss were not dependent on the depression diagnosis. The relatively small sample size and the selected patient sample limit the generalisability of the results. Somatic symptoms of depression are also common in chronic pain and should not be excluded when diagnosing depression in pain patients. Regardless of the assessment method, diagnosing depression in chronic pain remains a challenge and requires careful interpretation of symptoms.

Germline mutations in the proof-reading domains of POLE and POLD1 predispose to colorectal adenomas and carcinomas

PubMed Central

Palles, Claire; Cazier, Jean-Baptiste; Howarth, Kimberley M; Domingo, Enric; Jones, Angela M.; Broderick, Peter; Kemp, Zoe; Spain, Sarah L; Almeida, Estrella Guarino; Salguero, Israel; Sherborne, Amy; Chubb, Daniel; Carvajal-Carmona, Luis G; Ma, Yusanne; Kaur, Kulvinder; Dobbins, Sara; Barclay, Ella; Gorman, Maggie; Martin, Lynn; Kovac, Michal B; Humphray, Sean; Lucassen, Anneke; Holmes, Christopher; Bentley, David; Donnelly, Peter; Taylor, Jenny; Petridis, Christos; Roylance, Rebecca; Sawyer, Elinor J; Kerr, David J.; Clark, Susan; Grimes, Jonathan; Kearsey, Stephen E; Thomas, Huw JW; McVean, Gilean; Houlston, Richard S; Tomlinson, Ian

2013-01-01

Many individuals with multiple or large colorectal adenomas, or early-onset colorectal cancer (CRC), have no detectable germline mutations in the known cancer predisposition genes. Using whole-genome sequencing, supplemented by linkage and association analysis, we identified specific heterozygous POLE or POLD1 germline variants in several multiple adenoma and/or CRC cases, but in no controls. The susceptibility variants appear to have high penetrance. POLD1 is also associated with endometrial cancer predisposition. The mutations map to equivalent sites in the proof-reading (exonuclease) domain of DNA polymerases ε and δ, and are predicted to impair correction of mispaired bases inserted during DNA replication. In agreement with this prediction, mutation carriers’ tumours were microsatellite-stable, but tended to acquire base substitution mutations, as confirmed by yeast functional assays. Further analysis of published data showed that the recently-described group of hypermutant, microsatellite-stable CRCs is likely to be caused by somatic POLE exonuclease domain mutations. PMID:23263490

Pre-screening method for somatic cell contamination in human sperm epigenetic studies.

PubMed

Jenkins, Timothy G; Liu, Lihua; Aston, Kenneth I; Carrell, Douglas T

2018-04-01

Sperm epigenetic profiles are frequently studied and are of great interest in many fields. One major technical concern when assessing these marks is the potential for somatic cell contamination. Because somatic cells have dramatically different epigenetic signatures, even small levels of contamination can result in significant problems in analysis and interpretation of data. In this study we evaluate an assay, which we designed to offer a reliable 'pre-screen' for somatic cell contamination that directly assesses the DNA being used in the study to determine tissue purity. In brief, we designed an inexpensive and simple assay that utilizes the strong differential methylation between sperm and somatic cells at four genomic loci to assess the general purity of samples prior to performing expensive and time intensive assays. The assay is able to reliably detect contamination qualitatively by running the sample on an agarose gel, or quantitatively with the use of a bioanalyzer. With this technique we have found that we can detect potentially contaminating signals in samples of many different types, including those from patients with poor sperm phenotypes (oligozoospermia, asthenozoospermia, and teratozoospermia). We also have found that the use of multiple sites to determine potential contamination is key, as some conditions (asthenozoospermia specifically) appear at one site to reflect a somatic-like profile, while at all other sites it appears to have very typical sperm DNA methylation signatures. Taken together, the use of the assay described herein was effective at identifying contamination and could be implemented in many labs to quickly and inexpensively pre-screen samples prior to performing far more expensive and labor intensive procedures. Additionally, the principles applied to the development of this assay could be easily adapted for the development of other assays to pre-screen different tissue/cell types or model organisms.

Recurrent TERT promoter mutations identified in a large-scale study of multiple tumour types are associated with increased TERT expression and telomerase activation.

PubMed

Huang, Dong-Sheng; Wang, Zhaohui; He, Xu-Jun; Diplas, Bill H; Yang, Rui; Killela, Patrick J; Meng, Qun; Ye, Zai-Yuan; Wang, Wei; Jiang, Xiao-Ting; Xu, Li; He, Xiang-Lei; Zhao, Zhong-Sheng; Xu, Wen-Juan; Wang, Hui-Ju; Ma, Ying-Yu; Xia, Ying-Jie; Li, Li; Zhang, Ru-Xuan; Jin, Tao; Zhao, Zhong-Kuo; Xu, Ji; Yu, Sheng; Wu, Fang; Liang, Junbo; Wang, Sizhen; Jiao, Yuchen; Yan, Hai; Tao, Hou-Quan

2015-05-01

Several somatic mutation hotspots were recently identified in the telomerase reverse transcriptase (TERT) promoter region in human cancers. Large scale studies of these mutations in multiple tumour types are limited, in particular in Asian populations. This study aimed to: analyse TERT promoter mutations in multiple tumour types in a large Chinese patient cohort, investigate novel tumour types and assess the functional significance of the mutations. TERT promoter mutation status was assessed by Sanger sequencing for 13 different tumour types and 799 tumour tissues from Chinese cancer patients. Thymic epithelial tumours, gastrointestinal leiomyoma, and gastric schwannoma were included, for which the TERT promoter has not been previously sequenced. Functional studies included TERT expression by reverse-transcriptase quantitative polymerase chain reaction (RT-qPCR), telomerase activity by the telomeric repeat amplification protocol (TRAP) assay and promoter activity by the luciferase reporter assay. TERT promoter mutations were highly frequent in glioblastoma (83.9%), urothelial carcinoma (64.5%), oligodendroglioma (70.0%), medulloblastoma (33.3%) and hepatocellular carcinoma (31.4%). C228T and C250T were the most common mutations. In urothelial carcinoma, several novel rare mutations were identified. TERT promoter mutations were absent in gastrointestinal stromal tumour (GIST), thymic epithelial tumours, gastrointestinal leiomyoma, gastric schwannoma, cholangiocarcinoma, gastric and pancreatic cancer. TERT promoter mutations highly correlated with upregulated TERT mRNA expression and telomerase activity in adult gliomas. These mutations differentially enhanced the transcriptional activity of the TERT core promoter. TERT promoter mutations are frequent in multiple tumour types and have similar distributions in Chinese cancer patients. The functional significance of these mutations reflect the importance to telomere maintenance and hence tumourigenesis, making them potential therapeutic targets. Copyright © 2015 Elsevier Ltd. All rights reserved.

Recurrent TERT promoter mutations identified in a large-scale study of multiple tumor types are associated with increased TERT expression and telomerase activation

PubMed Central

Huang, Dong-Sheng; Wang, Zhaohui; He, Xu-Jun; Diplas, Bill H.; Yang, Rui; Killela, Patrick J.; Liang, Junbo; Meng, Qun; Ye, Zai-Yuan; Wang, Wei; Jiang, Xiao-Ting; Xu, Li; He, Xiang-Lei; Zhao, Zhong-Sheng; Xu, Wen-Juan; Wang, Hui-Ju; Ma, Ying-Yu; Xia, Ying-Jie; Li, Li; Zhang, Ru-Xuan; Jin, Tao; Zhao, Zhong-Kuo; Xu, Ji; Yu, Sheng; Wu, Fang; Wang, Si-Zhen; Jiao, Yu-Chen; Yan, Hai; Tao, Hou-Quan

2015-01-01

Background Several somatic mutation hotspots were recently identified in the TERT promoter region in human cancers. Large scale studies of these mutations in multiple tumor types are limited, in particular in Asian populations. This study aimed to: analyze TERT promoter mutations in multiple tumor types in a large Chinese patient cohort, investigate novel tumor types and assess the functional significance of the mutations. Methods TERT promoter mutation status was assessed by Sanger sequencing for 13 different tumor types and 799 tumor tissues from Chinese cancer patients. Thymic epithelial tumors, gastrointestinal leiomyoma, and gastric schwannoma were included, for which the TERT promoter has not been previously sequenced. Functional studies included TERT expression by RT-qPCR, telomerase activity by the TRAP assay, and promoter activity by the luciferase reporter assay. Results TERT promoter mutations were highly frequent in glioblastoma (83.9%), urothelial carcinoma (64.5%), oligodendroglioma (70.0%), medulloblastoma (33.3%), and hepatocellular carcinoma (31.4%). C228T and C250T were the most common mutations. In urothelial carcinoma, several novel rare mutations were identified. TERT promoter mutations were absent in GIST, thymic epithelial tumors, gastrointestinal leiomyoma, gastric schwannoma, cholangiocarcinoma, gastric and pancreatic cancer. TERT promoter mutations highly correlated with upregulated TERT mRNA expression and telomerase activity in adult gliomas. These mutations differentially enhanced the transcriptional activity of the TERT core promoter. Conclusions TERT promoter mutations are frequent in multiple tumor types and have similar distributions in Chinese cancer patients. The functional significance of these mutations reflect the importance to telomere maintenance and hence tumorigenesis, making them potential therapeutic targets. PMID:25843513

Nanog1 in NTERA-2 and Recombinant NanogP8 from Somatic Cancer Cells Adopt Multiple Protein Conformations and Migrate at Multiple M.W Species

PubMed Central

Liu, Bigang; Badeaux, Mark D.; Choy, Grace; Chandra, Dhyan; Shen, Irvin; Jeter, Collene R.; Rycaj, Kiera; Lee, Chia-Fang; Person, Maria D.; Liu, Can; Chen, Yueping; Shen, Jianjun; Jung, Sung Yun; Qin, Jun; Tang, Dean G.

2014-01-01

Human Nanog1 is a 305-amino acid (aa) homeodomain-containing transcription factor critical for the pluripotency of embryonic stem (ES) and embryonal carcinoma (EC) cells. Somatic cancer cells predominantly express a retrogene homolog of Nanog1 called NanogP8, which is ∼99% similar to Nanog at the aa level. Although the predicted M.W of Nanog1/NanogP8 is ∼35 kD, both have been reported to migrate, on Western blotting (WB), at apparent molecular masses of 29–80 kD. Whether all these reported protein bands represent authentic Nanog proteins is unclear. Furthermore, detailed biochemical studies on Nanog1/NanogpP8 have been lacking. By combining WB using 8 anti-Nanog1 antibodies, immunoprecipitation, mass spectrometry, and studies using recombinant proteins, here we provide direct evidence that the Nanog1 protein in NTERA-2 EC cells exists as multiple M.W species from ∼22 kD to 100 kD with a major 42 kD band detectable on WB. We then demonstrate that recombinant NanogP8 (rNanogP8) proteins made in bacteria using cDNAs from multiple cancer cells also migrate, on denaturing SDS-PAGE, at ∼28 kD to 180 kD. Interestingly, different anti-Nanog1 antibodies exhibit differential reactivity towards rNanogP8 proteins, which can spontaneously form high M.W protein species. Finally, we show that most long-term cultured cancer cell lines seem to express very low levels of or different endogenous NanogP8 protein that cannot be readily detected by immunoprecipitation. Altogether, the current study reveals unique biochemical properties of Nanog1 in EC cells and NanogP8 in somatic cancer cells. PMID:24598770

L(3)mbt and the LINT complex safeguard cellular identity in the Drosophila ovary.

PubMed

Coux, Rémi-Xavier; Teixeira, Felipe Karam; Lehmann, Ruth

2018-04-04

Maintenance of cellular identity is essential for tissue development and homeostasis. At the molecular level, cell identity is determined by the coordinated activation and repression of defined sets of genes. The tumor suppressor L(3)mbt has been shown to secure cellular identity in Drosophila larval brains by repressing germline-specific genes. Here, we interrogate the temporal and spatial requirements for L(3)mbt in the Drosophila ovary, and show that it safeguards the integrity of both somatic and germline tissues. l(3)mbt mutant ovaries exhibit multiple developmental defects, which we find to be largely caused by the inappropriate expression of a single gene, nanos , a key regulator of germline fate, in the somatic ovarian cells. In the female germline, we find that L(3)mbt represses testis-specific and neuronal genes. At the molecular level, we show that L(3)mbt function in the ovary is mediated through its co-factor Lint-1 but independently of the dREAM complex. Together, our work uncovers a more complex role for L(3)mbt than previously understood and demonstrates that L(3)mbt secures tissue identity by preventing the simultaneous expression of original identity markers and tissue-specific misexpression signatures. © 2018. Published by The Company of Biologists Ltd.

Health Effects Associated With Geographical Area of Residence During the 1991 Gulf War: A Comparative Health Study of Iraqi Soldiers and Civilians

PubMed Central

Jamil, Hikmet; Hamdan, Thamer A.; Grzybowski, Mary; Arnetz, Bengt B.

2011-01-01

Context Although Iraqis sustained the gravest exposure conditions during the 1991 Gulf War (GW), little is known about the possible relationship between environmental exposures during the GW and long-term health in Iraqis. Objective To study the relationship between distance from Kuwait during the GW and somatic health among Iraqi Soldiers vs civilians. Methods A survey questionnaire was distributed to a sample of 742 GW veterans and 413 civilians in Iraq. The odds ratios were calculated for somatic disorders as a function of distance from Kuwait during the GW, as well as a self-reported environmental exposure index. Results Soldiers reported a significantly higher prevalence of somatic disorders as compared to civilians. Soldiers closest to Kuwait reported significantly more somatic disorders as compared to Soldiers deployed further away from Kuwait. Conclusion Iraqi GW veterans are at an increased risk of numerous somatic disorders. Soldiers are at an increased risk compared to civilians, suggesting that war-associated exposures are of etiologic relevance. PMID:21805460

PTENα, a PTEN isoform translated through alternative initiation, regulates mitochondrial function and energy metabolism.

PubMed

Liang, Hui; He, Shiming; Yang, Jingyi; Jia, Xinying; Wang, Pan; Chen, Xi; Zhang, Zhong; Zou, Xiajuan; McNutt, Michael A; Shen, Wen Hong; Yin, Yuxin

2014-05-06

PTEN is one of the most frequently mutated genes in human cancer. It is known that PTEN has a wide range of biological functions beyond tumor suppression. Here, we report that PTENα, an N-terminally extended form of PTEN, functions in mitochondrial metabolism. Translation of PTENα is initiated from a CUG codon upstream of and in-frame with the coding region of canonical PTEN. Eukaryotic translation initiation factor 2A (eIF2A) controls PTENα translation, which requires a CUG-centered palindromic motif. We show that PTENα induces cytochrome c oxidase activity and ATP production in mitochondria. TALEN-mediated somatic deletion of PTENα impairs mitochondrial respiratory chain function. PTENα interacts with canonical PTEN to increase PINK1 protein levels and promote energy production. Our studies demonstrate the importance of eIF2A-mediated alternative translation for generation of protein diversity in eukaryotic systems and provide insights into the mechanism by which the PTEN family is involved in multiple cellular processes. Copyright © 2014 Elsevier Inc. All rights reserved.

Functional decline and herpes zoster in older people: an interplay of multiple factors.

PubMed

2015-12-01

Herpes zoster is a frequent painful infectious disease whose incidence and severity increase with age. In older people, there is a strong bidirectional link between herpes zoster and functional decline, which refers to a decrement in ability to perform activities of daily living due to ageing and disabilities. However, the exact nature of such link remains poorly established. Based on the opinion from a multidisciplinary group of experts, we here propose a new model to account for the interplay between infection, somatic/psychiatric comorbidity, coping skills, polypharmacy, and age, which may account for the functional decline related to herpes zoster in older patients. This model integrates the risk of decompensation of underlying disease; the risk of pain becoming chronic (e.g. postherpetic neuralgia); the risk of herpes zoster non-pain complications; the detrimental impact of herpes zoster on quality of life, functioning, and mood; the therapeutic difficulties due to multimorbidity, polypharmacy, and ageing; and the role of stressful life events in the infection itself and comorbid depression. This model underlines the importance of early treatment, strengthening coping, and vaccine prevention.

Insights into wild-type and mutant p53 functions provided by genetically engineered mice.

PubMed

Donehower, Lawrence A

2014-06-01

Recent whole-exome sequencing studies of numerous human cancers have now conclusively shown that the TP53 tumor-suppressor gene is the most frequently mutated gene in human cancers. Despite extensive studies of the TP53 gene and its encoded protein (p53), our understanding of how TP53 mutations contribute to cancer initiation and progression remain incomplete. Genetically engineered mice with germline or inducible Trp53 somatic mutations have provided important insights into the mechanisms by which different types of p53 mutation influence cancer development. Trp53 germline mutations that alter specific p53 structural domains or posttranslation modification sites have benefitted our understanding of wild-type p53 functions in a whole organism context. Moreover, genetic approaches to reestablish functional wild-type p53 to p53-deficient tissues and tumors have increased our understanding of the therapeutic potential of restoring functional p53 signaling to cancers. This review outlines many of the key insights provided by the various categories of Trp53 mutant mice that have been generated by multiple genetic engineering approaches. © 2014 WILEY PERIODICALS, INC.

Combined mismatch repair and POLE/POLD1 defects explain unresolved suspected Lynch syndrome cancers

PubMed Central

Jansen, Anne ML; van Wezel, Tom; van den Akker, Brendy EWM; Ventayol Garcia, Marina; Ruano, Dina; Tops, Carli MJ; Wagner, Anja; Letteboer, Tom GW; Gómez-García, Encarna B; Devilee, Peter; Wijnen, Juul T; Hes, Frederik J; Morreau, Hans

2016-01-01

Many suspected Lynch Syndrome (sLS) patients who lack mismatch repair (MMR) germline gene variants and MLH1 or MSH2 hypermethylation are currently explained by somatic MMR gene variants or, occasionally, by germline POLE variants. To further investigate unexplained sLS patients, we analyzed leukocyte and tumor DNA of 62 sLS patients using gene panel sequencing including the POLE, POLD1 and MMR genes. Forty tumors showed either one, two or more somatic MMR variants predicted to affect function. Nine sLS tumors showed a likely ultramutated phenotype and were found to carry germline (n=2) or somatic variants (n=7) in the POLE/POLD1 exonuclease domain (EDM). Six of these POLE/POLD1-EDM mutated tumors also carried somatic MMR variants. Our findings suggest that faulty proofreading may result in loss of MMR and thereby in microsatellite instability. PMID:26648449

Functional and structural microanatomy of the fetal sciatic nerve.

PubMed

Creze, Maud; Zaitouna, Mazen; Krystel, Nyangoh Timoh; Diallo, Djibril; Lebacle, Cédric; Bellin, Marie-France; Ducreux, Denis; Benoit, Gérard; Bessede, Thomas

2017-10-01

The ultrastructure of a nerve has implications for surgical nerve repair. The aim of our study was to characterize the fascicular versus fibrillar anatomy and the autonomic versus somatic nature of the fetal sciatic nerve (SN). Immunohistochemistry for vesicular acetylcholine transporter, tyrosine hydroxylase, and peripheral myelin protein 22 was performed to identify cholinergic, adrenergic, and somatic axons, respectively, in the human fetal SN. Two-dimensional (2D) analysis and 3D reconstructions were performed. The fetal SN is composed of one-third stromal tissue and two-thirds neural tissue. Autonomic fibers are predominant over somatic fibers within the neural tissue. The distribution of somatic fibers is initially random, but then become topographically organized after intra- and interfascicular rearrangements have occurred within the nerve. The fetal model presents limitations but enables illustration of the nature of the nerve fibers and the 3D fascicular anatomy of the SN. Muscle Nerve 56: 787-796, 2017. © 2017 Wiley Periodicals, Inc.

The Impacts of Migraine among Outpatients with Major Depressive Disorder at a Two-Year Follow-Up

PubMed Central

Hung, Ching-I; Liu, Chia-Yih; Yang, Ching-Hui; Wang, Shuu-Jiun

2015-01-01

Background No study has investigated the impacts of migraine on depression, anxiety, and somatic symptoms and remission at the two-year follow-up point among patients with major depressive disorder (MDD). This study aimed to investigate the above issues. Methods Psychiatric outpatients with MDD recruited at baseline were investigated at a two-year follow-up (N = 106). The Hamilton Depression Rating Scale, Hospital Anxiety and Depression Scale, and Depression and Somatic Symptoms Scale were used. Migraine was diagnosed according to the International Classification of Headache Disorders, 2nd edition. The patients were divided into no migraine, inactive migraine, and active migraine subgroups. Multiple logistic regressions were used to investigate the significant factors related to full remission of depression. Results Among patients without pharmacotherapy at the follow-up, patients with active migraine had significantly greater severities of anxiety and somatic symptoms as compared with patients without migraine; moreover, patients with active migraine had the lowest improvement percentage and full remission rate. There were no significant differences in depression, anxiety, and somatic symptoms between patients with inactive migraine and those without migraine. Active headache at follow-up was a significant factor related to a lower full remission rate. Conclusions Active headache at follow-up was associated with a lower rate of full remission and more residual anxiety and somatic symptoms at follow-up among patients with migraine. Physicians should integrate a treatment plan for depression and migraine for the treatment of patients with MDD. PMID:26000962

The Impacts of Migraine among Outpatients with Major Depressive Disorder at a Two-Year Follow-Up.

PubMed

Hung, Ching-I; Liu, Chia-Yih; Yang, Ching-Hui; Wang, Shuu-Jiun

2015-01-01

No study has investigated the impacts of migraine on depression, anxiety, and somatic symptoms and remission at the two-year follow-up point among patients with major depressive disorder (MDD). This study aimed to investigate the above issues. Psychiatric outpatients with MDD recruited at baseline were investigated at a two-year follow-up (N = 106). The Hamilton Depression Rating Scale, Hospital Anxiety and Depression Scale, and Depression and Somatic Symptoms Scale were used. Migraine was diagnosed according to the International Classification of Headache Disorders, 2nd edition. The patients were divided into no migraine, inactive migraine, and active migraine subgroups. Multiple logistic regressions were used to investigate the significant factors related to full remission of depression. Among patients without pharmacotherapy at the follow-up, patients with active migraine had significantly greater severities of anxiety and somatic symptoms as compared with patients without migraine; moreover, patients with active migraine had the lowest improvement percentage and full remission rate. There were no significant differences in depression, anxiety, and somatic symptoms between patients with inactive migraine and those without migraine. Active headache at follow-up was a significant factor related to a lower full remission rate. Active headache at follow-up was associated with a lower rate of full remission and more residual anxiety and somatic symptoms at follow-up among patients with migraine. Physicians should integrate a treatment plan for depression and migraine for the treatment of patients with MDD.

Psychological distress longitudinally mediates the effect of vertigo symptoms on vertigo-related handicap.

PubMed

Probst, Thomas; Dinkel, Andreas; Schmid-Mühlbauer, Gabriele; Radziej, Katharina; Limburg, Karina; Pieh, Christoph; Lahmann, Claas

2017-02-01

Vertigo symptoms can lead to more or less vertigo-related handicap. This longitudinal study investigated whether depression, anxiety, and/or somatization mediate the relationship between vertigo symptoms and vertigo-related handicap. N=111 patients with vertigo/dizziness provided complete data on the following measures: Vertigo symptoms at baseline, depression at 6-month follow-up, anxiety at 6-month follow-up, somatization at 6-month follow-up, and vertigo handicap at 12-month follow-up. Mediation analyses with bootstrapping were performed to investigate the mediating role of anxiety, depression, and somatization in the relationship between vertigo symptoms and vertigo-related handicap. When the mediating role of anxiety, depression, and somatization was evaluated separately from each other in single mediation models, the effect vertigo symptoms at baseline exerted on vertigo-related handicap at 12-month follow-up was significantly mediated by depression at 6-month follow-up (p<0.05), by anxiety at 6-month follow-up (p<0.05), as well as by somatization at 6-month follow-up (p<0.05). When statistically controlling for the other mediators in a multiple mediator model, only depression at 6-month follow-up mediated the effect of vertigo symptoms at baseline on vertigo-related handicap at 12-month follow-up (p<0.05). Psychological distress is an important mechanism in the process how vertigo symptoms lead to vertigo-related handicap. Copyright © 2016 Elsevier Inc. All rights reserved.

Stochastic modeling indicates that aging and somatic evolution in the hematopoetic system are driven by non-cell-autonomous processes.

PubMed

Rozhok, Andrii I; Salstrom, Jennifer L; DeGregori, James

2014-12-01

Age-dependent tissue decline and increased cancer incidence are widely accepted to be rate-limited by the accumulation of somatic mutations over time. Current models of carcinogenesis are dominated by the assumption that oncogenic mutations have defined advantageous fitness effects on recipient stem and progenitor cells, promoting and rate-limiting somatic evolution. However, this assumption is markedly discrepant with evolutionary theory, whereby fitness is a dynamic property of a phenotype imposed upon and widely modulated by environment. We computationally modeled dynamic microenvironment-dependent fitness alterations in hematopoietic stem cells (HSC) within the Sprengel-Liebig system known to govern evolution at the population level. Our model for the first time integrates real data on age-dependent dynamics of HSC division rates, pool size, and accumulation of genetic changes and demonstrates that somatic evolution is not rate-limited by the occurrence of mutations, but instead results from aged microenvironment-driven alterations in the selective/fitness value of previously accumulated genetic changes. Our results are also consistent with evolutionary models of aging and thus oppose both somatic mutation-centric paradigms of carcinogenesis and tissue functional decline. In total, we demonstrate that aging directly promotes HSC fitness decline and somatic evolution via non-cell-autonomous mechanisms.

Pituitary Volumes Are Reduced in Patients with Somatization Disorder

PubMed Central

Yildirim, Hanefi; Sirlier, Burcu; Kayali, Alperen

2012-01-01

Objective Despite of the suggested physiological relationship between somatoform disorder and disturbances in HPA axis function no volumetric study of pituitary volumes in somatization disorder has been carried out. Therefore, we aimed to use structural MRI to evaluate the pituitary volumes of the patients with somatization disorder. Methods Eighteen female patients with somatization disorder according to DSM-IV and same number of healthy controls were included into the study. All subjects were scanned using a 1.5-T General Electric (GE; Milwaukee, USA) scanner. Pituitary volume measurements were determined by using manuallly tracings according to standard antomical atlases. Results It was found significantly smaller pituitary volumes of the whole group of somatization patients compared to healthy (t=-3.604, p=0.001). ANCOVA predicting pituitary volumes demonstrated a significant main effect of diagnostic group (F=13.530, p<0.001) but TBV (F=1.924, p>0.05) or age (F=1.159, p>0.05). It was determined that there was no significant correlation between smaller pituitary volumes and the duration of illness (r=0.16, p>0.05) in the patient group. Conclusion In conclusion, we suggest that the patients with somatization disorder might have significantly smaller pituitary volumes compared to healthy control subjects. PMID:22993528

Three forms of somatization presenting in primary care settings in Spain.

PubMed

García-Campayo, J; Lobo, A; Pérez-Echeverría, M J; Campos, R

1998-09-01

The objective of this paper is to study the prevalence and clinical characteristics of functional, hypochondriacal, and presenting somatization (FSTS, HSTS, and PSTS, respectively) defined by standardized criteria, as well as the validity of their distinction in primary care in Spain. A two-stage epidemiological study of a representative sample (N = 1559) of primary care patients was carried out. In the first phase, the validated Spanish versions of General Health Questionnaire, Mini-Mental State Examination, and CAGE were used. In the second phase, the Standardized Polyvalent Psychiatric Interview, an interview for the multiaxial assessment of medical patients, was employed. The prevalence of any form of somatization in Spain was 21.3% (FSTS: 16.2%, PSTS: 9.4%, HSTS: 6.7%). Overlap of any of the three clinical forms was very frequent (42.7%). FSTS patients tended to be more chronic and showed higher scores in fatigue but lower scores in both depression and anxiety. Chronicity was frequent among somatizers, particularly in those who fulfilled more than one kind of somatization. Differences in diagnostic distribution among the three groups were also observed. In conclusion, this is the first study giving support to the validity of the distinction among three types of somatization in Spain, but overlap was more frequent than reported in North American studies.

Somatic Embryogenesis in Peach Palm Using the Thin Cell Layer Technique: Induction, Morpho-histological Aspects and AFLP Analysis of Somaclonal Variation

PubMed Central

Steinmacher, D. A.; Krohn, N. G.; Dantas, A. C. M.; Stefenon, V. M.; Clement, C. R.; Guerra, M. P.

2007-01-01

Background and Aims The thin cell layer (TCL) technique is based on the use of very small explants and has allowed enhanced in vitro morphogenesis in several plant species. The present study evaluated the TCL technique as a procedure for somatic embryo production and plantlet regeneration of peach palm. Methods TCL explants from different positions in the shoot apex and leaf sheath of peach palm were cultivated in MS culture medium supplemented with 0–600 µm Picloram in the presence of activated charcoal. The production of primary calli and embryogenic calli was evaluated in these different conditions. Histological and amplified fragment length polymorphism (AFLP) analyses were conducted to study in vitro morphogenetic responses and genetic stability, respectively, of the regenerated plantlets. Key Results Abundant primary callus induction was observed from TCLs of the shoot meristem in culture media supplemented with 150–600 µm Picloram (83–97 %, respectively). The production of embryogenic calli depends on Picloram concentration and explant position. The best response observed was 43 % embryogenic callus production from shoot meristem TCL on 300 µm Picloram. In maturation conditions, 34 ± 4 somatic embryos per embryogenic callus were obtained, and 45·0 ± 3·4 % of these fully developed somatic embryos were converted, resulting in plantlets ready for acclimatization, of which 80 % survived. Histological studies revealed that the first cellular division events occurred in cells adjacent to vascular tissue, resulting in primary calli, whose growth was ensured by a meristematic zone. A multicellular origin of the resulting somatic embryos arising from the meristematic zone is suggested. During maturation, histological analyses revealed bipolarization of the somatic embryos, as well as the development of new somatic embryos. AFLP analyses revealed that 92 % of the regenerated plantlets were true to type. The use of TCL explants considerably improves the number of calli and somatic embryos produced in comparison with previously described protocols for in vitro regeneration of peach palm. Conclusions The present study suggests that the TCL somatic embryogenesis protocol developed is feasible, although it still requires further optimization for in vitro multiplication of peach palm, especially the use of similar explants obtained from adult palm trees. PMID:17670751

CSR-1 and P granules suppress sperm-specific transcription in the C. elegans germline

PubMed Central

Campbell, Anne C.; Updike, Dustin L.

2015-01-01

Germ granules (P granules) in C. elegans are required for fertility and function to maintain germ cell identity and pluripotency. Sterility in the absence of P granules is often accompanied by the misexpression of soma-specific proteins and the initiation of somatic differentiation in germ cells. To investigate whether this is caused by the accumulation of somatic transcripts, we performed mRNA-seq on dissected germlines with and without P granules. Strikingly, we found that somatic transcripts do not increase in the young adult germline when P granules are impaired. Instead, we found that impairing P granules causes sperm-specific mRNAs to become highly overexpressed. This includes the accumulation of major sperm protein (MSP) transcripts in germ cells, a phenotype that is suppressed by feminization of the germline. A core component of P granules, the endo-siRNA-binding Argonaute protein CSR-1, has recently been ascribed with the ability to license transcripts for germline expression. However, impairing CSR-1 has very little effect on the accumulation of its mRNA targets. Instead, we found that CSR-1 functions with P granules to prevent MSP and sperm-specific mRNAs from being transcribed in the hermaphrodite germline. These findings suggest that P granules protect germline integrity through two different mechanisms, by (1) preventing the inappropriate expression of somatic proteins at the level of translational regulation, and by (2) functioning with CSR-1 to limit the domain of sperm-specific expression at the level of transcription. PMID:25968310

Somatic symptoms of generalized anxiety disorder from the DSM-IV: associations with pathological worry and depression symptoms in a nonclinical sample.

PubMed

Joormann, J; Stöber, J

1999-01-01

The present study investigates specificity of the six somatic symptoms that are associated with generalized anxiety disorder (GAD), according to the fourth edition of the Diagnostic and Statistical Manual of Mental Disorders. A nonclinical sample of 183 students provided severity ratings for (a) restlessness, (b) easily fatigued, (c) difficulty concentrating, (d) irritability, (e) muscle tension, and (f) sleep disturbance. In addition, they responded to questionnaires assessing pathological worry and depression symptoms. Partial correlations and multiple regression analyses indicated that only muscle tension showed a unique relation to pathological worry. In contrast, difficulty concentrating was exclusively related to depression symptoms. Present findings corroborate psychophysiological findings that elevated muscle tension is a specific characteristic of pathological worriers. Moreover, they suggest that the problem of unclear boundaries between GAD and major depression may be reduced if future revisions of the somatic symptom list for GAD emphasize muscle tension while de-emphasizing difficulty concentrating.

TumorNext-Lynch-MMR: a comprehensive next generation sequencing assay for the detection of germline and somatic mutations in genes associated with mismatch repair deficiency and Lynch syndrome.

PubMed

Gray, Phillip N; Tsai, Pei; Chen, Daniel; Wu, Sitao; Hoo, Jayne; Mu, Wenbo; Li, Bing; Vuong, Huy; Lu, Hsiao-Mei; Batth, Navanjot; Willett, Sara; Uyeda, Lisa; Shah, Swati; Gau, Chia-Ling; Umali, Monalyn; Espenschied, Carin; Janicek, Mike; Brown, Sandra; Margileth, David; Dobrea, Lavinia; Wagman, Lawrence; Rana, Huma; Hall, Michael J; Ross, Theodora; Terdiman, Jonathan; Cullinane, Carey; Ries, Savita; Totten, Ellen; Elliott, Aaron M

2018-04-17

The current algorithm for Lynch syndrome diagnosis is highly complex with multiple steps which can result in an extended time to diagnosis while depleting precious tumor specimens. Here we describe the analytical validation of a custom probe-based NGS tumor panel, TumorNext-Lynch-MMR, which generates a comprehensive genetic profile of both germline and somatic mutations that can accelerate and streamline the time to diagnosis and preserve specimen. TumorNext-Lynch-MMR can detect single nucleotide variants, small insertions and deletions in 39 genes that are frequently mutated in Lynch syndrome and colorectal cancer. Moreover, the panel provides microsatellite instability status and detects loss of heterozygosity in the five Lynch genes; MSH2 , MSH6 , MLH1 , PMS2 and EPCAM . Clinical cases are described that highlight the assays ability to differentiate between somatic and germline mutations, precisely classify variants and resolve discordant cases.

TumorNext-Lynch-MMR: a comprehensive next generation sequencing assay for the detection of germline and somatic mutations in genes associated with mismatch repair deficiency and Lynch syndrome

PubMed Central

Gray, Phillip N.; Tsai, Pei; Chen, Daniel; Wu, Sitao; Hoo, Jayne; Mu, Wenbo; Li, Bing; Vuong, Huy; Lu, Hsiao-Mei; Batth, Navanjot; Willett, Sara; Uyeda, Lisa; Shah, Swati; Gau, Chia-Ling; Umali, Monalyn; Espenschied, Carin; Janicek, Mike; Brown, Sandra; Margileth, David; Dobrea, Lavinia; Wagman, Lawrence; Rana, Huma; Hall, Michael J.; Ross, Theodora; Terdiman, Jonathan; Cullinane, Carey; Ries, Savita; Totten, Ellen; Elliott, Aaron M.

2018-01-01

The current algorithm for Lynch syndrome diagnosis is highly complex with multiple steps which can result in an extended time to diagnosis while depleting precious tumor specimens. Here we describe the analytical validation of a custom probe-based NGS tumor panel, TumorNext-Lynch-MMR, which generates a comprehensive genetic profile of both germline and somatic mutations that can accelerate and streamline the time to diagnosis and preserve specimen. TumorNext-Lynch-MMR can detect single nucleotide variants, small insertions and deletions in 39 genes that are frequently mutated in Lynch syndrome and colorectal cancer. Moreover, the panel provides microsatellite instability status and detects loss of heterozygosity in the five Lynch genes; MSH2, MSH6, MLH1, PMS2 and EPCAM. Clinical cases are described that highlight the assays ability to differentiate between somatic and germline mutations, precisely classify variants and resolve discordant cases. PMID:29755653

Phylogenetic analysis of metastatic progression in breast cancer using somatic mutations and copy number aberrations

PubMed Central

Brown, David; Smeets, Dominiek; Székely, Borbála; Larsimont, Denis; Szász, A. Marcell; Adnet, Pierre-Yves; Rothé, Françoise; Rouas, Ghizlane; Nagy, Zsófia I.; Faragó, Zsófia; Tőkés, Anna-Mária; Dank, Magdolna; Szentmártoni, Gyöngyvér; Udvarhelyi, Nóra; Zoppoli, Gabriele; Pusztai, Lajos; Piccart, Martine; Kulka, Janina; Lambrechts, Diether; Sotiriou, Christos; Desmedt, Christine

2017-01-01

Several studies using genome-wide molecular techniques have reported various degrees of genetic heterogeneity between primary tumours and their distant metastases. However, it has been difficult to discern patterns of dissemination owing to the limited number of patients and available metastases. Here, we use phylogenetic techniques on data generated using whole-exome sequencing and copy number profiling of primary and multiple-matched metastatic tumours from ten autopsied patients to infer the evolutionary history of breast cancer progression. We observed two modes of disease progression. In some patients, all distant metastases cluster on a branch separate from their primary lesion. Clonal frequency analyses of somatic mutations show that the metastases have a monoclonal origin and descend from a common ‘metastatic precursor’. Alternatively, multiple metastatic lesions are seeded from different clones present within the primary tumour. We further show that a metastasis can be horizontally cross-seeded. These findings provide insights into breast cancer dissemination. PMID:28429735

In Vitro Mass Propagation of Cymbopogon citratus Stapf., a Medicinal Gramineae.

PubMed

Quiala, Elisa; Barbón, Raúl; Capote, Alina; Pérez, Naivy; Jiménez, Elio

2016-01-01

Cymbopogon citratus (D.C.) Stapf. is a medicinal plant source of lemon grass oils with multiple uses in the pharmaceutical and food industry. Conventional propagation in semisolid culture medium has become a fast tool for mass propagation of lemon grass, but the production cost must be lower. A solution could be the application of in vitro propagation methods based on liquid culture advantages and automation. This chapter provides two efficient protocols for in vitro propagation via organogenesis and somatic embryogenesis of this medicinal plant. Firstly, we report the production of shoots using a temporary immersion system (TIS). Secondly, a protocol for somatic embryogenesis using semisolid culture for callus formation and multiplication, and liquid culture in a rotatory shaker and conventional bioreactors for the maintenance of embryogenic culture, is described. Well-developed plants can be achieved from both protocols. Here we provide a fast and efficient technology for mass propagation of this medicinal plant taking the advantage of liquid culture and automation.

BMP signalling in human fetal ovary somatic cells is modulated in a gene-specific fashion by GREM1 and GREM2

PubMed Central

Bayne, Rosemary A.; Donnachie, Douglas J.; Kinnell, Hazel L.; Childs, Andrew J.; Anderson, Richard A.

2016-01-01

STUDY QUESTION Do changes in the expression of bone morphogenetic proteins (BMPs) 2 and 4, and their antagonists Gremlin1 (GREM1) and Gremlin2 (GREM2) during human fetal ovarian development impact on BMP pathway activity and lead to changes in gene expression that may influence the fate and/or function of ovarian somatic cells? STUDY FINDING BMPs 2 and 4 differentially regulate gene expression in cultured human fetal ovarian somatic cells. Expression of some, but not all BMP target genes is antagonised by GREM1 and GREM2, indicating the existence of a mechanism to fine-tune BMP signal intensity in the ovary. Leucine-rich repeat-containing G-protein coupled receptor 5 (LGR5), a marker of immature ovarian somatic cells, is identified as a novel transcriptional target of BMP4. WHAT IS KNOWN ALREADY Extensive re-organisation of the germ and somatic cell populations in the feto-neonatal ovary culminates in the formation of primordial follicles, which provide the basis for a female's future fertility. BMP growth factors play important roles at many stages of ovarian development and function. GREM1, an extracellular antagonist of BMP signalling, regulates the timing of primordial follicle formation in the mouse ovary, and mRNA levels of BMP4 decrease while those of BMP2 increase prior to follicle formation in the human fetal ovary. STUDY DESIGN, SAMPLES/MATERIALS, METHODS Expression of genes encoding BMP pathway components, BMP antagonists and markers of ovarian somatic cells were determined by quantitative (q)RT-PCR in human fetal ovaries (from 8 to 21 weeks gestation) and fetal ovary-derived somatic cell cultures. Ovarian expression of GREM1 protein was confirmed by immunoblotting. Primary human fetal ovarian somatic cell cultures were derived from disaggregated ovaries by differential adhesion and cultured in the presence of recombinant human BMP2 or BMP4, with or without the addition of GREM1 or GREM2. MAIN RESULTS AND THE ROLE OF CHANCE We demonstrate that the expression of BMP antagonists GREM1, GREM2 and CHRD  increases in the lead-up to primordial follicle formation in the human fetal ovary, and that the BMP pathway is active in cultured ovarian somatic cells. This leads to differential changes in the expression of a number of genes, some of which are further modulated by GREM1 and/or GREM2. The positive transcriptional regulation of LGR5 (a marker of less differentiated somatic cells) by BMP4 in vitro suggests that increasing levels of GREM1 and reduced levels of BMP4 as the ovary develops in vivo may act to reduce LGR5 levels and allow pre-granulosa cell differentiation. LIMITATIONS, REASONS FOR CAUTION While we have demonstrated that markers of different somatic cell types are expressed in the cultured ovarian somatic cells, their proportions may not represent the same cells in the intact ovary which also contains germ cells. WIDER IMPLICATIONS OF THE FINDINGS This study extends previous work identifying germ cells as targets of ovarian BMP signalling, and suggests BMPs may regulate the development of both germ and somatic cells in the developing ovary around the time of follicle formation. LARGE SCALE DATA Not applicable. STUDY FUNDING/COMPETING INTERESTS This work was supported by The UK Medical Research Council (Grant No.: G1100357 to RAA), and Medical Research Scotland (Grant No. 345FRG to AJC). The authors have no competing interests to declare. PMID:27385727

BMP signalling in human fetal ovary somatic cells is modulated in a gene-specific fashion by GREM1 and GREM2.

PubMed

Bayne, Rosemary A; Donnachie, Douglas J; Kinnell, Hazel L; Childs, Andrew J; Anderson, Richard A

2016-09-01

Do changes in the expression of bone morphogenetic proteins (BMPs) 2 and 4, and their antagonists Gremlin1 (GREM1) and Gremlin2 (GREM2) during human fetal ovarian development impact on BMP pathway activity and lead to changes in gene expression that may influence the fate and/or function of ovarian somatic cells? BMPs 2 and 4 differentially regulate gene expression in cultured human fetal ovarian somatic cells. Expression of some, but not all BMP target genes is antagonised by GREM1 and GREM2, indicating the existence of a mechanism to fine-tune BMP signal intensity in the ovary. Leucine-rich repeat-containing G-protein coupled receptor 5 (LGR5), a marker of immature ovarian somatic cells, is identified as a novel transcriptional target of BMP4. Extensive re-organisation of the germ and somatic cell populations in the feto-neonatal ovary culminates in the formation of primordial follicles, which provide the basis for a female's future fertility. BMP growth factors play important roles at many stages of ovarian development and function. GREM1, an extracellular antagonist of BMP signalling, regulates the timing of primordial follicle formation in the mouse ovary, and mRNA levels of BMP4 decrease while those of BMP2 increase prior to follicle formation in the human fetal ovary. Expression of genes encoding BMP pathway components, BMP antagonists and markers of ovarian somatic cells were determined by quantitative (q)RT-PCR in human fetal ovaries (from 8 to 21 weeks gestation) and fetal ovary-derived somatic cell cultures. Ovarian expression of GREM1 protein was confirmed by immunoblotting. Primary human fetal ovarian somatic cell cultures were derived from disaggregated ovaries by differential adhesion and cultured in the presence of recombinant human BMP2 or BMP4, with or without the addition of GREM1 or GREM2. We demonstrate that the expression of BMP antagonists GREM1, GREM2 and CHRD  increases in the lead-up to primordial follicle formation in the human fetal ovary, and that the BMP pathway is active in cultured ovarian somatic cells. This leads to differential changes in the expression of a number of genes, some of which are further modulated by GREM1 and/or GREM2. The positive transcriptional regulation of LGR5 (a marker of less differentiated somatic cells) by BMP4 in vitro suggests that increasing levels of GREM1 and reduced levels of BMP4 as the ovary develops in vivo may act to reduce LGR5 levels and allow pre-granulosa cell differentiation. While we have demonstrated that markers of different somatic cell types are expressed in the cultured ovarian somatic cells, their proportions may not represent the same cells in the intact ovary which also contains germ cells. This study extends previous work identifying germ cells as targets of ovarian BMP signalling, and suggests BMPs may regulate the development of both germ and somatic cells in the developing ovary around the time of follicle formation. Not applicable. This work was supported by The UK Medical Research Council (Grant No.: G1100357 to RAA), and Medical Research Scotland (Grant No. 345FRG to AJC). The authors have no competing interests to declare. © The Author 2016. Published by Oxford University Press on behalf of the European Society of Human Reproduction and Embryology.

Local anesthesia selection algorithm in patients with concomitant somatic diseases.

PubMed

Anisimova, E N; Sokhov, S T; Letunova, N Y; Orekhova, I V; Gromovik, M V; Erilin, E A; Ryazantsev, N A

2016-01-01

The paper presents basic principles of local anesthesia selection in patients with concomitant somatic diseases. These principles are history taking; analysis of drugs interaction with local anesthetic and sedation agents; determination of the functional status of the patient; patient anxiety correction; dental care with monitoring of hemodynamics parameters. It was found that adhering to this algorithm promotes prevention of urgent conditions in patients in outpatient dentistry.

Central sensitivity syndromes: a new paradigm and group nosology for fibromyalgia and overlapping conditions, and the related issue of disease versus illness.

PubMed

Yunus, Muhammad B

2008-06-01

To discuss the current terminologies used for fibromyalgia syndrome (FMS) and related overlapping conditions, to examine if central sensitivity syndromes (CSS) is the appropriate nosology for these disorders, and to explore the issue of disease versus illness. A literature search was performed through PubMed, Web of Science, and ScienceDirect using a number of keywords, eg, functional somatic syndromes, somatoform disorders, medically unexplained symptoms, organic and nonorganic, and diseases and illness. Relevant articles were then reviewed and representative ones cited. Terminologies currently used for CSS conditions predominantly represent a psychosocial construct and are inappropriate. On the other hand, CSS seems to be the logical nosology based on a biopsychosocial model. Such terms as "medically unexplained symptoms," "somatization," "somatization disorder," and "functional somatic syndromes" in the context of CSS should be abandoned. Given current scientific knowledge, the concept of disease-illness dualism has no rational basis and impedes proper patient-physician communication, resulting in poor patient care. The concept of CSS is likely to promote research, education, and proper patient management. CSS seems to be a useful paradigm and an appropriate terminology for FMS and related conditions. The disease-illness, as well as organic/non-organic dichotomy, should be rejected.

[PIWI protein as a nucleolus visitor in Drosophila melanogaster].

PubMed

Mikhaleva, E A; Iakushev, E Iu; Stoliarenko, A D; Klenov, M S; Pozovskiĭ, Ia M; Gvozdev, V A

2015-01-01

The evolutionarily conserved nuclear Piwi protein of Drosophila melanogaster is a representative of the Argonaute small RNA binding protein family. Guided by small piRNAs, Piwi functions in transposon silencing in somatic and germ cells of the gonad. We found that in ovarian somatic and germ cells, as well as in the established ovarian somatic cell line, Piwi is concentrated predominantly in the nucleolus--the main nuclear compartment, participating not only in rRNA synthesis, but also in various cell stress responses. We demonstrated the colocalization of Piwi with nucleolar marker proteins--fibrillarin and Nopp140. A mutation preventing Piwi transport to the nucleus and disturbing transposon silencing (piwi(Nt)) leads to 6-8-fold upregulation of rRNA genes expression, as evaluated by the level of transcripts of transposon insertions in 28S rRNA genes. RNase treatment of live cultured ovarian somatic cells depletes Piwi from the nucleolus. The same effect is observed upon inhibiting RNA polymerase I which transcribes rRNA, but not RNA polymerase II. In contrast, upon heat shock Piwi is concentrated in the nucleolus and is depleted from the nucleoplasm. These results implicate Piwi in RNA polymerase activity modulation and stress response in the nucleolus. We discuss possible noncanonical Piwi functions along with its canonical role in transposon silencing by piRNAs.

Expression and function of CCL2/CCR2 in rat micturition reflexes and somatic sensitivity with urinary bladder inflammation

PubMed Central

Arms, Lauren; Girard, Beatrice M.; Malley, Susan E.

2013-01-01

Chemokines are proinflammatory mediators of the immune response, and there is growing evidence for chemokine/receptor signaling involvement in pronociception. Bladder pain syndrome (BPS)/interstitial cystitis (IC) is a chronic pain syndrome characterized by pain, pressure, or discomfort perceived to be bladder-related with at least one urinary symptom. We have explored the expression and functional roles of CCL2 (monocyte chemoattractant protein-1) and its high-affinity receptor, CCR2, in micturition reflex function and somatic sensitivity in rats with urinary bladder inflammation induced by cyclophosphamide (CYP) treatment of varying duration (4 h, 48 h, chronic). Real-time quantitative RT-PCR, ELISAs, and immunohistochemistry demonstrated significant (P ≤ 0.01) increases in CCL2 and CCR2 expression in the urothelium and in Fast Blue-labeled bladder afferent neurons in lumbosacral dorsal root ganglia with CYP-induced cystitis. Intravesical infusion of RS504393 (5 μM), a specific CCR2 antagonist, reduced voiding frequency and increased bladder capacity and void volume in rats with CYP-induced cystitis (4 h), as determined with open outlet, conscious cystometry. In addition, CCR2 blockade, at the level of the urinary bladder, reduced referred somatic sensitivity of the hindpaw and pelvic region in rats with CYP treatment, as determined with von Frey filament testing. We provide evidence of functional roles for CCL2/CCR2 signaling at the level of the urinary bladder in reducing voiding frequency and somatic sensitivity following CYP-induced cystitis (4 h). These studies suggest that chemokines/receptors may be novel targets with therapeutic potential in the context of urinary bladder inflammation. PMID:23594826

Symptoms, the nature of fibromyalgia, and diagnostic and statistical manual 5 (DSM-5) defined mental illness in patients with rheumatoid arthritis and fibromyalgia.

PubMed

Wolfe, Frederick; Walitt, Brian T; Katz, Robert S; Häuser, Winfried

2014-01-01

To describe and evaluate somatic symptoms in patients with rheumatoid arthritis (RA) and fibromyalgia, determine the relation between somatization syndromes and fibromyalgia, and evaluate symptom data in light of the Diagnostic and Statistical Manual-5 (DSM-5) criteria for somatic symptom disorder. We administered the Patient Health Questionnaire-15 (PHQ-15), a measure of somatic symptom severity to 6,233 persons with fibromyalgia, RA, and osteoarthritis. PHQ-15 scores of 5, 10, and 15 represent low, medium, and high somatic symptom severity cut-points. A likely somatization syndrome was diagnosed when PHQ-15 score was ≥10. The intensity of fibromyalgia diagnostic symptoms was measured by the polysymptomatic distress (PSD) scale. 26.4% of RA patients and 88.9% with fibromyalgia had PHQ-15 scores ≥10 compared with 9.3% in the general population. With each step-wise increase in PHQ-15 category, more abnormal mental and physical health status scores were observed. RA patients satisfying fibromyalgia criteria increased from 1.2% in the PHQ-15 low category to 88.9% in the high category. The sensitivity and specificity of PHQ-15≥10 for fibromyalgia diagnosis was 80.9% and 80.0% (correctly classified = 80.3%) compared with 84.3% and 93.7% (correctly classified = 91.7%) for the PSD scale. 51.4% of fibromyalgia patients and 14.8% with RA had fatigue, sleep or cognitive problems that were severe, continuous, and life-disturbing; and almost all fibromyalgia patients had severe impairments of function and quality of life. All patients with fibromyalgia will satisfy the DSM-5 "A" criterion for distressing somatic symptoms, and most would seem to satisfy DSM-5 "B" criterion because symptom impact is life-disturbing or associated with substantial impairment of function and quality of life. But the "B" designation requires special knowledge that symptoms are "disproportionate" or "excessive," something that is uncertain and controversial. The reliability and validity of DSM-5 criteria in this population is likely to be low.

Symptoms, the Nature of Fibromyalgia, and Diagnostic and Statistical Manual 5 (DSM-5) Defined Mental Illness in Patients with Rheumatoid Arthritis and Fibromyalgia

PubMed Central

Wolfe, Frederick; Walitt, Brian T.; Katz, Robert S.; Häuser, Winfried

2014-01-01

Purpose To describe and evaluate somatic symptoms in patients with rheumatoid arthritis (RA) and fibromyalgia, determine the relation between somatization syndromes and fibromyalgia, and evaluate symptom data in light of the Diagnostic and Statistical Manual-5 (DSM-5) criteria for somatic symptom disorder. Methods We administered the Patient Health Questionnaire-15 (PHQ-15), a measure of somatic symptom severity to 6,233 persons with fibromyalgia, RA, and osteoarthritis. PHQ-15 scores of 5, 10, and 15 represent low, medium, and high somatic symptom severity cut-points. A likely somatization syndrome was diagnosed when PHQ-15 score was ≥10. The intensity of fibromyalgia diagnostic symptoms was measured by the polysymptomatic distress (PSD) scale. Results 26.4% of RA patients and 88.9% with fibromyalgia had PHQ-15 scores ≥10 compared with 9.3% in the general population. With each step-wise increase in PHQ-15 category, more abnormal mental and physical health status scores were observed. RA patients satisfying fibromyalgia criteria increased from 1.2% in the PHQ-15 low category to 88.9% in the high category. The sensitivity and specificity of PHQ-15≥10 for fibromyalgia diagnosis was 80.9% and 80.0% (correctly classified = 80.3%) compared with 84.3% and 93.7% (correctly classified = 91.7%) for the PSD scale. 51.4% of fibromyalgia patients and 14.8% with RA had fatigue, sleep or cognitive problems that were severe, continuous, and life-disturbing; and almost all fibromyalgia patients had severe impairments of function and quality of life. Conclusions All patients with fibromyalgia will satisfy the DSM-5 “A” criterion for distressing somatic symptoms, and most would seem to satisfy DSM-5 “B” criterion because symptom impact is life-disturbing or associated with substantial impairment of function and quality of life. But the “B” designation requires special knowledge that symptoms are “disproportionate” or “excessive,” something that is uncertain and controversial. The reliability and validity of DSM-5 criteria in this population is likely to be low. PMID:24551146

Compartmentalized beta subunit distribution determines characteristics and ethanol sensitivity of somatic, dendritic, and terminal large-conductance calcium-activated potassium channels in the rat central nervous system.

PubMed

Wynne, P M; Puig, S I; Martin, G E; Treistman, S N

2009-06-01

Neurons are highly differentiated and polarized cells, whose various functions depend upon the compartmentalization of ion channels. The rat hypothalamic-neurohypophysial system (HNS), in which cell bodies and dendrites reside in the hypothalamus, physically separated from their nerve terminals in the neurohypophysis, provides a particularly powerful preparation in which to study the distribution and regional properties of ion channel proteins. Using electrophysiological and immunohistochemical techniques, we characterized the large-conductance calcium-activated potassium (BK) channel in each of the three primary compartments (soma, dendrite, and terminal) of HNS neurons. We found that dendritic BK channels, in common with somatic channels but in contrast to nerve terminal channels, are insensitive to iberiotoxin. Furthermore, analysis of dendritic BK channel gating kinetics indicates that they, like somatic channels, have fast activation kinetics, in contrast to the slow gating of terminal channels. Dendritic and somatic channels are also more sensitive to calcium and have a greater conductance than terminal channels. Finally, although terminal BK channels are highly potentiated by ethanol, somatic and dendritic channels are insensitive to the drug. The biophysical and pharmacological properties of somatic and dendritic versus nerve terminal channels are consistent with the characteristics of exogenously expressed alphabeta1 versus alphabeta4 channels, respectively. Therefore, one possible explanation for our findings is a selective distribution of auxiliary beta1 subunits to the somatic and dendritic compartments and beta4 to the terminal compartment. This hypothesis is supported immunohistochemically by the appearance of distinct punctate beta1 or beta4 channel clusters in the membrane of somatic and dendritic or nerve terminal compartments, respectively.

Lung Cancer: One Disease or Many.

PubMed

O'Brien, Timothy D; Jia, Peilin; Aldrich, Melinda C; Zhao, Zhongming

2018-06-05

Lung cancer is classified as a single entity comprised of multiple histological subtypes. But how similar are these subtypes on a genetic level? This paper aims to address this question through a concise overview of germline and somatic differences between small cell lung cancer, lung adenocarcinoma, and lung squamous cell carcinoma. We reveal the weak overlap found between these 3 lung cancer subtypes using published data from one of the largest germline genetic studies on lung cancer to date and somatic mutation data from Catalogue of Somatic Mutations in Cancer (COSMIC). These data indicate that these 3 subtypes share very little with each other at the genetic level. At the germline SNP level, only 24 independent SNPs from 2 chromosomes were shared across all 3 subtypes. We also demonstrate that only 30 unique cancer-specific mutations overlap the 3 subtypes from COSMIC, and that this is fewer than overlapping mutations chosen at random. Finally, we show that only 3 somatic mutational signatures are shared between these 3 subtypes. This paper highlights that these 3 lung cancer subtypes may be distinct diseases at the genetic level. In the era of precision medicine, we feel that these genomic differences will be of utmost importance in the choice of lung cancer therapy in the future. © 2018 S. Karger AG, Basel.

Quality of life related to health chronic kidney disease: Predictive importance of mood and somatic symptoms.

PubMed

Perales Montilla, Carmen M; Duschek, Stefan; Reyes Del Paso, Gustavo A

2016-01-01

To compare the predictive capacity of self-reported somatic symptoms and mood (depression and anxiety) on health-related quality of life (HRQOL) in patients with chronic renal disease. Data were obtained from 52 patients undergoing haemodialysis. Measures included a) the SF-36 health survey, b) the somatic symptoms scale revised (ESS-R) and c) the hospital anxiety and depression scale (HADS). Multiple regression was the main method of statistical analysis. Patients exhibited HRQOL levels below normative values, with anxiety and depression prevalence at 36.5% and 27%, respectively. Mood was the strongest predictor of physical (β=-.624) and mental (β=-.709) HRQOL. Somatic symptoms were also associated with physical HRQOL, but their predictive value was weaker (β=-.270). These results indicate that mood is a superior predictor of the physical and mental components of HRQOL in patients compared with the number and severity of physical symptoms. The data underline the importance of assessing negative emotional states (depression and anxiety) in kidney patients as a basis for intervention, which may facilitate reduction of the impact of chronic renal disease on HRQOL. Copyright © 2016 Sociedad Española de Nefrología. Published by Elsevier España, S.L.U. All rights reserved.

The role of chromatin modifications in somatic embryogenesis in plants

PubMed Central

De-la-Peña, Clelia; Nic-Can, Geovanny I.; Galaz-Ávalos, Rosa M.; Avilez-Montalvo, Randy; Loyola-Vargas, Víctor M.

2015-01-01

Somatic embryogenesis (SE) is a powerful tool for plant genetic improvement when used in combination with traditional agricultural techniques, and it is also an important technique to understand the different processes that occur during the development of plant embryogenesis. SE onset depends on a complex network of interactions among plant growth regulators, mainly auxins and cytokinins, during the proembryogenic early stages, and ethylene and gibberellic and abscisic acids later in the development of the somatic embryos. These growth regulators control spatial and temporal regulation of multiple genes in order to initiate change in the genetic program of somatic cells, as well as moderating the transition between embryo developmental stages. In recent years, epigenetic mechanisms have emerged as critical factors during SE. Some early reports indicate that auxins and in vitro conditions modify the levels of DNA methylation in embryogenic cells. The changes in DNA methylation patterns are associated with the regulation of several genes involved in SE, such as WUS, BBM1, LEC, and several others. In this review, we highlight the more recent discoveries in the understanding of the role of epigenetic regulation of SE. In addition, we include a survey of different approaches to the study of SE, and new opportunities to focus SE studies. PMID:26347757

Is psychotherapy for functional somatic syndromes harmful? A mixed methods study on negative effects.

PubMed

Holsting, A F; Pedersen, H F; Rask, M T; Frostholm, L; Schröder, A

2017-07-01

Concern for negative effects of psychotherapy for functional somatic syndromes (FSS) has been expressed by clinicians and some patient associations, which may prevent patients from seeking treatment. Therefore, we sought to explore the occurrence and characteristics of negative effects from group-based psychotherapy as experienced by patients with severe or multiple FSS. An adapted version of the explanatory sequential mixed methods design was applied. We used data from an on-going pilot study on Acceptance and Commitment Therapy and Mindfulness-Based Stress Reduction. Negative effects were measured by Inventory for the assessment of Negative Effects of Psychotherapy (INEP). In addition, telephone interviews were conducted with randomly chosen patients and patients who reported negative effects. The latter were asked to elaborate on their INEP response. Quantitative data were analysed descriptively while interview transcripts were explored by thematic analysis. Eighty patients responded to the questionnaire (89%). Negative effects to different extent (from 'slightly agree' to 'fully agree') were reported by 25 (31%). The most frequent negative effects were dependence on the therapist (12%), feeling down after therapy (6%) and insurance problems (7%). By exploring 27 participants' experiences of negative effects 3 main themes were identified: relations in therapy, outcome and transition from therapy to everyday life. Patients with FSS reported a few specific negative effects, all with low frequency. Generally, therapy was well-received. Some patients did however express negative effects both within and outside the therapeutic context. It is important to inform patients about potential negative effects prior to psychotherapy. Copyright © 2017 Elsevier Inc. All rights reserved.

Novel functions for the RNA-binding protein ETR-1 in Caenorhabditis elegans reproduction and engulfment of germline apoptotic cell corpses

PubMed Central

Boateng, Ruby; Nguyen, Ken C.Q.; Hall, David H.; Golden, Andy; Allen, Anna K.

2017-01-01

RNA-binding proteins (RBPs) are essential regulators of gene expression that act through a variety of mechanisms to ensure the proper post-transcriptional regulation of their target RNAs. RBPs in multiple species have been identified as playing crucial roles during development and as having important functions in various adult organ systems, including the heart, nervous, muscle, and reproductive systems. ETR-1, a highly conserved ELAV-Type RNA-binding protein belonging to the CELF/Bruno protein family, has been previously reported to be involved in C. elegans muscle development. Animals depleted of ETR-1 have been previously characterized as arresting at the two-fold stage of embryogenesis. In this study, we show that ETR-1 is expressed in the hermaphrodite somatic gonad and germ line, and that reduction of ETR-1 via RNA interference (RNAi) results in reduced hermaphrodite fecundity. Detailed characterization of this fertility defect indicates that ETR-1 is required in both the somatic tissue and the germ line to ensure wild-type reproductive levels. Additionally, the ability of ETR-1 depletion to suppress the published WEE-1.3-depletion infertility phenotype is dependent on ETR-1 being reduced in the soma. Within the germline of etr-1(RNAi) hermaphrodite animals, we observe a decrease in average oocyte size and an increase in the number of germline apoptotic cell corpses as evident by an increased number of CED-1::GFP and acridine orange positive apoptotic germ cells. Transmission Electron Microscopy (TEM) studies confirm the significant increase in apoptotic cells in ETR-1-depleted animals, and reveal a failure of the somatic gonadal sheath cells to properly engulf dying germ cells in etr-1(RNAi) animals. Through investigation of an established engulfment pathway in C. elegans, we demonstrate that co-depletion of CED-1 and ETR-1 suppresses both the reduced fecundity and the increase in the number of apoptotic cell corpses observed in etr-1(RNAi) animals. Combined, this data identifies a novel role for ETR-1 in hermaphrodite gametogenesis and in the process of engulfment of germline apoptotic cell corpses. PMID:28648844

Role of the body self and self-esteem in experiencing the intensity of menopausal symptoms.

PubMed

Włodarczyk, Małgorzata; Dolińska-Zygmunt, Grażyna

2017-10-29

The aim of the study was to test differences in self-esteem and strength of the body self, body image, comfort with closeness with others and body protection among women reporting high and low intensity of psychological, vasomotor and somatic symptoms of menopause. The sample included 201 women aged 45-55 years. The Menopause Symptom List was used to test the intensity of menopausal symptoms, the Body Self Questionnaire was used to diagnose the body self, and the Rosenberg Self-Esteem Scale was used to examine participants'levels of self-esteem. Differences between women experiencing high and low intensity of symptoms were analyzed using Student's t-test for independent samples. Women experiencing high-intensity psychological, vasomotor and somatic symptoms of menopause showed significantly lower self-esteem and poorer body-self functioning in all its dimensions except for body protection. Women experiencing high-intensity psychological, vasomotor and somatic symptoms of menopause demonstrated poorer functioning of the body self and lower self-esteem.

Germline mutations and somatic inactivation of TRIM28 in Wilms tumour

PubMed Central

Halliday, Benjamin J.; Markie, David M.; Grundy, Richard G.; Ludgate, Jackie L.; Black, Michael A.; Weeks, Robert J.; Catchpoole, Daniel R.; Reeve, Anthony E.

2018-01-01

Wilms tumour is a childhood tumour that arises as a consequence of somatic and rare germline mutations, the characterisation of which has refined our understanding of nephrogenesis and carcinogenesis. Here we report that germline loss of function mutations in TRIM28 predispose children to Wilms tumour. Loss of function of this transcriptional co-repressor, which has a role in nephrogenesis, has not previously been associated with cancer. Inactivation of TRIM28, either germline or somatic, occurred through inactivating mutations, loss of heterozygosity or epigenetic silencing. TRIM28-mutated tumours had a monomorphic epithelial histology that is uncommon for Wilms tumour. Critically, these tumours were negative for TRIM28 immunohistochemical staining whereas the epithelial component in normal tissue and other Wilms tumours stained positively. These data, together with a characteristic gene expression profile, suggest that inactivation of TRIM28 provides the molecular basis for defining a previously described subtype of Wilms tumour, that has early age of onset and excellent prognosis. PMID:29912901

Plantform Bioreactor for Mass Micropropagation of Date Palm.

PubMed

Almusawi, Abdulminam H A; Sayegh, Abdullah J; Alshanaw, Ansam M S; Griffis, John L

2017-01-01

A novel protocol for the commercial production of date palm through micropropagation is presented. This protocol includes the use of a semisolid medium alternation or in combination with a temporary immersion system (TIS, Plantform bioreactor) in date palm micropropagation. The use of the Plantform bioreactor for date palm results in an improved multiplication rate, reduced micropropagation time, and improved weaning success. It also reduces the cost of saleable units and thus improves economic return for commercial micropropagation. The use of the Plantform bioreactor successfully addresses other hindrances that can occur during the scale-up of date palm micropropagation, including asynchrony of somatic embryos, limited maturation of somatic embryos, and highly variable germination frequencies of embryos.

The relationships between symptoms and quality of life over the course of cognitive-behavioral therapy for panic disorder in Japan.

PubMed

Ogawa, Sei; Kondo, Masaki; Okazaki, Jynya; Imai, Risa; Ino, Keiko; Furukawa, Toshi A; Akechi, Tatsuo

2017-06-01

This study examined the relationships between changes in symptoms and changes in quality of life (QOL) during cognitive-behavioral therapy (CBT) for panic disorder (PD). We treated 198 PD patients with group CBT in Japan. Using multiple regression analysis, we examined the associations between changes in QOL and changes in PD symptoms or comorbid psychological symptoms during CBT. Changes in anticipatory anxiety, agoraphobic fear/avoidance, and somatization were significant predictors of changes in some aspects of QOL. It might be useful to decrease somatization, anticipatory anxiety, and agoraphobic fear to improve QOL in CBT for PD. © 2016 John Wiley & Sons Australia, Ltd.

Co-Morbidity of PTSD and Immune System Dysfunction: Opportunities for Treatment

PubMed Central

Neigh, Gretchen N.; Ali, Fariya F.

2016-01-01

Posttraumatic stress disorder (PTSD) is defined as a psychiatric disorder; however, PTSD co-occurs with multiple somatic manifestations. People living with PTSD commonly manifest dysregulations in the systems that regulate the stress response, including the hypothalamic-pituitary-adrenal (HPA) axis, and development of a pro-inflammatory state. Additionally, somatic autoimmune and inflammatory diseases and disorders have a high rate of co-morbidity with PTSD. Recognition and understanding of the compounding effect that these disease states can have on each other, evidenced from poorer treatment outcomes and accelerated disease progression in patients suffering from co-morbid PTSD and/or other autoimmune and inflammatory diseases, has the potential to lead to additional treatment opportunities. PMID:27479489

[Functional somatic syndromes from the view of cultural anthropology].

PubMed

Nakagami, Ayako; Tsujiuchi, Takuya

2009-09-01

The functional somatic syndromes have acquired major socio-cultural and political dimensions. Socio-cultural factors clearly affect symptoms, suffering, and disability perception and reporting. And knowledge of explanatory models of bodily distress for patients from different cultural backgrounds is useful in the establishment of a stable doctor -patient relationship. FSS may be an operational category to bridge between medical explanatory model and patient's model. According to medical anthropology, sickness has two faces; illness and disease. "Disease" is the problem from the practitioner's perspective, and "illness" is the human experience of symptoms and suffering. In this paper, the anthropological research on chronic fatigue syndrome as "not real" illness experience was described.

Functional enucleation of porcine oocytes for somatic cell nuclear transfer using femtosecond laser pulses

NASA Astrophysics Data System (ADS)

Kuetemeyer, K.; Lucas-Hahn, A.; Petersen, B.; Hassel, P.; Lemme, E.; Niemann, H.; Heisterkamp, A.

2010-02-01

Cloning of several mammalian species has been achieved by somatic cell nuclear transfer over the last decade. However, this method still results in very low efficiencies originating from biological and technical aspects. The highly-invasive mechanical enucleation belongs to the technical aspects and requires considerable micromanipulation skill. In this paper, we present a novel non-invasive method for combined oocyte imaging and automated functional enucleation using femtosecond (fs) laser pulses. After three-dimensional imaging of Hoechst-labeled porcine oocytes by multiphoton microscopy, our self-developed software automatically determined the metaphase plate position and shape. Subsequent irradiation of this volume with the very same laser at higher pulse energies in the low-density-plasma regime was used for metaphase plate ablation. We show that functional fs laser-based enucleation of porcine oocytes completely inhibited further embryonic development while maintaining intact oocyte morphology. In contrast, non-irradiated oocytes were able to develop to the blastocyst stage without significant differences to control oocytes. Our results indicate that fs laser systems offer great potential for oocyte imaging and enucleation as a fast, easy to use and reliable tool which may improve the efficiency of somatic cell clone production.

Intragenerational social mobility and functional somatic symptoms in a northern Swedish context: analyses of diagonal reference models.

PubMed

Jonsson, Frida; Sebastian, Miguel San; Hammarström, Anne; Gustafsson, Per E

2017-01-03

Research indicate that social class mobility could be potentially important for health, but whether this is due to the movement itself or a result of people having been integrated in different class contexts is, to date, difficult to infer. In addition, although several theories suggest that transitions between classes in the social hierarchy can be stressful experiences, few studies have empirically examined whether such movements may have health effects, over and above the implications of "being" in these classes. In an attempt to investigate whether intragenerational social mobility is associated with functional somatic symptoms in mid-adulthood, the current study tests three partially contrasting theories. The dissociative theory suggests that mobility in general and upward mobility in particular may be linked to psychological distress, while the falling from grace theory indicates that downward mobility is especially stressful. In contrast, the acculturation theory holds that the health implications of social mobility is not due to the movement itself but attributed to the class contexts in which people find themselves. Diagonal Reference Models were used on a sample of 924 individuals who in 1981 graduated from 9 th grade in the municipality of Luleå, Sweden. Social mobility was operationalized as change in occupational class between age 30 and 42 (measured in 1995 and 2007). The health outcome was functional somatic symptoms at age 42, defined as a clustering self-reported physical symptoms, palpitation and sleeping difficulties during the last 12 months. Overall mobility was not associated with higher levels of functional somatic symptoms compared to being immobile (p = 0.653). After controlling for prior and current class, sex, parental social position, general health, civil status, education and unemployment, the association between downward mobility was borderline significant (p = 0.055) while upward mobility was associated with lower levels of functional somatic symptoms (p = 0.03). The current study did not find unanimous support for any of the theories. Nevertheless, it sheds light on the possibility that upward mobility may be beneficial to reduce stress-related health problems in mid-life over and above the exposure to prior and current class, while downward mobility can be of less importance for middle-age health complaints.

PIWI proteins and PIWI-interacting RNAs function in Hydra somatic stem cells

PubMed Central

Juliano, Celina E.; Reich, Adrian; Liu, Na; Götzfried, Jessica; Zhong, Mei; Uman, Selen; Reenan, Robert A.; Wessel, Gary M.; Steele, Robert E.; Lin, Haifan

2014-01-01

PIWI proteins and their bound PIWI-interacting RNAs (piRNAs) are found in animal germlines and are essential for fertility, but their functions outside of the gonad are not well understood. The cnidarian Hydra is a simple metazoan with well-characterized stem/progenitor cells that provides a unique model for analysis of PIWI function. Here we report that Hydra has two PIWI proteins, Hydra PIWI (Hywi) and Hydra PIWI-like (Hyli), both of which are expressed in all Hydra stem/progenitor cells, but not in terminally differentiated cells. We identified ∼15 million piRNAs associated with Hywi and/or Hyli and found that they exhibit the ping-pong signature of piRNA biogenesis. Hydra PIWI proteins are strictly cytoplasmic and thus likely act as posttranscriptional regulators. To explore this function, we generated a Hydra transcriptome for piRNA mapping. piRNAs map to transposons with a 25- to 35-fold enrichment compared with the abundance of transposon transcripts. By sequencing the small RNAs specific to the interstitial, ectodermal, and endodermal lineages, we found that the targeting of transposons appears to be largely restricted to the interstitial lineage. We also identified putative nontransposon targets of the pathway unique to each lineage. Finally we demonstrate that hywi function is essential in the somatic epithelial lineages. This comprehensive analysis of the PIWI–piRNA pathway in the somatic stem/progenitor cells of a nonbilaterian animal suggests that this pathway originated with broader stem cell functionality. PMID:24367095

PIWI proteins and PIWI-interacting RNAs function in Hydra somatic stem cells.

PubMed

Juliano, Celina E; Reich, Adrian; Liu, Na; Götzfried, Jessica; Zhong, Mei; Uman, Selen; Reenan, Robert A; Wessel, Gary M; Steele, Robert E; Lin, Haifan

2014-01-07

PIWI proteins and their bound PIWI-interacting RNAs (piRNAs) are found in animal germlines and are essential for fertility, but their functions outside of the gonad are not well understood. The cnidarian Hydra is a simple metazoan with well-characterized stem/progenitor cells that provides a unique model for analysis of PIWI function. Here we report that Hydra has two PIWI proteins, Hydra PIWI (Hywi) and Hydra PIWI-like (Hyli), both of which are expressed in all Hydra stem/progenitor cells, but not in terminally differentiated cells. We identified ∼15 million piRNAs associated with Hywi and/or Hyli and found that they exhibit the ping-pong signature of piRNA biogenesis. Hydra PIWI proteins are strictly cytoplasmic and thus likely act as posttranscriptional regulators. To explore this function, we generated a Hydra transcriptome for piRNA mapping. piRNAs map to transposons with a 25- to 35-fold enrichment compared with the abundance of transposon transcripts. By sequencing the small RNAs specific to the interstitial, ectodermal, and endodermal lineages, we found that the targeting of transposons appears to be largely restricted to the interstitial lineage. We also identified putative nontransposon targets of the pathway unique to each lineage. Finally we demonstrate that hywi function is essential in the somatic epithelial lineages. This comprehensive analysis of the PIWI-piRNA pathway in the somatic stem/progenitor cells of a nonbilaterian animal suggests that this pathway originated with broader stem cell functionality.

University of Texas MD Anderson Cancer Center: High-Throughput Screening Identifying Driving Mutations in Endometrial Cancer | Office of Cancer Genomics

Cancer.gov

Recent advances in next-generation sequencing technology have enabled the unprecedented characterization of a full spectrum of somatic alterations in cancer genomes. Given the large numbers of somatic mutations typically detected by this approach, a key challenge in the downstream analysis is to distinguish “drivers” that functionally contribute to tumorigenesis from “passengers” that occur as the consequence of genomic instability.

Identification and characterization of bZIP-type transcription factors involved in carrot (Daucus carota L.) somatic embryogenesis.

PubMed

Guan, Yucheng; Ren, Haibo; Xie, He; Ma, Zeyang; Chen, Fan

2009-10-01

Seed dormancy is an important adaptive trait that enables seeds of many species to remain quiescent until conditions become favorable for germination. Abscisic acid (ABA) plays an important role in these developmental processes. Like dormancy and germination, the elongation of carrot somatic embryo radicles is retarded by sucrose concentrations at or above 6%, and normal growth resumes at sucrose concentrations below 3%. Using a yeast one-hybrid screening system, we isolated two bZIP-type transcription factors, CAREB1 and CAREB2, from a cDNA library prepared from carrot somatic embryos cultured in a high-sucrose medium. Both CAREB1 and CAREB2 were localized to the nucleus, and specifically bound to the ABA response element (ABRE) in the Dc3 promoter. Expression of CAREB2 was induced in seedlings by drought and exogenous ABA application; whereas expression of CAREB1 increased during late embryogenesis, and reduced dramatically when somatic embryos were treated with fluridone, an inhibitor of ABA synthesis. Overexpression of CAREB1 caused somatic embryos to develop slowly when cultured in low-sucrose medium, and retarded the elongation of the radicles. These results indicate that CAREB1 and CAREB2 have similar DNA-binding activities, but play different roles during carrot development. Our results indicate that CAREB1 functions as an important trans-acting factor in the ABA signal transduction pathway during carrot somatic embryogenesis.

Somatic Pairing of Chromosome 19 in Renal Oncocytoma Is Associated with Deregulated ELGN2-Mediated Oxygen-Sensing Response

PubMed Central

Petillo, David; Westphal, Michael; Koelzer, Katherine; Metcalf, Julie L.; Zhang, Zhongfa; Matsuda, Daisuke; Dykema, Karl J.; Houseman, Heather L.; Kort, Eric J.; Furge, Laura L.; Kahnoski, Richard J.; Richard, Stéphane; Vieillefond, Annick; Swiatek, Pamela J.; Teh, Bin Tean; Ohh, Michael; Furge, Kyle A.

2008-01-01

Chromosomal abnormalities, such as structural and numerical abnormalities, are a common occurrence in cancer. The close association of homologous chromosomes during interphase, a phenomenon termed somatic chromosome pairing, has been observed in cancerous cells, but the functional consequences of somatic pairing have not been established. Gene expression profiling studies revealed that somatic pairing of chromosome 19 is a recurrent chromosomal abnormality in renal oncocytoma, a neoplasia of the adult kidney. Somatic pairing was associated with significant disruption of gene expression within the paired regions and resulted in the deregulation of the prolyl-hydroxylase ELGN2, a key protein that regulates the oxygen-dependent degradation of hypoxia-inducible factor (HIF). Overexpression of ELGN2 in renal oncocytoma increased ubiquitin-mediated destruction of HIF and concomitantly suppressed the expression of several HIF-target genes, including the pro-death BNIP3L gene. The transcriptional changes that are associated with somatic pairing of chromosome 19 mimic the transcriptional changes that occur following DNA amplification. Therefore, in addition to numerical and structural chromosomal abnormalities, alterations in chromosomal spatial dynamics should be considered as genomic events that are associated with tumorigenesis. The identification of EGLN2 as a significantly deregulated gene that maps within the paired chromosome region directly implicates defects in the oxygen-sensing network to the biology of renal oncocytoma. PMID:18773095

Evolutionary origins of germline segregation in Metazoa: evidence for a germ stem cell lineage in the coral Orbicella faveolata (Cnidaria, Anthozoa).

PubMed

Barfield, Sarah; Aglyamova, Galina V; Matz, Mikhail V

2016-01-13

The ability to segregate a committed germ stem cell (GSC) lineage distinct from somatic cell lineages is a characteristic of bilaterian Metazoans. However, the occurrence of GSC lineage specification in basally branching Metazoan phyla, such as Cnidaria, is uncertain. Without an independently segregated GSC lineage, germ cells and their precursors must be specified throughout adulthood from continuously dividing somatic stem cells, generating the risk of propagating somatic mutations within the individual and its gametes. To address the potential for existence of a GSC lineage in Anthozoa, the sister-group to all remaining Cnidaria, we identified moderate- to high-frequency somatic mutations and their potential for gametic transfer in the long-lived coral Orbicella faveolata (Anthozoa, Cnidaria) using a 2b-RAD sequencing approach. Our results demonstrate that somatic mutations can drift to high frequencies (up to 50%) and can also generate substantial intracolonial genetic diversity. However, these somatic mutations are not transferable to gametes, signifying the potential for an independently segregated GSC lineage in O. faveolata. In conjunction with previous research on germ cell development in other basally branching Metazoan species, our results suggest that the GSC system may be a Eumetazoan characteristic that evolved in association with the emergence of greater complexity in animal body plan organization and greater specificity of stem cell functions. © 2016 The Author(s).

Evolutionary origins of germline segregation in Metazoa: evidence for a germ stem cell lineage in the coral Orbicella faveolata (Cnidaria, Anthozoa)

PubMed Central

Barfield, Sarah; Aglyamova, Galina V.; Matz, Mikhail V.

2016-01-01

The ability to segregate a committed germ stem cell (GSC) lineage distinct from somatic cell lineages is a characteristic of bilaterian Metazoans. However, the occurrence of GSC lineage specification in basally branching Metazoan phyla, such as Cnidaria, is uncertain. Without an independently segregated GSC lineage, germ cells and their precursors must be specified throughout adulthood from continuously dividing somatic stem cells, generating the risk of propagating somatic mutations within the individual and its gametes. To address the potential for existence of a GSC lineage in Anthozoa, the sister-group to all remaining Cnidaria, we identified moderate- to high-frequency somatic mutations and their potential for gametic transfer in the long-lived coral Orbicella faveolata (Anthozoa, Cnidaria) using a 2b-RAD sequencing approach. Our results demonstrate that somatic mutations can drift to high frequencies (up to 50%) and can also generate substantial intracolonial genetic diversity. However, these somatic mutations are not transferable to gametes, signifying the potential for an independently segregated GSC lineage in O. faveolata. In conjunction with previous research on germ cell development in other basally branching Metazoan species, our results suggest that the GSC system may be a Eumetazoan characteristic that evolved in association with the emergence of greater complexity in animal body plan organization and greater specificity of stem cell functions. PMID:26763699

CSR-1 and P granules suppress sperm-specific transcription in the C. elegans germline.

PubMed

Campbell, Anne C; Updike, Dustin L

2015-05-15

Germ granules (P granules) in C. elegans are required for fertility and function to maintain germ cell identity and pluripotency. Sterility in the absence of P granules is often accompanied by the misexpression of soma-specific proteins and the initiation of somatic differentiation in germ cells. To investigate whether this is caused by the accumulation of somatic transcripts, we performed mRNA-seq on dissected germlines with and without P granules. Strikingly, we found that somatic transcripts do not increase in the young adult germline when P granules are impaired. Instead, we found that impairing P granules causes sperm-specific mRNAs to become highly overexpressed. This includes the accumulation of major sperm protein (MSP) transcripts in germ cells, a phenotype that is suppressed by feminization of the germline. A core component of P granules, the endo-siRNA-binding Argonaute protein CSR-1, has recently been ascribed with the ability to license transcripts for germline expression. However, impairing CSR-1 has very little effect on the accumulation of its mRNA targets. Instead, we found that CSR-1 functions with P granules to prevent MSP and sperm-specific mRNAs from being transcribed in the hermaphrodite germline. These findings suggest that P granules protect germline integrity through two different mechanisms, by (1) preventing the inappropriate expression of somatic proteins at the level of translational regulation, and by (2) functioning with CSR-1 to limit the domain of sperm-specific expression at the level of transcription. © 2015. Published by The Company of Biologists Ltd.

The relationship of PTSD to key somatic complaints and cultural syndromes among Cambodian refugees attending a psychiatric clinic: the Cambodian Somatic Symptom and Syndrome Inventory (CSSI).

PubMed

Hinton, Devon E; Kredlow, M Alexandra; Pich, Vuth; Bui, Eric; Hofmann, Stefan G

2013-06-01

This article describes a culturally sensitive questionnaire for the assessment of the effects of trauma in the Cambodian refugee population, the Cambodian Somatic Symptom and Syndrome Inventory (CSSI), and gives the results of a survey with the instrument. The survey examined the relationship of the CSSI, the two CSSI subscales, and the CSSI items to posttraumatic stress disorder (PTSD) severity and self-perceived functioning. A total of 226 traumatized Cambodian refugees were assessed at a psychiatric clinic in Lowell, MA, USA. There was a high correlation of the CSSI, the CSSI somatic and syndrome scales, and all the CSSI items to the PTSD Checklist (PCL), a measure of PTSD severity. All the CSSI items varied greatly across three levels of PTSD severity, and patients with higher levels of PTSD had very high scores on certain CSSI-assessed somatic items such as dizziness, orthostatic dizziness (upon standing), and headache, and on certain CSSI-assessed cultural syndromes such as khyâl attacks, "fear of fainting and dying upon standing up," and "thinking a lot." The CSSI was more highly correlated than the PCL to self-perceived disability assessed by the Short Form-12 Health Survey (SF-12). The study demonstrates that the somatic symptoms and cultural syndromes described by the CSSI form a central part of the Cambodian refugee trauma ontology. The survey indicates that locally salient somatic symptoms and cultural syndromes need be profiled to adequately assess the effects of trauma.

Axonal propagation of simple and complex spikes in cerebellar Purkinje neurons.

PubMed

Khaliq, Zayd M; Raman, Indira M

2005-01-12

In cerebellar Purkinje neurons, the reliability of propagation of high-frequency simple spikes and spikelets of complex spikes is likely to regulate inhibition of Purkinje target neurons. To test the extent to which a one-to-one correspondence exists between somatic and axonal spikes, we made dual somatic and axonal recordings from Purkinje neurons in mouse cerebellar slices. Somatic action potentials were recorded with a whole-cell pipette, and the corresponding axonal signals were recorded extracellularly with a loose-patch pipette. Propagation of spontaneous and evoked simple spikes was highly reliable. At somatic firing rates of approximately 200 spikes/sec, <10% of spikes failed to propagate, with failures becoming more frequent only at maximal somatic firing rates (approximately 260 spikes/sec). Complex spikes were elicited by climbing fiber stimulation, and their somatic waveforms were modulated by tonic current injection, as well as by paired stimulation to depress the underlying EPSCs. Across conditions, the mean number of propagating action potentials remained just above two spikes per climbing fiber stimulation, but the instantaneous frequency of the propagating spikes changed, from approximately 375 Hz during somatic hyperpolarizations that silenced spontaneous firing to approximately 150 Hz during spontaneous activity. The probability of propagation of individual spikelets could be described quantitatively as a saturating function of spikelet amplitude, rate of rise, or preceding interspike interval. The results suggest that ion channels of Purkinje axons are adapted to produce extremely short refractory periods and that brief bursts of forward-propagating action potentials generated by complex spikes may contribute transiently to inhibition of postsynaptic neurons.

Anhedonia is associated with poor health status and more somatic and cognitive symptoms in patients with coronary artery disease.

PubMed

Pelle, Aline J; Pedersen, Susanne S; Erdman, Ruud A M; Kazemier, Marten; Spiering, Marquita; van Domburg, Ron T; Denollet, Johan

2011-06-01

The effectiveness of cardiac rehabilitation (CR) in patients with coronary artery disease (CAD) is moderated by negative emotions and clinical factors, but no studies evaluated the role of positive emotions. This study examined whether anhedonia (i.e. the lack of positive affect) moderated the effectiveness of CR on health status and somatic and cognitive symptoms. CAD patients (n = 368) filled out the Hospital Anxiety and Depression Scale (HADS) to assess anhedonia at the start of CR, and the Short-Form Health Survey (SF-36) and the Health Complaints Scale (HCS) at the start of CR and at 3 months to assess health status and somatic and cognitive symptoms, respectively. Adjusting for clinical and demographic factors, health status improved significantly during the follow-up (F(1,357) = 10.84, P = .001). Anhedonic patients reported poorer health status compared with non-anhedonic patients, with anhedonia exerting a stable effect over time (F(1,358) = 34.80, P < .001). Somatic and cognitive symptoms decreased over time (F(1,358) = 3.85, P = .05). Anhedonics experienced more benefits in terms of somatic and cognitive symptoms over time (F(1,358) = 13.00, P < .001). Anhedonic patients reported poorer health status and higher levels of somatic and cognitive symptoms prior to and after CR. Somatic and cognitive symptoms differed as a function of anhedonia over time, but health status did not. Anhedonia might provide a new avenue for secondary prevention in CAD.

Influence of Competitive-Anxiety on Heart Rate Variability in Swimmers

PubMed Central

Fortes, Leonardo S.; da Costa, Bruna D. V.; Paes, Pedro P.; do Nascimento Júnior, José R.A.; Fiorese, Lenamar; Ferreira, Maria E.C.

2017-01-01

The aim of this study was to analyze the relationship between competitive anxiety and heart rate variability (HRV) in swimming athletes. A total of 66 volunteers (41 male and 27 female) who swam the 400-m freestyle in the Brazilian Swimming Championships participated. Thirty minutes before the 400-m freestyle event, the athletes answered the Competitive Anxiety Inventory (CSAI-2R) questionnaire, then underwent anthropometric (body weight, height, and skinfold thickness) and HRV measurements. Then, at a second meeting, held 3 h after the 400-m freestyle event, the athletes returned to the evaluation room for HRV measurement (Polar® RS800cx, Kempele, Finland). Multiple linear regression was used to evaluate the relationship between competitive anxiety and HRV. The multiple linear regression was performed in three blocks (block 1: cognitive anxiety, block 2: somatic anxiety, and block 3: self-confidence), adopting the forward model. The results indicated a significant association between cognitive anxiety (p = 0.001) and HRV. An increased magnitude of the association was observed when somatic anxiety was inserted in the model (p = 0.001). In contrast, self-confidence showed, which was inserted in block 3, no relationship with HRV (p = 0.27). It was concluded that cognitive and somatic anxieties were associated with the HRV of swimmers. Athletes with a high magnitude of cognitive and/or somatic anxiety demonstrated more significant autonomic nervous system disturbance. Practically, psychological interventions are needed to improve anxiety states that are specific to perform well, and to improve HRV. Key points The level of competitive-anxiety can predict HRV’s response after competition in young swimming athletes. Young swimming athletes who demonstrate higher competitive-anxiety, may present high autonomic nervous system disorder, which can be evaluated by HRV. Coaches are encouraged to periodically evaluate the competitive-anxiety of young swimming athletes. PMID:29238249

Pan-arthropod analysis reveals somatic piRNAs as an ancestral defence against transposable elements.

PubMed

Lewis, Samuel H; Quarles, Kaycee A; Yang, Yujing; Tanguy, Melanie; Frézal, Lise; Smith, Stephen A; Sharma, Prashant P; Cordaux, Richard; Gilbert, Clément; Giraud, Isabelle; Collins, David H; Zamore, Phillip D; Miska, Eric A; Sarkies, Peter; Jiggins, Francis M

2018-01-01

In animals, small RNA molecules termed PIWI-interacting RNAs (piRNAs) silence transposable elements (TEs), protecting the germline from genomic instability and mutation. piRNAs have been detected in the soma in a few animals, but these are believed to be specific adaptations of individual species. Here, we report that somatic piRNAs were probably present in the ancestral arthropod more than 500 million years ago. Analysis of 20 species across the arthropod phylum suggests that somatic piRNAs targeting TEs and messenger RNAs are common among arthropods. The presence of an RNA-dependent RNA polymerase in chelicerates (horseshoe crabs, spiders and scorpions) suggests that arthropods originally used a plant-like RNA interference mechanism to silence TEs. Our results call into question the view that the ancestral role of the piRNA pathway was to protect the germline and demonstrate that small RNA silencing pathways have been repurposed for both somatic and germline functions throughout arthropod evolution.

Remembrance of things past retrieved from the Paramecium genome.

PubMed

Sperling, Linda

2011-01-01

Paramecium and other ciliates are the only unicellular eukaryotes that separate germinal and somatic functions. A germline micronucleus transmits the genetic information to sexual progeny, while a somatic macronucleus expresses the genetic information during vegetative growth to determine the phenotype. At each sexual generation, a new macronucleus develops from the zygotic nucleus through programmed rearrangements of the germline genome. Paramecium tetraurelia somatic genome sequencing, reviewed here, has provided insight into the organization and evolution of the genome. A series of at least 3 whole genome duplications was detected in the Paramecium lineage and selective pressures that determine the fate of the gene duplicates analyzed. Variability in the somatic DNA was characterized and could be attributed to the genome rearrangement processes. Since, in Paramecium, alternative genome rearrangement patterns can be inherited across sexual generations by homology-dependent epigenetic mechanisms and can affect phenotype, I discuss the possibility that ciliate nuclear dimorphism buffers genetic variation hidden in the germline. Copyright © 2011 Institut Pasteur. Published by Elsevier SAS. All rights reserved.

Psychosomatics: a current overview.

PubMed

Fischbein, José Eduardo

2011-02-01

The term 'psychosomatic' has typically defined a series of illnesses in which somatic injury breaks out from psychic conflict not recognized as such. Currently, health is considered the only psychosomatic state of integration of mind and soma: an ideal state of integration. Somatic pathology is an effect of mind/body splitting. In the heterogeneous 'field of psychosomatics' interaction between psyche and soma ranges from classical psychosomatic illness to sporadic episodes in which the body has responded to an inability to process mental conflict. The author briefly reviews the development of psychoanalytic thought on psychosomatics in Argentina. He suggests the need to find appropriate conceptual tools to approach the mental structure underlying this pathology. He presents his ideas about the mental functioning of patients with somatization disorders. He introduces the concept of somatic event as a restitution phenomenon through which the subject attempts to re-establish self-integration and links with reality. He also offers some reflections on temporality and on changes in psychoanalytic technique with these patients. A clinical case illustrates his ideas. Copyright © 2011 Institute of Psychoanalysis.

MutationAligner: a resource of recurrent mutation hotspots in protein domains in cancer

PubMed Central

Gauthier, Nicholas Paul; Reznik, Ed; Gao, Jianjiong; Sumer, Selcuk Onur; Schultz, Nikolaus; Sander, Chris; Miller, Martin L.

2016-01-01

The MutationAligner web resource, available at http://www.mutationaligner.org, enables discovery and exploration of somatic mutation hotspots identified in protein domains in currently (mid-2015) more than 5000 cancer patient samples across 22 different tumor types. Using multiple sequence alignments of protein domains in the human genome, we extend the principle of recurrence analysis by aggregating mutations in homologous positions across sets of paralogous genes. Protein domain analysis enhances the statistical power to detect cancer-relevant mutations and links mutations to the specific biological functions encoded in domains. We illustrate how the MutationAligner database and interactive web tool can be used to explore, visualize and analyze mutation hotspots in protein domains across genes and tumor types. We believe that MutationAligner will be an important resource for the cancer research community by providing detailed clues for the functional importance of particular mutations, as well as for the design of functional genomics experiments and for decision support in precision medicine. MutationAligner is slated to be periodically updated to incorporate additional analyses and new data from cancer genomics projects. PMID:26590264

The SPADE Symptom Cluster in Primary Care Patients With Chronic Pain.

PubMed

Davis, Lorie L; Kroenke, Kurt; Monahan, Patrick; Kean, Jacob; Stump, Timothy E

2016-05-01

Sleep disturbance, pain, anxiety, depression, and low energy/fatigue, the SPADE pentad, are the most prevalent and co-occurring symptoms in the general population and clinical practice. Co-occurrence of SPADE symptoms may produce additive impairment and negatively affect treatment response, potentially undermining patients' health and functioning. The purpose of this paper is to determine: (1) prevalence and comorbidity (ie, clustering) of SPADE symptoms; (2) internal reliability and construct validity of a composite SPADE symptom score derived from the Patient-Reported Outcomes Measurement Information System (PROMIS) measures; and (3) whether improvement in somatic symptom burden represented by a composite score predicted subsequent measures of functional status at 3 and 12 months follow-up. Secondary analysis of data from the Stepped Care to Optimize Pain care Effectiveness study, a randomized trial of a collaborative care intervention for Veterans with chronic pain. Most patients had multiple SPADE symptoms; only 9.6% of patients were monosymptomatic. The composite PROMIS symptom score had good internal reliability (Cronbach's alpha=0.86) and construct validity and strongly correlated with multiple measures of functional status; improvement in the composite score significantly correlated with higher scores for 5 of 6 functional status outcomes. The standardized error of measurement (SEM) for the composite T-score was 2.84, suggesting a 3-point difference in an individual's composite score may be clinically meaningful. Brief PROMIS measures may be useful in evaluating SPADE symptoms and overall symptom burden. Because symptom burden may predict functional status outcomes, better identification and management of comorbid symptoms may be warranted.

The Theobroma cacao B3 domain transcription factor TcLEC2 plays a duel role in control of embryo development and maturation.

PubMed

Zhang, Yufan; Clemens, Adam; Maximova, Siela N; Guiltinan, Mark J

2014-04-24

The Arabidopsis thaliana LEC2 gene encodes a B3 domain transcription factor, which plays critical roles during both zygotic and somatic embryogenesis. LEC2 exerts significant impacts on determining embryogenic potential and various metabolic processes through a complicated genetic regulatory network. An ortholog of the Arabidopsis Leafy Cotyledon 2 gene (AtLEC2) was characterized in Theobroma cacao (TcLEC2). TcLEC2 encodes a B3 domain transcription factor preferentially expressed during early and late zygotic embryo development. The expression of TcLEC2 was higher in dedifferentiated cells competent for somatic embryogenesis (embryogenic calli), compared to non-embryogenic calli. Transient overexpression of TcLEC2 in immature zygotic embryos resulted in changes in gene expression profiles and fatty acid composition. Ectopic expression of TcLEC2 in cacao leaves changed the expression levels of several seed related genes. The overexpression of TcLEC2 in cacao explants greatly increased the frequency of regeneration of stably transformed somatic embryos. TcLEC2 overexpressing cotyledon explants exhibited a very high level of embryogenic competency and when cultured on hormone free medium, exhibited an iterative embryogenic chain-reaction. Our study revealed essential roles of TcLEC2 during both zygotic and somatic embryo development. Collectively, our evidence supports the conclusion that TcLEC2 is a functional ortholog of AtLEC2 and that it is involved in similar genetic regulatory networks during cacao somatic embryogenesis. To our knowledge, this is the first detailed report of the functional analysis of a LEC2 ortholog in a species other then Arabidopsis. TcLEC2 could potentially be used as a biomarker for the improvement of the SE process and screen for elite varieties in cacao germplasm.

Cognitive-behavioral therapy for somatization and symptom syndromes: a critical review of controlled clinical trials.

PubMed

Kroenke, K; Swindle, R

2000-01-01

Few treatments for somatization have been proven effective. In the past decade, however, clinical trials of cognitive-behavioral therapy (CBT) have been promising. Our aim was to critically review and synthesize the evidence from these trials. A search of the Medline database from 1966 through July 1999 was conducted to identify controlled trials designed to evaluate the efficacy of CBT in patients with somatization or symptom syndromes. A total of 31 controlled trials (29 randomized and 2 nonrandomized) were identified. Twenty-five studies targeted a specific syndrome (e.g. chronic fatigue, irritable bowel, pain) while 6 focused on more general somatization or hypochondriasis. Primary outcome assessment included physical symptoms, psychological distress and functional status in 28, 26 and 19 studies, respectively. Physical symptoms appeared the most responsive: CBT-treated patients improved more than control subjects in 71% of the studies and showed possibly greater improvement (i.e., a trend) in another 11% of the studies. A definite or possible advantage of CBT for reducing psychological distress was demonstrated in only 38 and 8% of studies, and for improving functional status in 47 and 26%. Group therapy and interventions as brief as 5 sessions proved efficacious. Benefits were sustained for up to 12 months. CBT can be an effective treatment for patients with somatization or symptom syndromes. Benefits can occur whether or not psychological distress is ameliorated. Since chronic symptoms are exceptionally common and most studies were conducted in referral populations, the optimal sequencing of CBT in treating primary care patients and the identification of those most likely to accept and respond to therapy should be further evaluated. Copyright 2000 S. Karger AG, Basel.

Effect of nutritional rehabilitation on gastric motility and somatization in adolescents with anorexia.

PubMed

Perez, Maria E; Coley, Brian; Crandall, Wallace; Di Lorenzo, Carlo; Bravender, Terrill

2013-09-01

To examine gastric function, as well as the presence of somatic complaints, anxiety symptoms, and functional gastrointestinal disorders (FGIDs), in adolescents with anorexia nervosa (AN) before and after nutritional rehabilitation. Sixteen females with AN and 22 healthy controls with similar demographic profiles were included. Gastric emptying (measured as residual gastric volume) and gastric accommodation (measured as postprandial antral diameter) were assessed with abdominal ultrasonography. Participants completed the Children's Somatization Inventory (CSI), the Screen for Child Anxiety-Related Emotional Disorders, and the Questionnaire on Pediatric Gastrointestinal Symptoms-Rome III version. All testing was repeated 3-4 months later. Body mass index in the AN group improved over time (P = .012). Fasting gastric parameters were similar in the 2 groups. Maximum postprandial antral diameter was significantly greater in controls compared with the AN group (P = .008). Only adolescents with AN demonstrated a significant increase in maximum postprandial diameter at repeat testing (P = .009). There was no difference in residual gastric volume between the 2 groups. Initial CSI scores were higher in adolescents with AN (P < .0001), including higher scores for nausea and abdominal pain. CSI scores were significantly lower in adolescents with AN (P = .035). Initial scores on the Screen for Child Anxiety-Related Emotional Disorders were significantly higher in adolescents with AN (P = .0005), but did not change over time. Adolescents with AN met significantly more criteria for FGIDs (P = .003). Adolescents with AN have impaired gastric accommodation that improves after nutritional rehabilitation, have significantly more somatic complaints, and meet more criteria for anxiety disorders and FGIDs. After nutritional rehabilitation, somatization improves and FGIDs become less common, but symptoms of anxiety persist. Copyright © 2013 Mosby, Inc. All rights reserved.

University of Texas MD Anderson Cancer Center (UT-MDACC): High-Throughput Screening Identifying Driving Mutations in Endometrial Cancer | Office of Cancer Genomics

Cancer.gov

Recent advances in next-generation sequencing technology have enabled the unprecedented characterization of a full spectrum of somatic alterations in cancer genomes. Given the large numbers of somatic mutations typically detected by this approach, a key challenge in the downstream analysis is to distinguish “drivers” that functionally contribute to tumorigenesis from “passengers” that occur as the consequence of genomic instability.

Functional Genomic Landscape of Human Breast Cancer Drivers, Vulnerabilities, and Resistance.

PubMed

Marcotte, Richard; Sayad, Azin; Brown, Kevin R; Sanchez-Garcia, Felix; Reimand, Jüri; Haider, Maliha; Virtanen, Carl; Bradner, James E; Bader, Gary D; Mills, Gordon B; Pe'er, Dana; Moffat, Jason; Neel, Benjamin G

2016-01-14

Large-scale genomic studies have identified multiple somatic aberrations in breast cancer, including copy number alterations and point mutations. Still, identifying causal variants and emergent vulnerabilities that arise as a consequence of genetic alterations remain major challenges. We performed whole-genome small hairpin RNA (shRNA) "dropout screens" on 77 breast cancer cell lines. Using a hierarchical linear regression algorithm to score our screen results and integrate them with accompanying detailed genetic and proteomic information, we identify vulnerabilities in breast cancer, including candidate "drivers," and reveal general functional genomic properties of cancer cells. Comparisons of gene essentiality with drug sensitivity data suggest potential resistance mechanisms, effects of existing anti-cancer drugs, and opportunities for combination therapy. Finally, we demonstrate the utility of this large dataset by identifying BRD4 as a potential target in luminal breast cancer and PIK3CA mutations as a resistance determinant for BET-inhibitors. Copyright © 2016 Elsevier Inc. All rights reserved.

The Association Between Headaches and Temporomandibular Disorders is Confounded by Bruxism and Somatic Symptoms.

PubMed

van der Meer, Hedwig A; Speksnijder, Caroline M; Engelbert, Raoul H H; Lobbezoo, Frank; Nijhuis-van der Sanden, Maria W G; Visscher, Corine M

2017-09-01

The objective of this observational study was to establish the possible presence of confounders on the association between temporomandibular disorders (TMD) and headaches in a patient population from a TMD and Orofacial Pain Clinic. Several subtypes of headaches have been diagnosed: self-reported headache, (probable) migraine, (probable) tension-type headache, and secondary headache attributed to TMD. The presence of TMD was subdivided into 2 subtypes: painful TMD and function-related TMD. The associations between the subtypes of TMD and headaches were evaluated by single regression models. To study the influence of possible confounding factors on this association, the regression models were extended with age, sex, bruxism, stress, depression, and somatic symptoms. Of the included patients (n=203), 67.5% experienced headaches. In the subsample of patients with a painful TMD (n=58), the prevalence of self-reported headaches increased to 82.8%. The associations found between self-reported headache and (1) painful TMD and (2) function-related TMD were confounded by the presence of somatic symptoms. For probable migraine, both somatic symptoms and bruxism confounded the initial association found with painful TMD. The findings of this study imply that there is a central working mechanism overlapping TMD and headache. Health care providers should not regard these disorders separately, but rather look at the bigger picture to appreciate the complex nature of the diagnostic and therapeutic process.

Genome multiplication as adaptation to tissue survival: evidence from gene expression in mammalian heart and liver.

PubMed

Anatskaya, Olga V; Vinogradov, Alexander E

2007-01-01

To elucidate the functional significance of genome multiplication in somatic tissues, we performed a large-scale analysis of ploidy-associated changes in expression of non-tissue-specific (i.e., broadly expressed) genes in the heart and liver of human and mouse (6585 homologous genes were analyzed). These species have inverse patterns of polyploidization in cardiomyocytes and hepatocytes. The between-species comparison of two pairs of homologous tissues with crisscross contrast in ploidy levels allows the removal of the effects of species and tissue specificity on the profile of gene activity. The different tests performed from the standpoint of modular biology revealed a consistent picture of ploidy-associated alteration in a wide range of functional gene groups. The major effects consisted of hypoxia-inducible factor-triggered changes in main cellular processes and signaling pathways, activation of defense against DNA lesions, acceleration of protein turnover and transcription, and the impairment of apoptosis, the immune response, and cytoskeleton maintenance. We also found a severe decline in aerobic respiration and stimulation of sugar and fatty acid metabolism. These metabolic rearrangements create a special type of metabolism that can be considered intermediate between aerobic and anaerobic. The metabolic and physiological changes revealed (reflected in the alteration of gene expression) help explain the unique ability of polyploid tissues to combine proliferation and differentiation, which are separated in diploid tissues. We argue that genome multiplication promotes cell survival and tissue regeneration under stressful conditions.

Role of Somatic Testicular Cells during Mouse Spermatogenesis in Three-Dimensional Collagen Gel Culture System

PubMed Central

Khajavi, Noushafarin; Akbari, Mohammad; Abolhassani, Farid; Dehpour, Ahmad Reza; Koruji, Morteza; Habibi Roudkenar, Mehryar

2014-01-01

Objective Spermatogonial stem cells (SSCs) are the only cell type that can restore fertility to an infertile recipient following transplantation. Much effort has been made to develop a protocol for differentiating isolated SSCs in vitro. Recently, three-dimensional (3D) culture system has been introduced as an appropriate microenvironment for clonal expansion and differentiation of SSCs. This system provides structural support and multiple options for several manipulation such as addition of different cells. Somatic cells have a critical role in stimulating spermatogenesis. They provide complex cell to cell interaction, transport proteins and produce enzymes and regulatory factors. This study aimed to optimize the culture condition by adding somatic testicular cells to the collagen gel culture system in order to induce spermatogenesis progression. Materials and Methods In this experimental study, the disassociation of SSCs was performed by using a two-step enzymatic digestion of type I collagenase, hyaluronidase and DNase. Somatic testicular cells including Sertoli cells and peritubular cells were obtained after the second digestion. SSCs were isolated by Magnetic Activated Cell Sorting (MACS) using GDNF family receptor alpha-1 (Gfrα-1) antibody. Two experimental designs were investigated. 1. Gfrα-1 positive SSCs were cultured in a collagen solution. 2. Somatic testicular cells were added to the Gfrα-1 positive SSCs in a collagen solution. Spermatogenesis progression was determined after three weeks by staining of synaptonemal complex protein 3 (SCP3)-positive cells. Semi-quantitative Reverse Transcription PCR was undertaken for SCP3 as a meiotic marker and, Crem and Thyroid transcription factor-1 (TTF1) as post meiotic markers. For statistical analysis student t test was performed. Results Testicular supporter cells increased the expression of meiotic and post meiotic markers and had a positive effect on extensive colony formation. Conclusion Collagen gel culture system supported by somatic testicular cells provides a microenvironment that mimics seminiferous epithelium and induces spermatogenesis in vitro. PMID:24518977

Phylogenetic Copy-Number Factorization of Multiple Tumor Samples.

PubMed

Zaccaria, Simone; El-Kebir, Mohammed; Klau, Gunnar W; Raphael, Benjamin J

2018-04-16

Cancer is an evolutionary process driven by somatic mutations. This process can be represented as a phylogenetic tree. Constructing such a phylogenetic tree from genome sequencing data is a challenging task due to the many types of mutations in cancer and the fact that nearly all cancer sequencing is of a bulk tumor, measuring a superposition of somatic mutations present in different cells. We study the problem of reconstructing tumor phylogenies from copy-number aberrations (CNAs) measured in bulk-sequencing data. We introduce the Copy-Number Tree Mixture Deconvolution (CNTMD) problem, which aims to find the phylogenetic tree with the fewest number of CNAs that explain the copy-number data from multiple samples of a tumor. We design an algorithm for solving the CNTMD problem and apply the algorithm to both simulated and real data. On simulated data, we find that our algorithm outperforms existing approaches that either perform deconvolution/factorization of mixed tumor samples or build phylogenetic trees assuming homogeneous tumor samples. On real data, we analyze multiple samples from a prostate cancer patient, identifying clones within these samples and a phylogenetic tree that relates these clones and their differing proportions across samples. This phylogenetic tree provides a higher resolution view of copy-number evolution of this cancer than published analyses.

Enhancing knowledge discovery from cancer genomics data with Galaxy

PubMed Central

Albuquerque, Marco A.; Grande, Bruno M.; Ritch, Elie J.; Pararajalingam, Prasath; Jessa, Selin; Krzywinski, Martin; Grewal, Jasleen K.; Shah, Sohrab P.; Boutros, Paul C.

2017-01-01

Abstract The field of cancer genomics has demonstrated the power of massively parallel sequencing techniques to inform on the genes and specific alterations that drive tumor onset and progression. Although large comprehensive sequence data sets continue to be made increasingly available, data analysis remains an ongoing challenge, particularly for laboratories lacking dedicated resources and bioinformatics expertise. To address this, we have produced a collection of Galaxy tools that represent many popular algorithms for detecting somatic genetic alterations from cancer genome and exome data. We developed new methods for parallelization of these tools within Galaxy to accelerate runtime and have demonstrated their usability and summarized their runtimes on multiple cloud service providers. Some tools represent extensions or refinement of existing toolkits to yield visualizations suited to cohort-wide cancer genomic analysis. For example, we present Oncocircos and Oncoprintplus, which generate data-rich summaries of exome-derived somatic mutation. Workflows that integrate these to achieve data integration and visualizations are demonstrated on a cohort of 96 diffuse large B-cell lymphomas and enabled the discovery of multiple candidate lymphoma-related genes. Our toolkit is available from our GitHub repository as Galaxy tool and dependency definitions and has been deployed using virtualization on multiple platforms including Docker. PMID:28327945

Enhancing knowledge discovery from cancer genomics data with Galaxy.

PubMed

Albuquerque, Marco A; Grande, Bruno M; Ritch, Elie J; Pararajalingam, Prasath; Jessa, Selin; Krzywinski, Martin; Grewal, Jasleen K; Shah, Sohrab P; Boutros, Paul C; Morin, Ryan D

2017-05-01

The field of cancer genomics has demonstrated the power of massively parallel sequencing techniques to inform on the genes and specific alterations that drive tumor onset and progression. Although large comprehensive sequence data sets continue to be made increasingly available, data analysis remains an ongoing challenge, particularly for laboratories lacking dedicated resources and bioinformatics expertise. To address this, we have produced a collection of Galaxy tools that represent many popular algorithms for detecting somatic genetic alterations from cancer genome and exome data. We developed new methods for parallelization of these tools within Galaxy to accelerate runtime and have demonstrated their usability and summarized their runtimes on multiple cloud service providers. Some tools represent extensions or refinement of existing toolkits to yield visualizations suited to cohort-wide cancer genomic analysis. For example, we present Oncocircos and Oncoprintplus, which generate data-rich summaries of exome-derived somatic mutation. Workflows that integrate these to achieve data integration and visualizations are demonstrated on a cohort of 96 diffuse large B-cell lymphomas and enabled the discovery of multiple candidate lymphoma-related genes. Our toolkit is available from our GitHub repository as Galaxy tool and dependency definitions and has been deployed using virtualization on multiple platforms including Docker. © The Author 2017. Published by Oxford University Press.

Increasing the treatment motivation of patients with somatic symptom disorder: applying the URICA-S scale.

PubMed

Mander, Johannes; Schaller, Georg; Bents, Hinrich; Dinger, Ulrike; Zipfel, Stephan; Junne, Florian

2017-07-03

Therapeutic intervention programs for somatic symptom disorder (SSD) show only small-to-moderate effect sizes. These effects are partly explained by the motivational problems of SSD patients. Hence, fostering treatment motivation could increase treatment success. One central aspect in SSD patients might be damage to motivation because of symptomatic relapses. Consequently, the aim of the present study was to investigate associations between motivational relapse struggle and therapeutic outcome in SSD patients. We assessed 84 inpatients diagnosed with SSD in the early, middle and late stages of their inpatient treatment. The maintenance subscale of the University of Rhode Island Change Assessment-Short (URICA-S) was applied as a measure to assess motivational relapse struggle. Additionally, patients completed measures of treatment outcome that focus on clinical symptoms, stress levels and interpersonal functioning. The results from multiple regression analyses indicate that higher URICA-S maintenance scores assessed in early stages of inpatient treatment were related to more negative treatment outcomes in SSD patients. SSD patients with ambivalent treatment motivation may fail in their struggle against relapse over the course of therapy. The URICA-S maintenance score assessed at therapy admission facilitated early identification of SSD patients who are at greater risk of relapse. Future studies should incorporate randomized controlled trials to investigate whether this subgroup could benefit from motivational interventions that address relapse.

State-dependent physiological maintenance in a long-lived ectotherm, the painted turtle (Chrysemys picta).

PubMed

Schwanz, Lisa; Warner, Daniel A; McGaugh, Suzanne; Di Terlizzi, Roberta; Bronikowski, Anne

2011-01-01

Energy allocation among somatic maintenance, reproduction and growth varies not only among species, but among individuals according to states such as age, sex and season. Little research has been conducted on the somatic (physiological) maintenance of long-lived organisms, particularly ectotherms such as reptiles. In this study, we examined sex differences and age- and season-related variation in immune function and DNA repair efficiency in a long-lived reptile, the painted turtle (Chrysemys picta). Immune components tended to be depressed during hibernation, in winter, compared with autumn or spring. Increased heterophil count during hibernation provided the only support for winter immunoenhancement. In juvenile and adult turtles, we found little evidence for senescence in physiological maintenance, consistent with predictions for long-lived organisms. Among immune components, swelling in response to phytohemagglutinin (PHA) and control injection increased with age, whereas basophil count decreased with age. Hatchling turtles had reduced basophil counts and natural antibodies, indicative of an immature immune system, but demonstrated higher DNA repair efficiency than older turtles. Reproductively mature turtles had reduced lymphocytes compared with juvenile turtles in the spring, presumably driven by a trade-off between maintenance and reproduction. Sex had little influence on physiological maintenance. These results suggest that components of physiological maintenance are modulated differentially according to individual state and highlight the need for more research on the multiple components of physiological maintenance in animals of variable states.

Predicting persistence of functional abdominal pain from childhood into young adulthood.

PubMed

Horst, Sara; Shelby, Grace; Anderson, Julia; Acra, Sari; Polk, D Brent; Saville, Benjamin R; Garber, Judy; Walker, Lynn S

2014-12-01

Pediatric functional abdominal pain has been linked to functional gastrointestinal disorders (FGIDs) in adulthood, but little is known about patient characteristics in childhood that increase the risk for FGID in young adulthood. We investigated the contribution of gastrointestinal symptoms, extraintestinal somatic symptoms, and depressive symptoms in pediatric patients with functional abdominal pain and whether these predicted FGIDs later in life. In a longitudinal study, consecutive new pediatric patients, diagnosed with functional abdominal pain in a subspecialty clinic, completed a comprehensive baseline evaluation of the severity of their physical and emotional symptoms. They were contacted 5 to 15 years later and evaluated, based on Rome III symptom criteria, for abdominal pain-related FGIDs, including irritable bowel syndrome, functional dyspepsia, functional abdominal pain syndrome, and abdominal migraine. Controlling for age, sex, baseline severity of abdominal pain, and time to follow-up evaluation, multivariable logistic regression was used to evaluate the association of baseline gastrointestinal, extraintestinal somatic, and depressive symptoms in childhood with FGID in adolescence and young adulthood. Of 392 patients interviewed an average of 9.2 years after their initial evaluation, 41% (n = 162) met symptom criteria for FGID; most met the criteria for irritable bowel syndrome. Extraintestinal somatic and depressive symptoms at the initial pediatric evaluation were significant predictors of FGID later in life, after controlling for initial levels of GI symptoms. Age, sex, and abdominal pain severity at initial presentation were not significant predictors of FGID later in life. In pediatric patients with functional abdominal pain, assessment of extraintestinal and depressive symptoms may be useful in identifying those at risk for FGID in adolescence and young adulthood. Copyright © 2014 AGA Institute. Published by Elsevier Inc. All rights reserved.

Somatic Coliphage Profiles of Produce and Environmental Samples from Farms in Northern México.

PubMed

Bartz, Faith E; Hodge, Domonique Watson; Heredia, Norma; de Aceituno, Anna Fabiszewski; Solís, Luisa; Jaykus, Lee-Ann; Garcia, Santos; Leon, Juan S

2016-09-01

Somatic coliphages were quantified in 459 produce and environmental samples from 11 farms in Northern Mexico to compare amounts of somatic coliphages among different types of fresh produce and environmental samples across the production steps on farms. Rinsates from cantaloupe melons, jalapeño peppers, tomatoes, and the hands of workers, soil, and water were collected during 2011-2012 at four successive steps on each farm, from the field before harvest through the packing facility, and assayed by FastPhage MPN Quanti-tray method. Cantaloupe farm samples contained more coliphages than jalapeño or tomato (p range <0.01-0.03). Across production steps, jalapeños had higher coliphage percentages before harvest than during packing (p = 0.03), while tomatoes had higher coliphage concentrations at packing than all preceding production steps (p range <0.01-0.02). These findings support the use of targeted produce-specific interventions at multiple points in the process of growing and packing produce to reduce the risk of enteric virus contamination and improve food safety during fruit and vegetable production.

Evaluation of Chromosomal Instability in Diabetic Rats Treated with Naringin

PubMed Central

A. Bakheet, Saleh; M. Attia, Sabry

2011-01-01

We used the bone marrow DNA strand breaks, micronucleus formations, spermatocyte chromosomal aberrations, and sperm characteristic assays to investigate the chromosomal instability in somatic and germinal cells of diabetic rats treated with multiple doses of naringin. The obtained results revealed that naringin was neither cytotoxic nor genotoxic for the rats at all tested doses. Moreover, naringin significantly reduced the diabetes-induced chromosomal instability in somatic and germinal cells in a dose-dependent manner. In addition, diabetes induced marked biochemical alterations characteristic of oxidative stress including enhanced lipid peroxidation, accumulation of oxidized glutathione, reduction in reduced glutathione, and accumulation of intracellular reactive oxygen species. Treatment with naringin ameliorated these biochemical markers dose-dependently. In conclusion, naringin confers an appealing protective effect against diabetes-induced chromosomal instability towards rat somatic and germinal cells which might be explained partially via diminishing the de novo free radical generation induced by hyperglycemia. Thus, naringin might be a good candidate to reduce genotoxic risk associated with hyperglycemia and may provide decreases in the development of secondary malignancy and abnormal reproductive outcomes risks, which seems especially important for diabetic patients. PMID:21941606

Mental Health Problems in Children with Prader-Willi Syndrome

PubMed Central

Skokauskas, Norbert; Sweeny, Eileen; Meehan, Judith; Gallagher, Louise

2012-01-01

Background: Prader-Willi Syndrome (PWS) is a genetically determined neurodevelopmental disorder, which occurs in approximately one in 22000 births. Aims: This study aimed to investigate psychiatric characteristics of children diagnosed with PWS compared with an age-, gender- and IQ-matched control group. The parents of children with PWS were assessed for psychological distress in comparison to the parents of the control group. Methodological limitations identified in previous studies were addressed in the present study. Methods: Psychiatric problems were evaluated in a sample of children with genetically confirmed PWS and an age- and IQ-matched control group using the Child Behaviour Checklist 6–18. Parental psychological distress for both groups was evaluated with the Brief Symptom Inventory. Results: Children with PWS had more severe somatic, social, and thought problems, and were more withdrawn-depressed in comparison to controls. Borderline difficulties were detected for the affective, somatic, and attention deficit-hyperactivity CBCL DSM-orientated subscales in the PWS group. Parents of PWS children, in comparison to controls, had more somatization, phobic anxiety, obsessive-compulsive, and anxiety problems. Conclusions: PWS represents a complex psychological disorder with multiple areas of disturbances. PMID:22876265

Bacteria-Human Somatic Cell Lateral Gene Transfer Is Enriched in Cancer Samples

PubMed Central

Robinson, Kelly M.; White, James Robert; Ganesan, Ashwinkumar; Nourbakhsh, Syrus; Dunning Hotopp, Julie C.

2013-01-01

There are 10× more bacterial cells in our bodies from the microbiome than human cells. Viral DNA is known to integrate in the human genome, but the integration of bacterial DNA has not been described. Using publicly available sequence data from the human genome project, the 1000 Genomes Project, and The Cancer Genome Atlas (TCGA), we examined bacterial DNA integration into the human somatic genome. Here we present evidence that bacterial DNA integrates into the human somatic genome through an RNA intermediate, and that such integrations are detected more frequently in (a) tumors than normal samples, (b) RNA than DNA samples, and (c) the mitochondrial genome than the nuclear genome. Hundreds of thousands of paired reads support random integration of Acinetobacter-like DNA in the human mitochondrial genome in acute myeloid leukemia samples. Numerous read pairs across multiple stomach adenocarcinoma samples support specific integration of Pseudomonas-like DNA in the 5′-UTR and 3′-UTR of four proto-oncogenes that are up-regulated in their transcription, consistent with conversion to an oncogene. These data support our hypothesis that bacterial integrations occur in the human somatic genome and may play a role in carcinogenesis. We anticipate that the application of our approach to additional cancer genome projects will lead to the more frequent detection of bacterial DNA integrations in tumors that are in close proximity to the human microbiome. PMID:23840181

Persistent of Neck/Shoulder Pain among Computer Office Workers with Specific Attention to Pain Expectation, Somatization Tendency, and Beliefs.

PubMed

Sadeghian, Farideh; Raei, Mehdi; Amiri, Mohammad

2014-09-01

Neck and shoulder pains are the prevalent complaints among computer office workers. The purpose of this study was to assess the relationship of somatization tendency, expectation of pain, mental health and beliefs about causation of pain with persistence of neck/shoulder pains among computer office workers. This research is a kind of prospective cohort study with 1-year follow-up. It has done among all eligible computer office workers of Shahroud universities (n = 182) in 2008-2009 and 1-year later. Data were collected using the Cultural and Psychosocial Influences on Disability questionnaire. Multiple logistic regression analysis was used to analyze the data through SPSS (P < 0.05). At the baseline 100 (54.9%) of participants reported neck/shoulder pains and at follow-up 34.3% of them reported persistence pains. Significant relationships were found between persistence of neck/shoulder pains and negative expectation about pain in next 1-year P = 0.002, (odds ratio [OR] =8.3, 95% confidence interval [CI]: 2.1-32.9) and somatization tendency P = 0.01, (OR = 6.5, 95% CI: 1.6-27.4). Pain expectation and somatization tendency recognized as associated risk factors of persistent neck/shoulder pain among computer operators. This confirmed some other similar studies on work-related musculoskeletal disorders in Europe countries in recent years.

A randomized trial of treatments for high-utilizing somatizing patients.

PubMed

Barsky, Arthur J; Ahern, David K; Bauer, Mark R; Nolido, Nyryan; Orav, E John

2013-11-01

Somatization and hypochondriacal health anxiety are common sources of distress, impairment, and costly medical utilization in primary care practice. A range of interventions is needed to improve the care of these patients. To determine the effectiveness of two cognitive behavioral interventions for high-utilizing, somatizing patients, using the resources found in a routine care setting. Patients were randomly assigned to a two-step cognitive behavioral treatment program accompanied by a training seminar for their primary care physicians, or to relaxation training. Providers routinely working in these patients' primary care practices delivered the cognitive behavior therapy and relaxation training. A follow-up assessment was completed immediately prior to treatment and 6 and 12 months later. Eighty-nine medical outpatients with elevated levels of somatization, hypochondriacal health anxiety, and medical care utilization. Somatization and hypochondriasis, overall psychiatric distress, and role impairment were assessed with well-validated, self-report questionnaires. Outpatient visits and medical care costs before and after the intervention were obtained from the encounter claims database. At 6 month and 12 month follow-up, both intervention groups showed significant improvements in somatization (p < 0.01), hypochondriacal symptoms (p < 0.01), overall psychiatric distress (p < 0.01), and role impairment (p < 0.01). Outcomes did not differ significantly between the two groups. When both groups were combined, ambulatory visits declined from 10.3 to 8.8 (p = 0.036), and mean ambulatory costs decreased from $3,574 to $2,991 (pp = 0.028) in the year preceding versus the year following the interventions. Psychiatric visits and costs were unchanged. Two similar cognitive behavioral interventions, delivered with the resources available in routine primary care, improved somatization, hypochondriacal symptoms, overall psychiatric distress, and role function. They also reduced the ambulatory visits and costs of these high utilizing outpatients.

Beyond "somatization" and "psychologization": symptom-level variation in depressed Han Chinese and Euro-Canadian outpatients.

PubMed

Dere, Jessica; Sun, Jiahong; Zhao, Yue; Persson, Tonje J; Zhu, Xiongzhao; Yao, Shuqiao; Bagby, R Michael; Ryder, Andrew G

2013-01-01

The finding that people of Chinese heritage tend to emphasize somatic rather than psychological symptoms of depression has frequently been discussed in the culture and mental health literature since the 1970s. Recent studies have confirmed that Chinese samples report more somatic and fewer psychological depression symptoms compared to "Western" samples. The question remains, however, as to whether or not these effects are attributable to variation in all the constituent symptoms or to a subset. If the latter, there is the additional possibility that some symptoms might show a divergent pattern. Such findings would have implications for how cultural variations in symptom presentation are interpreted, and would also inform the cultural study of affective experiences more broadly. The current study addressed these issues in Chinese (n = 175) and Euro-Canadian (n = 107) psychiatric outpatients originally described by Ryder et al. (2008). Differential item functioning (DIF) was used to examine whether specific somatic and psychological symptoms diverged from the overall patterns of cultural variation. Chi-square analyses were used to examine atypical somatic symptoms (e.g., hypersomnia), previously neglected in this literature. No DIF was observed for the typical somatic symptoms, but Euro-Canadians reported greater levels of atypical somatic symptoms, and showed higher rates of atypical depression. DIF was observed for psychological symptoms-the Chinese reported high levels of "suppressed emotions" and "depressed mood," relative to their overall psychological symptom reporting. Chinese outpatients also spontaneously reported "depressed mood" at similar levels as the Euro-Canadians, contrary to prevailing ideas about Chinese unwillingness to discuss depression. Overall, the findings provide a more nuanced picture of how culture shapes symptom presentation and point toward future studies designed to unpack cultural variation in narrower subsets of depressive symptoms.

An Examination of a Yoga Intervention With Pediatric Burn Survivors.

PubMed

Conn, Amy S; Hall, Morgan S; Quinn, Kristen; Wiggins, Bradley; Memmott, Carolyn; Brusseau, Timothy A

Burn injuries have a major influence on the survivors' physical and psychological functioning. In pediatric burns, the consequences persist long after the injury. The objective of this study is to evaluate an existing yoga kids program to gain better understanding of the physical and psychosocial effects of a yoga practice among children with burn injuries. Thirty campers participated in a series of four (1 hour) yoga sessions during the summer of 2014. Nationally trained Instructors had taught children's yoga in the Southwestern United States for at least 10 years. A Yoga Evaluation Questionnaire, designed for children, was used to evaluate perceptions of somatic and cognitive anxiety before and after each Yoga session. Camper's age ranged from 6 to 12 years old with burn severities ranging from 5 to 75%. A dependent samples t-test was used to test for differences between composite pre- and postintervention scores for both somatic and cognitive anxiety. Significant effects emerged for somatic anxiety t(29) = -4.24, P < .001, d = 0.77, and cognitive anxiety t(29) = -4.188, P < .001, d = 0.76. For both cognitive and somatic anxiety, the postintervention composite mean scores were significantly higher, indicating a decrease in somatic and cognitive anxiety. This study suggests that participation in a Yoga program may lower perceptions of cognitive and somatic anxiety in pediatric burn survivors. Further, Yoga is one technique that may compliment the short- and long-term treatment of burn injuries.

47,XXX/48,XXXX in a retarded three year old girl with multiple somatic anomalies.

PubMed

Ioan, D; Hîrşovescu, N; Dumitriu, L; Belengeanu, V; Muşeţeanu, P; Maximilian, C

1985-01-01

A 3-year old girl with 47,XXX/48,XXXX caryotype is presented. She suffers from psychomotor retardation, dolichocephaly, malformed ears, "a false air of trisomy 21", malformation of the legs, obesity. The authors discuss briefly the available data on the triplo and tetra X phenotype and syndromes.

Somatics in Action: How "I Feel Three-Dimensional and Real" Improves Dance Education and Training

ERIC Educational Resources Information Center

Kearns, Lauren W.

2010-01-01

The contemporary dance world, both in academic and professional settings, asks dancers to consistently engage with increasingly complex conceptual and physical dance work. Dancers in both settings must assimilate complex movement patterns, combine the technical nuances of multiple genres, reflect upon and critically assess their dancing, and…

Sexual Abuse and the Problem of Embodiment.

ERIC Educational Resources Information Center

Young, Leslie

1992-01-01

Potential long-term effects of the trauma of severe sexual abuse on a child's sense of living in his/her body and in the world are explored. Trauma and dissociation are analyzed and linked to a posttraumatic sense of personal identity. Then dissociation, multiple personality disorder, eating disorders, somatization disorder, self-mutilation, and…

Divergent functions of the left and right central amygdala in visceral nociception

PubMed Central

Sadler, Katelyn E.; McQuaid, Neal A.; Cox, Abigail C.; Behun, Marissa N.; Trouten, Allison M.; Kolber, Benedict J.

2017-01-01

The left and right central amygdalae (CeA) are limbic regions involved in somatic and visceral pain processing. These 2 nuclei are asymmetrically involved in somatic pain modulation; pain-like responses on both sides of the body are preferentially driven by the right CeA, and in a reciprocal fashion, nociceptive somatic stimuli on both sides of the body predominantly alter molecular and physiological activities in the right CeA. Unknown, however, is whether this lateralization also exists in visceral pain processing and furthermore what function the left CeA has in modulating nociceptive information. Using urinary bladder distension (UBD) and excitatory optogenetics, a pronociceptive function of the right CeA was demonstrated in mice. Channelrhodopsin-2–mediated activation of the right CeA increased visceromotor responses (VMRs), while activation of the left CeA had no effect. Similarly, UBD-evoked VMRs increased after unilateral infusion of pituitary adenylate cyclase–activating polypeptide in the right CeA. To determine intrinsic left CeA involvement in bladder pain modulation, this region was optogenetically silenced during noxious UBD. Halorhodopsin (NpHR)-mediated inhibition of the left CeA increased VMRs, suggesting an ongoing antinociceptive function for this region. Finally, divergent left and right CeA functions were evaluated during abdominal mechanosensory testing. In naive animals, channelrhodopsin-2–mediated activation of the right CeA induced mechanical allodynia, and after cyclophosphamide-induced bladder sensitization, activation of the left CeA reversed referred bladder pain–like behaviors. Overall, these data provide evidence for functional brain lateralization in the absence of peripheral anatomical asymmetries. PMID:28225716

Divergent functions of the left and right central amygdala in visceral nociception.

PubMed

Sadler, Katelyn E; McQuaid, Neal A; Cox, Abigail C; Behun, Marissa N; Trouten, Allison M; Kolber, Benedict J

2017-04-01

The left and right central amygdalae (CeA) are limbic regions involved in somatic and visceral pain processing. These 2 nuclei are asymmetrically involved in somatic pain modulation; pain-like responses on both sides of the body are preferentially driven by the right CeA, and in a reciprocal fashion, nociceptive somatic stimuli on both sides of the body predominantly alter molecular and physiological activities in the right CeA. Unknown, however, is whether this lateralization also exists in visceral pain processing and furthermore what function the left CeA has in modulating nociceptive information. Using urinary bladder distension (UBD) and excitatory optogenetics, a pronociceptive function of the right CeA was demonstrated in mice. Channelrhodopsin-2-mediated activation of the right CeA increased visceromotor responses (VMRs), while activation of the left CeA had no effect. Similarly, UBD-evoked VMRs increased after unilateral infusion of pituitary adenylate cyclase-activating polypeptide in the right CeA. To determine intrinsic left CeA involvement in bladder pain modulation, this region was optogenetically silenced during noxious UBD. Halorhodopsin (NpHR)-mediated inhibition of the left CeA increased VMRs, suggesting an ongoing antinociceptive function for this region. Finally, divergent left and right CeA functions were evaluated during abdominal mechanosensory testing. In naive animals, channelrhodopsin-2-mediated activation of the right CeA induced mechanical allodynia, and after cyclophosphamide-induced bladder sensitization, activation of the left CeA reversed referred bladder pain-like behaviors. Overall, these data provide evidence for functional brain lateralization in the absence of peripheral anatomical asymmetries.

Scalable Open Science Approach for Mutation Calling of Tumor Exomes Using Multiple Genomic Pipelines.

PubMed

Ellrott, Kyle; Bailey, Matthew H; Saksena, Gordon; Covington, Kyle R; Kandoth, Cyriac; Stewart, Chip; Hess, Julian; Ma, Singer; Chiotti, Kami E; McLellan, Michael; Sofia, Heidi J; Hutter, Carolyn; Getz, Gad; Wheeler, David; Ding, Li

2018-03-28

The Cancer Genome Atlas (TCGA) cancer genomics dataset includes over 10,000 tumor-normal exome pairs across 33 different cancer types, in total >400 TB of raw data files requiring analysis. Here we describe the Multi-Center Mutation Calling in Multiple Cancers project, our effort to generate a comprehensive encyclopedia of somatic mutation calls for the TCGA data to enable robust cross-tumor-type analyses. Our approach accounts for variance and batch effects introduced by the rapid advancement of DNA extraction, hybridization-capture, sequencing, and analysis methods over time. We present best practices for applying an ensemble of seven mutation-calling algorithms with scoring and artifact filtering. The dataset created by this analysis includes 3.5 million somatic variants and forms the basis for PanCan Atlas papers. The results have been made available to the research community along with the methods used to generate them. This project is the result of collaboration from a number of institutes and demonstrates how team science drives extremely large genomics projects. Copyright © 2018 The Authors. Published by Elsevier Inc. All rights reserved.

Association between the Center for Epidemiologic Studies Depression Scale (CES-D) and mortality in a community sample: An artifact of the somatic complaints factor?1

PubMed Central

Pettit, Jeremy W.; Lewinsohn, Peter M.; Seeley, John R.; Roberts, Robert E.; Hibbard, Judith H.; Hurtado, Arnold V.

2009-01-01

Most previous studies of the depression-mortality association have not examined distinct depressive symptom clusters. This ex post facto study examined which aspects of depression may account for its association with mortality. The Center for Epidemiologic Studies Depression Scale (CES-D) was administered to 3,867 community dwelling adults. Cox proportional hazards procedures estimated the risk of mortality as a function of depression status and each of 4 CES-D factor scores. Depressed participants (CES-D ≥ 16) had a 1.23-fold higher risk of mortality (95% CI 1.03-1.49), adjusting for sociodemographics. Somatic Complaints (SC) was the only factor to predict mortality (HR 1.19, 95% CI 1.03-1.38). After excluding SC, CES-D scores no longer predicted mortality (HR .98, 95% CI .79-1.21). The association between CES-D depressive symptoms and mortality appears to be a function of the SC factor. The association between non-somatic depressive symptoms and mortality may not be as robust as past findings suggest. PMID:19936326

Association between the Center for Epidemiologic Studies Depression Scale (CES-D) and mortality in a community sample: An artifact of the somatic complaints factor?

PubMed

Pettit, Jeremy W; Lewinsohn, Peter M; Seeley, John R; Roberts, Robert E; Hibbard, Judith H; Hurtado, Arnold V

2008-05-01

Most previous studies of the depression-mortality association have not examined distinct depressive symptom clusters. This ex post facto study examined which aspects of depression may account for its association with mortality. The Center for Epidemiologic Studies Depression Scale (CES-D) was administered to 3,867 community dwelling adults. Cox proportional hazards procedures estimated the risk of mortality as a function of depression status and each of 4 CES-D factor scores. Depressed participants (CES-D ≥ 16) had a 1.23-fold higher risk of mortality (95% CI 1.03-1.49), adjusting for sociodemographics. Somatic Complaints (SC) was the only factor to predict mortality (HR 1.19, 95% CI 1.03-1.38). After excluding SC, CES-D scores no longer predicted mortality (HR .98, 95% CI .79-1.21). The association between CES-D depressive symptoms and mortality appears to be a function of the SC factor. The association between non-somatic depressive symptoms and mortality may not be as robust as past findings suggest.

Saliva amylase as a measure of sympathetic change elicited by autogenic training in patients with functional somatic syndromes.

PubMed

Kiba, Tadashi; Kanbara, Kenji; Ban, Ikumi; Kato, Fumie; Kawashima, Sadanobu; Saka, Yukie; Yamamoto, Kazumi; Nishiyama, Junji; Mizuno, Yasuyuki; Abe, Tetsuya; Fukunaga, Mikihiko

2015-12-01

The aim of this study was to discuss the effect of autogenic training (AT) on patients with functional somatic syndrome (FSS) using salivary amylase, the skin temperature of the finger, subjective severity of symptoms, and psychological characteristics as measures. We assessed 20 patients with FSS and 23 healthy controls before and after AT. Baseline levels of salivary amylase prior to an AT session were significantly higher in the FSS group than in the control group. However, this difference was not significant after AT. The skin temperature of the finger increased after AT in both the FSS and control groups. AT contributed to the improvement of somatic symptoms in patients with FSS. Our results regarding psychological characteristics suggest that mood disturbances are deeply involved in the pathology of FSS. Individuals with FSS exhibited elevated levels of sympathetic activity compared with healthy controls. Our data indicates that AT eased dysregulation of the autonomic nervous system in patients with FSS. Thus, salivary amylase may be a useful index of change induced by AT in patients with FSS.

Germline mutations affecting the proofreading domains of POLE and POLD1 predispose to colorectal adenomas and carcinomas.

PubMed

Palles, Claire; Cazier, Jean-Baptiste; Howarth, Kimberley M; Domingo, Enric; Jones, Angela M; Broderick, Peter; Kemp, Zoe; Spain, Sarah L; Guarino, Estrella; Guarino Almeida, Estrella; Salguero, Israel; Sherborne, Amy; Chubb, Daniel; Carvajal-Carmona, Luis G; Ma, Yusanne; Kaur, Kulvinder; Dobbins, Sara; Barclay, Ella; Gorman, Maggie; Martin, Lynn; Kovac, Michal B; Humphray, Sean; Lucassen, Anneke; Holmes, Christopher C; Bentley, David; Donnelly, Peter; Taylor, Jenny; Petridis, Christos; Roylance, Rebecca; Sawyer, Elinor J; Kerr, David J; Clark, Susan; Grimes, Jonathan; Kearsey, Stephen E; Thomas, Huw J W; McVean, Gilean; Houlston, Richard S; Tomlinson, Ian

2013-02-01

Many individuals with multiple or large colorectal adenomas or early-onset colorectal cancer (CRC) have no detectable germline mutations in the known cancer predisposition genes. Using whole-genome sequencing, supplemented by linkage and association analysis, we identified specific heterozygous POLE or POLD1 germline variants in several multiple-adenoma and/or CRC cases but in no controls. The variants associated with susceptibility, POLE p.Leu424Val and POLD1 p.Ser478Asn, have high penetrance, and POLD1 mutation was also associated with endometrial cancer predisposition. The mutations map to equivalent sites in the proofreading (exonuclease) domain of DNA polymerases ɛ and δ and are predicted to cause a defect in the correction of mispaired bases inserted during DNA replication. In agreement with this prediction, the tumors from mutation carriers were microsatellite stable but tended to acquire base substitution mutations, as confirmed by yeast functional assays. Further analysis of published data showed that the recently described group of hypermutant, microsatellite-stable CRCs is likely to be caused by somatic POLE mutations affecting the exonuclease domain.

Computational approaches to identify functional genetic variants in cancer genomes

PubMed Central

Gonzalez-Perez, Abel; Mustonen, Ville; Reva, Boris; Ritchie, Graham R.S.; Creixell, Pau; Karchin, Rachel; Vazquez, Miguel; Fink, J. Lynn; Kassahn, Karin S.; Pearson, John V.; Bader, Gary; Boutros, Paul C.; Muthuswamy, Lakshmi; Ouellette, B.F. Francis; Reimand, Jüri; Linding, Rune; Shibata, Tatsuhiro; Valencia, Alfonso; Butler, Adam; Dronov, Serge; Flicek, Paul; Shannon, Nick B.; Carter, Hannah; Ding, Li; Sander, Chris; Stuart, Josh M.; Stein, Lincoln D.; Lopez-Bigas, Nuria

2014-01-01

The International Cancer Genome Consortium (ICGC) aims to catalog genomic abnormalities in tumors from 50 different cancer types. Genome sequencing reveals hundreds to thousands of somatic mutations in each tumor, but only a minority drive tumor progression. We present the result of discussions within the ICGC on how to address the challenge of identifying mutations that contribute to oncogenesis, tumor maintenance or response to therapy, and recommend computational techniques to annotate somatic variants and predict their impact on cancer phenotype. PMID:23900255

Polycythemia and paraganglioma with a novel somatic HIF2A mutation in a male.

PubMed

Toyoda, Hidemi; Hirayama, Jyunya; Sugimoto, Yuka; Uchida, Keiichi; Ohishi, Kohshi; Hirayama, Masahiro; Komada, Yoshihiro

2014-06-01

Recently, a new syndrome of paraganglioma, somatostatinoma, and polycythemia has been discovered (known as Pacak-Zhuang syndrome). This new syndrome, with somatic HIF2A gain-of-function mutations, has never been reported in male patients. We describe a male patient with Pacak-Zhuang syndrome who carries a newly discovered HIF2A mutation. Congenital polycythemias have diverse etiologies, including germline mutations in the oxygen-sensing pathway. These include von Hippel-Lindau (Chuvash polycythemia), prolyl hydroxylase domain-containing protein-2, and hypoxia-inducible factor-2α (HIF-2α). Somatic gain-of-function mutations in the gene encoding HIF-2α were reported in patients with paraganglioma and polycythemia and have been found exclusively in female patients. Through sequencing of the HIF2A using DNA from paraganglioma in 15-year-old male patient, we identified a novel mutation of HIF2A: a heterozygous C to A substitution at base 1589 in exon 12 of HIF2A. The mutation was not found in germline DNA from leukocytes. The C1589A mutations resulted in substitution of alanine 530 in the HIF-2α protein with glutamic acid. This mutation is undoubtedly associated with increased HIF-2α activity and increased protein half-life, because it affects the vicinity of the prolyl hydroxylase target residue, proline 531. To our knowledge, this is the first report describing Pacak-Zhuang syndrome with somatic gain-of-function mutation in HIF2A in a male patient. Congenital polycythemia of unknown origin should raise suspicion for the novel disorder Pacak-Zhuang syndrome, even in male patients. Copyright © 2014 by the American Academy of Pediatrics.

Cryopyrin-associated Periodic Syndromes in Italian Patients: Evaluation of the Rate of Somatic NLRP3 Mosaicism and Phenotypic Characterization.

PubMed

Lasigliè, Denise; Mensa-Vilaro, Anna; Ferrera, Denise; Caorsi, Roberta; Penco, Federica; Santamaria, Giuseppe; Di Duca, Marco; Amico, Giulia; Nakagawa, Kenji; Antonini, Francesca; Tommasini, Alberto; Consolini, Rita; Insalaco, Antonella; Cattalini, Marco; Obici, Laura; Gallizzi, Romina; Santarelli, Francesca; Del Zotto, Genny; Severino, Mariasavina; Rubartelli, Anna; Ravazzolo, Roberto; Martini, Alberto; Ceccherini, Isabella; Nishikomori, Ryuta; Gattorno, Marco; Arostegui, Juan I; Borghini, Silvia

2017-11-01

To evaluate the rate of somatic NLRP3 mosaicism in an Italian cohort of mutation-negative patients with cryopyrin-associated periodic syndrome (CAPS). The study enrolled 14 patients with a clinical phenotype consistent with CAPS in whom Sanger sequencing of the NLRP3 gene yielded negative results. Patients' DNA were subjected to amplicon-based NLRP3 deep sequencing. Low-level somatic NLRP3 mosaicism has been detected in 4 patients, 3 affected with chronic infantile neurological cutaneous and articular syndrome and 1 with Muckle-Wells syndrome. Identified nucleotide substitutions encode for 4 different amino acid exchanges, with 2 of them being novel (p.Y563C and p.G564S). In vitro functional studies confirmed the deleterious behavior of the 4 somatic NLRP3 mutations. Among the different neurological manifestations detected, 1 patient displayed mild loss of white matter volume on brain magnetic resonance imaging. The allele frequency of somatic NLRP3 mutations occurs generally under 15%, considered the threshold of detectability using the Sanger method of DNA sequencing. Consequently, routine genetic diagnostic of CAPS should be currently performed by next-generation techniques ensuring high coverage to identify also low-level mosaicism, whose actual frequency is yet unknown and probably underestimated.

Retrotransposon Capture Sequencing (RC-Seq): A Targeted, High-Throughput Approach to Resolve Somatic L1 Retrotransposition in Humans.

PubMed

Sanchez-Luque, Francisco J; Richardson, Sandra R; Faulkner, Geoffrey J

2016-01-01

Mobile genetic elements (MGEs) are of critical importance in genomics and developmental biology. Polymorphic and somatic MGE insertions have the potential to impact the phenotype of an individual, depending on their genomic locations and functional consequences. However, the identification of polymorphic and somatic insertions among the plethora of copies residing in the genome presents a formidable technical challenge. Whole genome sequencing has the potential to address this problem; however, its efficacy depends on the abundance of cells carrying the new insertion. Robust detection of somatic insertions present in only a subset of cells within a given sample can also be prohibitively expensive due to a requirement for high sequencing depth. Here, we describe retrotransposon capture sequencing (RC-seq), a sequence capture approach in which Illumina libraries are enriched for fragments containing the 5' and 3' termini of specific MGEs. RC-seq allows the detection of known polymorphic insertions present in an individual, as well as the identification of rare or private germline insertions not previously described. Furthermore, RC-seq can be used to detect and characterize somatic insertions, providing a valuable tool to elucidate the extent and characteristics of MGE activity in healthy tissues and in various disease states.

Preinjury somatization symptoms contribute to clinical recovery after sport-related concussion.

PubMed

Nelson, Lindsay D; Tarima, Sergey; LaRoche, Ashley A; Hammeke, Thomas A; Barr, William B; Guskiewicz, Kevin; Randolph, Christopher; McCrea, Michael A

2016-05-17

To determine the degree to which preinjury and acute postinjury psychosocial and injury-related variables predict symptom duration following sport-related concussion. A total of 2,055 high school and collegiate athletes completed preseason evaluations. Concussed athletes (n = 127) repeated assessments serially (<24 hours and days 8, 15, and 45) postinjury. Cox proportional hazard modeling was used to predict concussive symptom duration (in days). Predictors considered included demographic and history variables; baseline psychological, neurocognitive, and balance functioning; acute injury characteristics; and postinjury clinical measures. Preinjury somatic symptom score (Brief Symptom Inventory-18 somatization scale) was the strongest premorbid predictor of symptom duration. Acute (24-hour) postconcussive symptom burden (Sport Concussion Assessment Tool-3 symptom severity) was the best injury-related predictor of recovery. These 2 predictors were moderately correlated (r = 0.51). Path analyses indicated that the relationship between preinjury somatization symptoms and symptom recovery was mediated by postinjury concussive symptoms. Preinjury somatization symptoms contribute to reported postconcussive symptom recovery via their influence on acute postconcussive symptoms. The findings highlight the relevance of premorbid psychological factors in postconcussive recovery, even in a healthy athlete sample relatively free of psychopathology or medical comorbidities. Future research should elucidate the neurobiopsychosocial mechanisms that explain the role of this individual difference variable in outcome following concussive injury. © 2016 American Academy of Neurology.

Embryogenic competence acquisition in sugarcane callus is associated with differential H+ pump abundance and activity.

PubMed

Passamani, Lucas Z; Bertolazi, Amanda A; Ramos, Alessandro C; Santa-Catarina, Claudete; Thelen, Jay J; Silveira, Vanildo

2018-06-22

Somatic embryogenesis is an important biological process in several plant species, including sugarcane. Proteomics approaches have shown that H + pumps are differentially regulated during somatic embryogenesis; however, the relationship between H + flux and embryogenic competence is still unclear. This work aimed to elucidate the association between extracellular H + flux and somatic embryo maturation in sugarcane. We performed a microsomal proteomics analysis and analyzed changes in extracellular H + flux and H + pump (P-H + -ATPase, V-H + -ATPase and H + -PPase) activity in embryogenic and non-embryogenic callus. A total of 657 proteins were identified, 16 of which were H + pumps. We observed that P-H + -ATPase and H + -PPase were more abundant in embryogenic callus. Compared with non-embryogenic callus, embryogenic callus showed higher H + influx, especially on maturation day 14, as well as higher H+ pump activity (mainly P-H+-ATPase and H+-PPase activity). H+-PPase appears to be the major H + pump in embryogenic callus during somatic embryo formation, functioning in both vacuole acidification and PPi homeostasis. These results provide evidence for an association between higher H + pump protein abundance and, consequently, higher H + flux and embryogenic competence acquisition in the callus of sugarcane, allowing for optimization of the somatic embryo conversion process by modulating the activities of these H + pumps.

A medical record review for functional somatic symptoms in children.

PubMed

Rask, Charlotte Ulrikka; Borg, Carsten; Søndergaard, Charlotte; Schulz-Pedersen, Søren; Thomsen, Per Hove; Fink, Per

2010-04-01

The objectives of this study were to develop and test a systematic medical record review for functional somatic symptoms (FSSs) in paediatric patients and to estimate the inter-rater reliability of paediatricians' recognition of FSSs and their associated impairments while using this method. We developed the Medical Record Review for Functional Somatic Symptoms in Children (MRFC) for retrospective medical record review. Described symptoms were categorised as probably, definitely, or not FSSs. FSS-associated impairment was also determined. Three paediatricians performed the MRFC on the medical records of 54 children with a diagnosed, well-defined physical disease and 59 with 'symptom' diagnoses. The inter-rater reliabilities of the recognition and associated impairment of FSSs were tested on 20 of these records. The MRFC allowed identification of subgroups of children with multisymptomatic FSSs, long-term FSSs, and/or impairing FSSs. The FSS inter-rater reliability was good (combined kappa=0.69) but only fair as far as associated impairment was concerned (combined kappa=0.29). In the hands of skilled paediatricians, the MRFC is a reliable method for identifying paediatric patients with diverse types of FSSs for clinical research. However, additional information is needed for reliable judgement of impairment. The method may also prove useful in clinical practice. Copyright 2010 Elsevier Inc. All rights reserved.

SUMOylation is developmentally regulated and required for cell pairing during conjugation in Tetrahymena thermophila.

PubMed

Nasir, Amjad M; Yang, Qianyi; Chalker, Douglas L; Forney, James D

2015-02-01

The covalent attachment of small ubiquitin-like modifier (SUMO) to target proteins regulates numerous nuclear events in eukaryotes, including transcription, mitosis and meiosis, and DNA repair. Despite extensive interest in nuclear pathways within the field of ciliate molecular biology, there have been no investigations of the SUMO pathway in Tetrahymena. The developmental program of sexual reproduction of this organism includes cell pairing, micronuclear meiosis, and the formation of a new somatic macronucleus. We identified the Tetrahymena thermophila SMT3 (SUMO) and UBA2 (SUMO-activating enzyme) genes and demonstrated that the corresponding green fluorescent protein (GFP) tagged gene products are found predominantly in the somatic macronucleus during vegetative growth. Use of an anti-Smt3p antibody to perform immunoblot assays with whole-cell lysates during conjugation revealed a large increase in SUMOylation that peaked during formation of the new macronucleus. Immunofluorescence using the same antibody showed that the increase was localized primarily within the new macronucleus. To initiate functional analysis of the SUMO pathway, we created germ line knockout cell lines for both the SMT3 and UBA2 genes and found both are essential for cell viability. Conditional Smt3p and Uba2p cell lines were constructed by incorporation of the cadmium-inducible metallothionein promoter. Withdrawal of cadmium resulted in reduced cell growth and increased sensitivity to DNA-damaging agents. Interestingly, Smt3p and Uba2p conditional cell lines were unable to pair during sexual reproduction in the absence of cadmium, consistent with a function early in conjugation. Our studies are consistent with multiple roles for SUMOylation in Tetrahymena, including a dynamic regulation associated with the sexual life cycle. Copyright © 2015, American Society for Microbiology. All Rights Reserved.

The molecular biology of prostate cancer: current understanding and clinical implications.

PubMed

Gandhi, Jason; Afridi, Adil; Vatsia, Sohrab; Joshi, Gargi; Joshi, Gunjan; Kaplan, Steven A; Smith, Noel L; Khan, Sardar Ali

2018-04-01

With continuous progress over the past few decades in understanding diagnosis, treatment, and genetics, much has been learned about the prostate cancer-diagnosed genome. A comprehensive MEDLINE® and Google scholar literature search was conducted using keyword variations relating to the genetics of prostate cancer such as chromosomal alterations, androgen receptor, castration-resistant, inheritance, polymorphisms, oncogenes, metastasis, biomarkers, and immunotherapy. Traditionally, androgen receptors (AR) have been the focus of research. Recently, identification of recurrent chromosomal alterations that lead to either multiplication of regions (gain-of-function) or deletion of regions (loss-of-function) has opened the door to greater genetic accessibility. These chromosomal aberrations lead to variation in copy number and gene expression. Some of these chromosomal alterations are inherited, while others undergo somatic mutations during disease progression. Inherited gene mutations that make one susceptible to prostate cancer have been identified with familial-linked studies. Somatic genes that progress tumorigenesis have also been identified. Research on the molecular biology of prostate cancer has characterized these genes into tumor suppressor genes or oncogenes. Additionally, genome-wide assay studies have identified many high-risk single-nucleotide polymorphisms recurrent throughout the prostate cancer-diagnosed genome. Castration-resistant prostate cancer is the most aggressive form of prostate cancer, and its research has elucidated many types of mutations associated with AR itself, including enhanced expression and amplification, point mutations, and alternative splicing. Understanding the molecular biology of prostate cancer has permitted more accurate identification using advanced biomarkers and therapy for aggressive forms using immunotherapy. An age-related disease, prostate cancer commands profound attention. With increasing life expectancy and the continuous pursuit of it, prostate cancer is a powerful obstacle best defeated using targeted therapies specifically designed for the unique molecular profile of the malignancy.

Psychological and interactional characteristics of patients with somatoform disorders: Validation of the Somatic Symptoms Experiences Questionnaire (SSEQ) in a clinical psychosomatic population.

PubMed

Herzog, Annabel; Voigt, Katharina; Meyer, Björn; Wollburg, Eileen; Weinmann, Nina; Langs, Gernot; Löwe, Bernd

2015-06-01

The new DSM-5 Somatic Symptom Disorder (SSD) emphasizes the importance of psychological processes related to somatic symptoms in patients with somatoform disorders. To address this, the Somatic Symptoms Experiences Questionnaire (SSEQ), the first self-report scale that assesses a broad range of psychological and interactional characteristics relevant to patients with a somatoform disorder or SSD, was developed. This prospective study was conducted to validate the SSEQ. The 15-item SSEQ was administered along with a battery of self-report questionnaires to psychosomatic inpatients. Patients were assessed with the Structured Clinical Interview for DSM-IV to confirm a somatoform, depressive, or anxiety disorder. Confirmatory factor analyses, tests of internal consistency and tests of validity were performed. Patients (n=262) with a mean age of 43.4 years, 60.3% women, were included in the analyses. The previously observed four-factor model was replicated and internal consistency was good (Cronbach's α=.90). Patients with a somatoform disorder had significantly higher scores on the SSEQ (t=4.24, p<.001) than patients with a depressive/anxiety disorder. Construct validity was shown by high correlations with other instruments measuring related constructs. Hierarchical multiple regression analyses showed that the questionnaire predicted health-related quality of life. Sensitivity to change was shown by significantly higher effect sizes of the SSEQ change scores for improved patients than for patients without improvement. The SSEQ appears to be a reliable, valid, and efficient instrument to assess a broad range of psychological and interactional features related to the experience of somatic symptoms. Copyright © 2015 Elsevier Inc. All rights reserved.

The effect of season on somatic cell count and the incidence of clinical mastitis.

PubMed

Olde Riekerink, R G M; Barkema, H W; Stryhn, H

2007-04-01

Bulk milk somatic cell count (BMSCC), individual cow somatic cell count (ICSCC), and incidence rate of clinical mastitis (IRCM) are all udder health parameters. So far, no studies have been reported on the effect of season on BMSCC, IRCM, and ICSCC in the same herds and period over multiple years. The objectives of this study were to determine the seasonal pattern over a 4-yr period of 1) BMSCC, 2) elevated ICSCC, 3) IRCM, and 4) pathogen-specific IRCM. Bulk milk somatic cell count, ICSCC, and pathogen-specific clinical mastitis data were recorded in 300 Dutch dairy farms. For the analyses of BMSCC, ICSCC, and IRCM, a mixed, a transitional, and a discrete time survival analysis model were used, respectively. Sine and cosine were included in the models to investigate seasonal patterns in the data. For all parameters, a seasonal effect was present. Bulk milk somatic cell count peaked in August to September in all 4 years. The probability of cows getting or maintaining a high ICSCC was highest in August and May, respectively. Older and late-lactation cows were more likely to develop or maintain a high ICSCC. Incidence rate of clinical mastitis was highest in December to January, except for Streptococcus uberis IRCM, which was highest in August. Totally confined herds had a higher Escherichia coli IRCM in summer than in winter. Compared with the major mastitis pathogens, the seasonal differences in IRCM were smaller for the minor pathogens. Distinguishing between Strep. uberis, Streptococcus dysgalactiae, Streptococcus agalactiae, and other streptococci is essential when identifying Streptococcus spp. because each of them has a unique epidemiology. Streptococcus uberis IRCM seemed to be associated with being on pasture, whereas E. coli IRCM was more housing-related.

An integrative somatic mutation analysis to identify pathways linked with survival outcomes across 19 cancer types

PubMed Central

Park, Sunho; Kim, Seung-Jun; Yu, Donghyeon; Peña-Llopis, Samuel; Gao, Jianjiong; Park, Jin Suk; Chen, Beibei; Norris, Jessie; Wang, Xinlei; Chen, Min; Kim, Minsoo; Yong, Jeongsik; Wardak, Zabi; Choe, Kevin; Story, Michael; Starr, Timothy; Cheong, Jae-Ho; Hwang, Tae Hyun

2016-01-01

Motivation: Identification of altered pathways that are clinically relevant across human cancers is a key challenge in cancer genomics. Precise identification and understanding of these altered pathways may provide novel insights into patient stratification, therapeutic strategies and the development of new drugs. However, a challenge remains in accurately identifying pathways altered by somatic mutations across human cancers, due to the diverse mutation spectrum. We developed an innovative approach to integrate somatic mutation data with gene networks and pathways, in order to identify pathways altered by somatic mutations across cancers. Results: We applied our approach to The Cancer Genome Atlas (TCGA) dataset of somatic mutations in 4790 cancer patients with 19 different types of tumors. Our analysis identified cancer-type-specific altered pathways enriched with known cancer-relevant genes and targets of currently available drugs. To investigate the clinical significance of these altered pathways, we performed consensus clustering for patient stratification using member genes in the altered pathways coupled with gene expression datasets from 4870 patients from TCGA, and multiple independent cohorts confirmed that the altered pathways could be used to stratify patients into subgroups with significantly different clinical outcomes. Of particular significance, certain patient subpopulations with poor prognosis were identified because they had specific altered pathways for which there are available targeted therapies. These findings could be used to tailor and intensify therapy in these patients, for whom current therapy is suboptimal. Availability and implementation: The code is available at: http://www.taehyunlab.org. Contact: jhcheong@yuhs.ac or taehyun.hwang@utsouthwestern.edu or taehyun.cs@gmail.com Supplementary information: Supplementary data are available at Bioinformatics online. PMID:26635139

Esophageal Sensorimotor Function and Psychological Factors Each Contribute to Symptom Severity in Globus Patients.

PubMed

Rommel, Nathalie; Van Oudenhove, Lukas; Arts, Joris; Caenepeel, Philip; Tack, Jan; Pauwels, Ans

2016-10-01

Altered upper esophageal sphincter (UES) and esophageal body (EB) sensorimotor function and psychosocial factors may both be involved in symptom generation in globus, but their common impact is not yet assessed. The aim of the study is (1) to compare UES and EB sensitivity and compliance of globus patients with healthy controls (HC); (2) to study the association of globus symptom severity (GSS) with UES and EB sensitivity and compliance, UES motor function and psychosocial factors. In 58 globus patients, GSS, somatization, and anxiety disorders were determined using validated questionnaires. In 26 HC and 42/58 patients, UES and EB sensitivity and compliance were assessed twice using barostat measurements. UES function of 27 globus patients was evaluated using high-resolution manometry. Bivariate correlations and a general linear model tested the association of these factors with GSS. UES and EB compliance did not differ between globus patients and HC. Upon repeated distension, UES habituation was seen in both groups, whereas EB sensitization (23.3±1.3 vs. 19.5±1.5 mm Hg, P<0.0001) only occurred in globus patients, (P=0.038). UES compliance (ρ=0.37, P=0.04), change in EB compliance upon repeated distension (ρ=0.45, P=0.007), somatization (ρ=0.43, P=0.003), panic disorder (t=3.04, P=0.004), and post-traumatic stress severity (ρ=0.40, P=0.005) were associated with GSS. UES compliance and somatization were independently associated with GSS. A trend (P=0.061) was found for the association of GSS with change in EB compliance. UES compliance, change in EB compliance, and somatization explain 40% of the variance in GSS. This indicates that globus is a complex disorder of the brain-gut axis rather than a "psychosomatic" disorder or a peripheral esophageal disorder.

SNPitty: An Intuitive Web Application for Interactive B-Allele Frequency and Copy Number Visualization of Next-Generation Sequencing Data.

PubMed

van Riet, Job; Krol, Niels M G; Atmodimedjo, Peggy N; Brosens, Erwin; van IJcken, Wilfred F J; Jansen, Maurice P H M; Martens, John W M; Looijenga, Leendert H; Jenster, Guido; Dubbink, Hendrikus J; Dinjens, Winand N M; van de Werken, Harmen J G

2018-03-01

Exploration and visualization of next-generation sequencing data are crucial for clinical diagnostics. Software allowing simultaneous visualization of multiple regions of interest coupled with dynamic heuristic filtering of genetic aberrations is, however, lacking. Therefore, the authors developed the web application SNPitty that allows interactive visualization and interrogation of variant call format files by using B-allele frequencies of single-nucleotide polymorphisms and single-nucleotide variants, coverage metrics, and copy numbers analysis results. SNPitty displays variant alleles and allelic imbalances with a focus on loss of heterozygosity and copy number variation using genome-wide heterozygous markers and somatic mutations. In addition, SNPitty is capable of generating predefined reports that summarize and highlight disease-specific targets of interest. SNPitty was validated for diagnostic interpretation of somatic events by showcasing a serial dilution series of glioma tissue. Additionally, SNPitty is demonstrated in four cancer-related scenarios encountered in daily clinical practice and on whole-exome sequencing data of peripheral blood from a Down syndrome patient. SNPitty allows detection of loss of heterozygosity, chromosomal and gene amplifications, homozygous or heterozygous deletions, somatic mutations, or any combination thereof in regions or genes of interest. Furthermore, SNPitty can be used to distinguish molecular relationships between multiple tumors from a single patient. On the basis of these data, the authors demonstrate that SNPitty is robust and user friendly in a wide range of diagnostic scenarios. Copyright © 2018 American Society for Investigative Pathology and the Association for Molecular Pathology. Published by Elsevier Inc. All rights reserved.

SMART precision cancer medicine: a FHIR-based app to provide genomic information at the point of care.

PubMed

Warner, Jeremy L; Rioth, Matthew J; Mandl, Kenneth D; Mandel, Joshua C; Kreda, David A; Kohane, Isaac S; Carbone, Daniel; Oreto, Ross; Wang, Lucy; Zhu, Shilin; Yao, Heming; Alterovitz, Gil

2016-07-01

Precision cancer medicine (PCM) will require ready access to genomic data within the clinical workflow and tools to assist clinical interpretation and enable decisions. Since most electronic health record (EHR) systems do not yet provide such functionality, we developed an EHR-agnostic, clinico-genomic mobile app to demonstrate several features that will be needed for point-of-care conversations. Our prototype, called Substitutable Medical Applications and Reusable Technology (SMART)® PCM, visualizes genomic information in real time, comparing a patient's diagnosis-specific somatic gene mutations detected by PCR-based hotspot testing to a population-level set of comparable data. The initial prototype works for patient specimens with 0 or 1 detected mutation. Genomics extensions were created for the Health Level Seven® Fast Healthcare Interoperability Resources (FHIR)® standard; otherwise, the prototype is a normal SMART on FHIR app. The PCM prototype can rapidly present a visualization that compares a patient's somatic genomic alterations against a distribution built from more than 3000 patients, along with context-specific links to external knowledge bases. Initial evaluation by oncologists provided important feedback about the prototype's strengths and weaknesses. We added several requested enhancements and successfully demonstrated the app at the inaugural American Society of Clinical Oncology Interoperability Demonstration; we have also begun to expand visualization capabilities to include cancer specimens with multiple mutations. PCM is open-source software for clinicians to present the individual patient within the population-level spectrum of cancer somatic mutations. The app can be implemented on any SMART on FHIR-enabled EHRs, and future versions of PCM should be able to evolve in parallel with external knowledge bases. © The Author 2016. Published by Oxford University Press on behalf of the American Medical Informatics Association. All rights reserved. For Permissions, please email: journals.permissions@oup.com.

Germline and somatic FGFR1 abnormalities in dysembryoplastic neuroepithelial tumors

PubMed Central

Rivera, Barbara; Gayden, Tenzin; Carrot-Zhang, Jian; Nadaf, Javad; Boshari, Talia; Faury, Damien; Zeinieh, Michele; Blanc, Romeo; Burk, David L.; Fahiminiya, Somayyeh; Bareke, Eric; Schüller, Ulrich; Monoranu, Camelia M.; Sträter, Ronald; Kerl, Kornelius; Niederstadt, Thomas; Kurlemann, Gerhard; Ellezam, Benjamin; Michalak, Zuzanna; Thom, Maria; Lockhart, Paul J.; Leventer, Richard J.; Ohm, Milou; MacGregor, Duncan; Jones, David; Karamchandani, Jason; Greenwood, Celia MT; Berghuis, Albert M.; Bens, Susanne; Siebert, Reiner; Zakrzewska, Magdalena; Liberski, Pawel P.; Zakrzewski, Krzysztof; Sisodiya, Sanjay M.; Paulus, Werner; Albrecht, Steffen; Hasselblatt, Martin; Jabado, Nada; Foulkes, William D; Majewski, Jacek

2016-01-01

Dysembryoplastic neuroepithelial tumor (DNET) is a benign brain tumor associated with intractable drug-resistant epilepsy. In order to identify underlying genetic alterations and molecular mechanisms, we examined three family members affected by multinodular DNETs as well as 100 sporadic tumors from 96 patients, which had been referred to us as DNETs. We performed whole-exome sequencing on 46 tumors and targeted sequencing for hotspot FGFR1 mutations and BRAF p.V600E was used on the remaining samples. FISH, copy number variation assays and Sanger sequencing were used to validate the findings. By whole exome sequencing of the familial cases, we identified a novel germline FGFR1 mutation, p.R661P. Somatic activating FGFR1 mutations (p.N546K or p.K656E) were observed in the tumor samples and further evidence for functional relevance was obtained by in silico modelling. The FGFR1 p.K656E mutation was confirmed to be in cis with the germline p.R661P variant. In 43 sporadic cases, in which the diagnosis of DNET could be confirmed on central blinded neuropathology review, FGFR1 alterations were also frequent and mainly comprised intragenic tyrosine kinase FGFR1 duplication and multiple mutants in cis (25/43; 58.1%) while BRAF p.V600E alterations were absent (0/43). In contrast, in 53 cases, in which the diagnosis of DNET was not confirmed, FGFR1 alterations were less common (10/53; 19%; p<0.0001) and hotspot BRAF p.V600E (12/53; 22.6%) (p<0.001) prevailed. We observed overexpression of phospho-ERK in FGFR1 p.R661P and p.N546K mutant expressing HEK293 cells as well as FGFR1 mutated tumor samples, supporting enhanced MAP kinase pathway activation under these conditions. In conclusion, constitutional and somatic FGFR1 alterations and MAP kinase pathway activation are key events in the pathogenesis of DNET. These findings point the way towards existing targeted therapies. PMID:26920151

PARP inhibitors--current status and the walk towards early breast cancer.

PubMed

Glendenning, Jennifer; Tutt, Andrew

2011-10-01

Epithelial carcinomas in general arise as a result of the acquisition of and selection for multiple mutations in a parental somatic cell clone within the tissues of the primary organ of origin. In the last two decades genome caretakers, which function in key areas of DNA damage response, have been recognized as important tumour suppressor genes. Inactivating mutations in these genes occur both as germline and/or somatic mutations with increasing evidence of epigenetic silencing as an additional cause of loss of function. In any event, loss of function in a tumour cell pre-cursor clone leads to accelerated mutation acquisition and underpins the aetiology of the tumour. With increasing understanding of the complex network that is the DNA damage response, signaling pathways already recognized to be central to the establishment of the cancer phenotype are gaining additional roles as controllers of DNA repair. This has relevance to identification of wider populations of patients with tumours susceptible to approaches that target DNA repair deficiency. These have classically been with DNA damaging chemotherapy but the recently developed small molecule inhibitors of DNA repair enzymes such as Poly-ADP polymerases PARP-1 and PARP-2 have been shown to target tumour deficiencies in DNA repair as well sensitizing to DNA damaging therapeutics such as radiation and chemotherapy. Early phase trials with efficacy endpoints have been presented for the PARP inhibitors AG014699, olaparib, veliparib, iniparib and MK4827. The results of the first phase II trials exploring monotherapy PARP inhibitor strategies, which are based on revisiting the concept of synthetic lethality, have emerged and are reviewed herein. The clinical trials that have or are exploring combinations with DNA damaging therapy in these contexts are discussed with particular reference to breast cancer, as are biomarkers that have been proposed and are being investigated to develop optimal drug schedule and patient selection criteria for these DNA repair targeting approaches. Copyright © 2011 Elsevier Ltd. All rights reserved.

Characterization of embryo-specific genes

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

Sung, Z.R.

1988-01-01

The objective of the proposed research is to characterize the structure and function of a set of genes whose expression is regulated in embryo development, and that are not expressed in mature tissues -- the embryogenic genes. In order to isolate these genes, we immunized a rabbit with total extracts of somatic embryos of carrot, and enriched the anti-embryo antiserum for antibodies reacting with extracts of carrot somatic embryos. Using this enriched antiserum, we screened a lambda gt11 cDNA library constructed from embryo poly A{sup +} RNA, and isolated 10 cDNA clones that detect embryogenic mRNAs. Monospecific antibodies have beenmore » purified for proteins corresponding to each cDNA sequence. Four cDNA clones were further characterized in terms of the expression of their corresponding mRNA and protein in somatic embryos of carrot. In some cases, comparable gene sequences or products have been detected in somatic and zygotic embryos of other plant species. The characteristics of these 4 cDNA clones -- clone Nos. 8, 59, and 66 -- are described in this report. 3 figs.« less

DNMT1 maintains progenitor function in self-renewing somatic tissue.

PubMed

Sen, George L; Reuter, Jason A; Webster, Daniel E; Zhu, Lilly; Khavari, Paul A

2010-01-28

Progenitor cells maintain self-renewing tissues throughout life by sustaining their capacity for proliferation while suppressing cell cycle exit and terminal differentiation. DNA methylation provides a potential epigenetic mechanism for the cellular memory needed to preserve the somatic progenitor state through repeated cell divisions. DNA methyltransferase 1 (DNMT1) maintains DNA methylation patterns after cellular replication. Although dispensable for embryonic stem cell maintenance, the role for DNMT1 in maintaining the progenitor state in constantly replenished somatic tissues, such as mammalian epidermis, is unclear. Here we show that DNMT1 is essential for epidermal progenitor cell function. DNMT1 protein was found enriched in undifferentiated cells, where it was required to retain proliferative stamina and suppress differentiation. In tissue, DNMT1 depletion led to exit from the progenitor cell compartment, premature differentiation and eventual tissue loss. Genome-wide analysis showed that a significant portion of epidermal differentiation gene promoters were methylated in self-renewing conditions but were subsequently demethylated during differentiation. Furthermore, UHRF1 (refs 9, 10), a component of the DNA methylation machinery that targets DNMT1 to hemi-methylated DNA, is also necessary to suppress premature differentiation and sustain proliferation. In contrast, Gadd45A and B, which promote active DNA demethylation, are required for full epidermal differentiation gene induction. These data demonstrate that proteins involved in the dynamic regulation of DNA methylation patterns are required for progenitor maintenance and self-renewal in mammalian somatic tissue.

Somatic experiencing: using interoception and proprioception as core elements of trauma therapy

PubMed Central

Payne, Peter; Levine, Peter A.; Crane-Godreau, Mardi A.

2015-01-01

Here we present a theory of human trauma and chronic stress, based on the practice of Somatic Experiencing® (SE), a form of trauma therapy that emphasizes guiding the client's attention to interoceptive, kinesthetic, and proprioceptive experience. SE™ claims that this style of inner attention, in addition to the use of kinesthetic and interoceptive imagery, can lead to the resolution of symptoms resulting from chronic and traumatic stress. This is accomplished through the completion of thwarted, biologically based, self-protective and defensive responses, and the discharge and regulation of excess autonomic arousal. We present this theory through a composite case study of SE treatment; based on this example, we offer a possible neurophysiological rationale for the mechanisms involved, including a theory of trauma and chronic stress as a functional dysregulation of the complex dynamical system formed by the subcortical autonomic, limbic, motor and arousal systems, which we term the core response network (CRN). We demonstrate how the methods of SE help restore functionality to the CRN, and we emphasize the importance of taking into account the instinctive, bodily based protective reactions when dealing with stress and trauma, as well as the effectiveness of using attention to interoceptive, proprioceptive and kinesthetic sensation as a therapeutic tool. Finally, we point out that SE and similar somatic approaches offer a supplement to cognitive and exposure therapies, and that mechanisms similar to those discussed in the paper may also be involved in the benefits of meditation and other somatic practices. PMID:25699005

Fibromyalgia: A Critical and Comprehensive Review.

PubMed

Borchers, Andrea T; Gershwin, M Eric

2015-10-01

Fibromyalgia is a disorder that is part of a spectrum of syndromes that lack precise classification. It is often considered as part of the global overview of functional somatic syndromes that are otherwise medically unexplained or part of a somatization disorder. Patients with fibromyalgia share symptoms with other functional somatic problems, including issues of myalgias, arthralgias, fatigue and sleep disturbances. Indeed, there is often diagnostic and classification overlap for the case definitions of a variety of somatization disorders. Fibromyalgia, however, is a critically important syndrome for physicians and scientists to be aware of. Patients should be taken very seriously and provided optimal care. Although inflammatory, infectious, and autoimmune disorders have all been ascribed to be etiological events in the development of fibromyalgia, there is very little data to support such a thesis. Many of these disorders are associated with depression and anxiety and may even be part of what has been sometimes called affected spectrum disorders. There is no evidence that physical trauma, i.e., automobile accidents, is associated with the development or exacerbation of fibromyalgia. Treatment should be placed on education, patient support, physical therapy, nutrition, and exercise, including the use of drugs that are approved for the treatment of fibromyalgia. Treatment should not include opiates and patients should not become poly pharmacies in which the treatment itself can lead to significant morbidities. Patients with fibromyalgia are living and not dying of this disorder and positive outlooks and family support are key elements in the management of patients.

Constitutional abnormalities of IDH1 combined with secondary mutations predispose a patient with Maffucci syndrome to acute lymphoblastic leukemia.

PubMed

Hirabayashi, Shinsuke; Seki, Masafumi; Hasegawa, Daisuke; Kato, Motohiro; Hyakuna, Nobuyuki; Shuo, Takuya; Kimura, Shunsuke; Yoshida, Kenichi; Kataoka, Keisuke; Fujii, Yoichi; Shiraishi, Yuichi; Chiba, Kenichi; Tanaka, Hiroko; Kiyokawa, Nobutaka; Miyano, Satoru; Ogawa, Seishi; Takita, Junko; Manabe, Atsushi

2017-12-01

Maffucci syndrome is a nonhereditary disorder caused by somatic mosaic isocitrate dehydrogenase 1 or 2 (IDH1 or IDH2) mutations and is characterized by multiple enchondromas along with hemangiomas. Malignant transformation of enchondromas to chondrosarcomas and secondary neoplasms, such as brain tumors or acute myeloid leukemia, are serious complications. A 15-year-old female with Maffucci syndrome developed B-cell precursor acute lymphoblastic leukemia (BCP-ALL). A somatic mutation in IDH1 was detected in hemangioma and leukemic cells. KRAS mutation and deletion of IKZF1 were detected in leukemic cells. Patients with Maffucci syndrome may, therefore, be at risk of BCP-ALL associated with secondary genetic events that affect lymphocyte differentiation. © 2017 Wiley Periodicals, Inc.

Integrated Molecular Characterization of Uterine Carcinosarcoma.

PubMed

Cherniack, Andrew D; Shen, Hui; Walter, Vonn; Stewart, Chip; Murray, Bradley A; Bowlby, Reanne; Hu, Xin; Ling, Shiyun; Soslow, Robert A; Broaddus, Russell R; Zuna, Rosemary E; Robertson, Gordon; Laird, Peter W; Kucherlapati, Raju; Mills, Gordon B; Weinstein, John N; Zhang, Jiashan; Akbani, Rehan; Levine, Douglas A

2017-03-13

We performed genomic, epigenomic, transcriptomic, and proteomic characterizations of uterine carcinosarcomas (UCSs). Cohort samples had extensive copy-number alterations and highly recurrent somatic mutations. Frequent mutations were found in TP53, PTEN, PIK3CA, PPP2R1A, FBXW7, and KRAS, similar to endometrioid and serous uterine carcinomas. Transcriptome sequencing identified a strong epithelial-to-mesenchymal transition (EMT) gene signature in a subset of cases that was attributable to epigenetic alterations at microRNA promoters. The range of EMT scores in UCS was the largest among all tumor types studied via The Cancer Genome Atlas. UCSs shared proteomic features with gynecologic carcinomas and sarcomas with intermediate EMT features. Multiple somatic mutations and copy-number alterations in genes that are therapeutic targets were identified. Copyright © 2017 Elsevier Inc. All rights reserved.

Efficient modification of the myostatin gene in porcine somatic cells and generation of knockout piglets.

PubMed

Rao, Shengbin; Fujimura, Tatsuya; Matsunari, Hitomi; Sakuma, Tetsushi; Nakano, Kazuaki; Watanabe, Masahito; Asano, Yoshinori; Kitagawa, Eri; Yamamoto, Takashi; Nagashima, Hiroshi

2016-01-01

Myostatin (MSTN) is a negative regulator of myogenesis, and disruption of its function causes increased muscle mass in various species. Here, we report the generation of MSTN-knockout (KO) pigs using genome editing technology combined with somatic-cell nuclear transfer (SCNT). Transcription activator-like effector nuclease (TALEN) with non-repeat-variable di-residue variations, called Platinum TALEN, was highly efficient in modifying genes in porcine somatic cells, which were then used for SCNT to create MSTN KO piglets. These piglets exhibited a double-muscled phenotype, possessing a higher body weight and longissimus muscle mass measuring 170% that of wild-type piglets, with double the number of muscle fibers. These results demonstrate that loss of MSTN increases muscle mass in pigs, which may help increase pork production for consumption in the future. © 2015 Wiley Periodicals, Inc.

DSM-IV hypochondriasis in primary care.

PubMed

Escobar, J I; Gara, M; Waitzkin, H; Silver, R C; Holman, A; Compton, W

1998-05-01

The object of this study was to assess the prevalence and correlates of the DSM-IV diagnosis of hypochondriasis in a primary care setting. A large sample (N = 1456) of primary care users was given a structured interview to make diagnoses of mood, anxiety, and somatoform disorders and estimate levels of disability. The prevalence of hypochondriasis (DSM-IV) was about 3%. Patients with this disorder had higher levels of medically unexplained symptoms (abridged somatization) and were more impaired in their physical functioning than patients without the disorder. Of the various psychopathologies examined, major depressive syndromes were the most frequent among patients with hypochondriasis. Interestingly, unlike somatization disorder, hypochondriasis was not related to any demographic factor. Hypochondriasis is a relatively rare condition in primary care that is largely separable from somatization disorder but seems closely intertwined with the more severe depressive syndromes.

The effects of congenital hypothyroidism using the hyt/hyt mouse on locomotor activity and learned behavior.

PubMed

Anthony, A; Adams, P M; Stein, S A

1993-09-01

The offspring of matings between hyt/hyt male mice and hyt/+ females were examined for somatic and behavioral differences. The hyt/hyt offspring displayed delayed somatic development for eye opening and ear extension relative to their euthyroid littermates. Behavioral measurement of locomotor activity indicated hyperactivity at 14 days of age and hypoactivity at 21 and 40 days relative to the euthyroid mice. Impaired swimming escape behavior and Morris maze spatial learning were observed in the hyt/hyt animals. Comparative evaluation of +/+ progenitor strain offspring having no hypothyroidism in their genetic background indicated significant differences in somatic and behavioral endpoints between the hyt/hyt and euthyroid (hyt/+, +/+) animals. These results confirm the utility of the hyt/hyt mouse for studies of the impact of congenital hypothyroidism on the functional development of the offspring.

Oncogenetic tree model of somatic mutations and DNA methylation in colon tumors.

PubMed

Sweeney, Carol; Boucher, Kenneth M; Samowitz, Wade S; Wolff, Roger K; Albertsen, Hans; Curtin, Karen; Caan, Bette J; Slattery, Martha L

2009-01-01

Our understanding of somatic alterations in colon cancer has evolved from a concept of a series of events taking place in a single sequence to a recognition of multiple pathways. An oncogenetic tree is a model intended to describe the pathways and sequence of somatic alterations in carcinogenesis without assuming that tumors will fall in mutually exclusive categories. We applied this model to data on colon tumor somatic alterations. An oncogenetic tree model was built using data on mutations of TP53, KRAS2, APC, and BRAF genes, methylation at CpG sites of MLH1 and TP16 genes, methylation in tumor (MINT) markers, and microsatellite instability (MSI) for 971 colon tumors from a population-based series. Oncogenetic tree analysis resulted in a reproducible tree with three branches. The model represents methylation of MINT markers as initiating a branch and predisposing to MSI, methylation of MHL1 and TP16, and BRAF mutation. APC mutation is the first alteration in an independent branch and is followed by TP53 mutation. KRAS2 mutation was placed a third independent branch, implying that it neither depends on, nor predisposes to, the other alterations. Individual tumors were observed to have alteration patterns representing every combination of one, two, or all three branches. The oncogenetic tree model assumptions are appropriate for the observed heterogeneity of colon tumors, and the model produces a useful visual schematic of the sequence of events in pathways of colon carcinogenesis.

Multilineage somatic activating mutations in HRAS and NRAS cause mosaic cutaneous and skeletal lesions, elevated FGF23 and hypophosphatemia

PubMed Central

Lim, Young H.; Ovejero, Diana; Sugarman, Jeffrey S.; DeKlotz, Cynthia M.C.; Maruri, Ann; Eichenfield, Lawrence F.; Kelley, Patrick K.; Jüppner, Harald; Gottschalk, Michael; Tifft, Cynthia J.; Gafni, Rachel I.; Boyce, Alison M.; Cowen, Edward W.; Bhattacharyya, Nisan; Guthrie, Lori C.; Gahl, William A.; Golas, Gretchen; Loring, Erin C.; Overton, John D.; Mane, Shrikant M.; Lifton, Richard P.; Levy, Moise L.; Collins, Michael T.; Choate, Keith A.

2014-01-01

Pathologically elevated serum levels of fibroblast growth factor-23 (FGF23), a bone-derived hormone that regulates phosphorus homeostasis, result in renal phosphate wasting and lead to rickets or osteomalacia. Rarely, elevated serum FGF23 levels are found in association with mosaic cutaneous disorders that affect large proportions of the skin and appear in patterns corresponding to the migration of ectodermal progenitors. The cause and source of elevated serum FGF23 is unknown. In those conditions, such as epidermal and large congenital melanocytic nevi, skin lesions are variably associated with other abnormalities in the eye, brain and vasculature. The wide distribution of involved tissues and the appearance of multiple segmental skin and bone lesions suggest that these conditions result from early embryonic somatic mutations. We report five such cases with elevated serum FGF23 and bone lesions, four with large epidermal nevi and one with a giant congenital melanocytic nevus. Exome sequencing of blood and affected skin tissue identified somatic activating mutations of HRAS or NRAS in each case without recurrent secondary mutation, and we further found that the same mutation is present in dysplastic bone. Our finding of somatic activating RAS mutation in bone, the endogenous source of FGF23, provides the first evidence that elevated serum FGF23 levels, hypophosphatemia and osteomalacia are associated with pathologic Ras activation and may provide insight in the heretofore limited understanding of the regulation of FGF23. PMID:24006476

Multilineage somatic activating mutations in HRAS and NRAS cause mosaic cutaneous and skeletal lesions, elevated FGF23 and hypophosphatemia.

PubMed

Lim, Young H; Ovejero, Diana; Sugarman, Jeffrey S; Deklotz, Cynthia M C; Maruri, Ann; Eichenfield, Lawrence F; Kelley, Patrick K; Jüppner, Harald; Gottschalk, Michael; Tifft, Cynthia J; Gafni, Rachel I; Boyce, Alison M; Cowen, Edward W; Bhattacharyya, Nisan; Guthrie, Lori C; Gahl, William A; Golas, Gretchen; Loring, Erin C; Overton, John D; Mane, Shrikant M; Lifton, Richard P; Levy, Moise L; Collins, Michael T; Choate, Keith A

2014-01-15

Pathologically elevated serum levels of fibroblast growth factor-23 (FGF23), a bone-derived hormone that regulates phosphorus homeostasis, result in renal phosphate wasting and lead to rickets or osteomalacia. Rarely, elevated serum FGF23 levels are found in association with mosaic cutaneous disorders that affect large proportions of the skin and appear in patterns corresponding to the migration of ectodermal progenitors. The cause and source of elevated serum FGF23 is unknown. In those conditions, such as epidermal and large congenital melanocytic nevi, skin lesions are variably associated with other abnormalities in the eye, brain and vasculature. The wide distribution of involved tissues and the appearance of multiple segmental skin and bone lesions suggest that these conditions result from early embryonic somatic mutations. We report five such cases with elevated serum FGF23 and bone lesions, four with large epidermal nevi and one with a giant congenital melanocytic nevus. Exome sequencing of blood and affected skin tissue identified somatic activating mutations of HRAS or NRAS in each case without recurrent secondary mutation, and we further found that the same mutation is present in dysplastic bone. Our finding of somatic activating RAS mutation in bone, the endogenous source of FGF23, provides the first evidence that elevated serum FGF23 levels, hypophosphatemia and osteomalacia are associated with pathologic Ras activation and may provide insight in the heretofore limited understanding of the regulation of FGF23.

Detection of somatic mutations by high-resolution DNA melting (HRM) analysis in multiple cancers.

PubMed

Gonzalez-Bosquet, Jesus; Calcei, Jacob; Wei, Jun S; Garcia-Closas, Montserrat; Sherman, Mark E; Hewitt, Stephen; Vockley, Joseph; Lissowska, Jolanta; Yang, Hannah P; Khan, Javed; Chanock, Stephen

2011-01-17

Identification of somatic mutations in cancer is a major goal for understanding and monitoring the events related to cancer initiation and progression. High resolution melting (HRM) curve analysis represents a fast, post-PCR high-throughput method for scanning somatic sequence alterations in target genes. The aim of this study was to assess the sensitivity and specificity of HRM analysis for tumor mutation screening in a range of tumor samples, which included 216 frozen pediatric small rounded blue-cell tumors as well as 180 paraffin-embedded tumors from breast, endometrial and ovarian cancers (60 of each). HRM analysis was performed in exons of the following candidate genes known to harbor established commonly observed mutations: PIK3CA, ERBB2, KRAS, TP53, EGFR, BRAF, GATA3, and FGFR3. Bi-directional sequencing analysis was used to determine the accuracy of the HRM analysis. For the 39 mutations observed in frozen samples, the sensitivity and specificity of HRM analysis were 97% and 87%, respectively. There were 67 mutation/variants in the paraffin-embedded samples, and the sensitivity and specificity for the HRM analysis were 88% and 80%, respectively. Paraffin-embedded samples require higher quantity of purified DNA for high performance. In summary, HRM analysis is a promising moderate-throughput screening test for mutations among known candidate genomic regions. Although the overall accuracy appears to be better in frozen specimens, somatic alterations were detected in DNA extracted from paraffin-embedded samples.

Detection of Somatic Mutations by High-Resolution DNA Melting (HRM) Analysis in Multiple Cancers

PubMed Central

Gonzalez-Bosquet, Jesus; Calcei, Jacob; Wei, Jun S.; Garcia-Closas, Montserrat; Sherman, Mark E.; Hewitt, Stephen; Vockley, Joseph; Lissowska, Jolanta; Yang, Hannah P.; Khan, Javed; Chanock, Stephen

2011-01-01

Identification of somatic mutations in cancer is a major goal for understanding and monitoring the events related to cancer initiation and progression. High resolution melting (HRM) curve analysis represents a fast, post-PCR high-throughput method for scanning somatic sequence alterations in target genes. The aim of this study was to assess the sensitivity and specificity of HRM analysis for tumor mutation screening in a range of tumor samples, which included 216 frozen pediatric small rounded blue-cell tumors as well as 180 paraffin-embedded tumors from breast, endometrial and ovarian cancers (60 of each). HRM analysis was performed in exons of the following candidate genes known to harbor established commonly observed mutations: PIK3CA, ERBB2, KRAS, TP53, EGFR, BRAF, GATA3, and FGFR3. Bi-directional sequencing analysis was used to determine the accuracy of the HRM analysis. For the 39 mutations observed in frozen samples, the sensitivity and specificity of HRM analysis were 97% and 87%, respectively. There were 67 mutation/variants in the paraffin-embedded samples, and the sensitivity and specificity for the HRM analysis were 88% and 80%, respectively. Paraffin-embedded samples require higher quantity of purified DNA for high performance. In summary, HRM analysis is a promising moderate-throughput screening test for mutations among known candidate genomic regions. Although the overall accuracy appears to be better in frozen specimens, somatic alterations were detected in DNA extracted from paraffin-embedded samples. PMID:21264207

Client Predictors of Short-term Psychotherapy Outcomes among Asian and White American Outpatients

PubMed Central

Kim, Jin E.; Zane, Nolan W.; Blozis, Shelley A.

2015-01-01

Purpose To examine predictors of psychotherapy outcomes, focusing on client characteristics that are especially salient for culturally diverse clients. Method Sixty clients (31 women; 27 White Americans, 33 Asian Americans) participated in this treatment study. Client characteristics were measured at pre-treatment, and outcomes were measured post-fourth session via therapist ratings of functioning and symptomatology. Regression analyses were utilized to test for predictors of outcomes, and bootstrap analyses were utilized to test for mediators. Results Higher levels of somatic symptoms predicted lower psychosocial functioning at post-treatment. Avoidant coping style predicted more negative symptoms and more psychological discomfort. Non-English language preference predicted worse outcomes; this effect was mediated by an avoidant coping style. Conclusions Language preference, avoidant coping style, and somatic symptoms predicted treatment outcome in a culturally diverse sample. Findings suggest that race/ethnicity-related variables may function through mediating proximal variables to affect outcomes. PMID:22836681

The use of centrifugation to study early Drosophila embryogenesis

NASA Technical Reports Server (NTRS)

Abbott, M. K.; Spooner, B. S. (Principal Investigator)

1993-01-01

By the end of 10th nuclear cycle, the somatic nuclei of the Drosophila embryo have migrated to the periphery of the egg. Centrifugation of embryos did not result in the displacement of these nuclei, since cytoskeletal elements anchor them to the cortex. But, mild centrifugal forces displace the centrally located, nascent yolk nuclei. If this increased sensitivity to hypergravity occurs before the beginning of nuclear differentiation during cycle 8, when the nascent yolk and somatic nuclei physically separate, then it would mark the earliest functional difference between these two lineages.

Efficient Generation of Somatic Cell Nuclear Transfer-Competent Porcine Cells with Mutated Alleles at Multiple Target Loci by Using CRISPR/Cas9 Combined with Targeted Toxin-Based Selection System.

PubMed

Sato, Masahiro; Miyoshi, Kazuchika; Nakamura, Shingo; Ohtsuka, Masato; Sakurai, Takayuki; Watanabe, Satoshi; Kawaguchi, Hiroaki; Tanimoto, Akihide

2017-12-04

The recent advancement in genome editing such a CRISPR/Cas9 system has enabled isolation of cells with knocked multiple alleles through a one-step transfection. Somatic cell nuclear transfer (SCNT) has been frequently employed as one of the efficient tools for the production of genetically modified (GM) animals. To use GM cells as SCNT donor, efficient isolation of transfectants with mutations at multiple target loci is often required. The methods for the isolation of such GM cells largely rely on the use of drug selection-based approach using selectable genes; however, it is often difficult to isolate cells with mutations at multiple target loci. In this study, we used a novel approach for the efficient isolation of porcine cells with at least two target loci mutations by one-step introduction of CRISPR/Cas9-related components. A single guide (sg) RNA targeted to GGTA1 gene, involved in the synthesis of cell-surface α-Gal epitope (known as xenogenic antigen), is always a prerequisite. When the transfected cells were reacted with toxin-labeled BS-I-B₄ isolectin for 2 h at 37 C to eliminate α-Gal epitope-expressing cells, the surviving clones lacked α-Gal epitope expression and were highly expected to exhibit induced mutations at another target loci. Analysis of these α-Gal epitope-negative surviving cells demonstrated a 100% occurrence of genome editing at target loci. SCNT using these cells as donors resulted in the production of cloned blastocysts with the genotype similar to that of the donor cells used. Thus, this novel system will be useful for SCNT-mediated acquisition of GM cloned piglets, in which multiple target loci may be mutated.

Symptoms of somatization as a rapid screening tool for mitochondrial dysfunction in depression

PubMed Central

Gardner, Ann; Boles, Richard G

2008-01-01

Aims Somatic symptomatology is common in depression, and is often attributed to the Freudian-inspired concept of "somatization". While the same somatic symptoms and depression are common in mitochondrial disease, in cases with concurrent mood symptoms the diagnosis of a mitochondrial disorder and related therapy are typically delayed for many years. A short screening tool that can identify patients with depression at high risk for having underlying mitochondrial dysfunction is presented. Methods Six items of the Karolinska Scales of Personality (KSP) were found to differentiate among 21 chronically-depressed Swedish subjects with low versus normal muscle ATP production rates. A screening tool consisting of the six KSP questions was validated in the relatives of American genetics clinic patients, including in 24 matrilineal relatives in families with maternally inherited mitochondrial disease and in 30 control relatives. Results Among the depressed Swedish patients, the screening tool was positive in 13/14 with low and 1/7 with normal mitochondrial function (P = 0.0003). Applied to the American relatives of patients, the screening tool was positive in 13/24 matrilineal relatives and in 1/30 control relatives (P = 2 × 10-5). Conclusion Our preliminary data suggest that a small number of specific somatic-related questions can be constructed into a valid screening tool for cases at high risk for having a component of energy metabolism in their pathogenesis. PMID:18294386

Mental health of residents during Obstetrics and Gynecology training in Thailand.

PubMed

Prasertsiri, K; Suntharasaj, T; Pitanupong, J

2006-03-01

To evaluate mental health of residents during Obstetrics and Gynecology training and identify the factors that affect mental health problems. During January-April 2004, one hundred and sixty Obstetrics and Gynecology residents (62% of 259) had completed a self-administered questionnaire composed of demographic data, workload, self-report of life stressors, and the Thai Mental Health Questionnaire (TMHQ-70). The prevalence of mental health problems was 29% (46/160). Somatization and social function were found in the first and second rank (18.1% and 11.9%), respectively. A resident who was younger than 25 years old, was married, cared for more than 20 patients per 8 hours in the labor room, performed more than 10 academic activities per year, or attended more than 5 examinations per year was at risk to develop social function problems. About one-third of residents training in Obstetrics and Gynecology have faced mental health problems--somatization, social function, depression and anxiety. The significant risk factors associated with social function problems were younger age, marriage and excessive workload

Women's health issues with fibromyalgia syndrome.

PubMed

Shaver, Joan L F; Wilbur, Joellen; Robinson, F Patrick; Wang, Edward; Buntin, Mary S

2006-11-01

Fibromyalgia syndrome (FMS) involves multiple sensory, somatic, and cognitive symptoms that are bound to affect or be affected by physical and mental health status and behavioral components of daily life. From a telephone survey of 442 women with and 205 women without FMS as volunteers, data were compared on (1) general health status, (2) reproductive and sleep-related diagnoses, and (3) lifestyle health behaviors. All multiple or logistics regression analyses for group differences were controlled for age, body mass index (BMI), race, employment status, marital status, having a college degree, low household income, and having ever been diagnosed with depression, with a Bonferroni p value correction for multiple indicators. Accordingly, FMS negatively impacted both perceived physical and mental health status, although relatively more so for physical (p < 0.017). Women with FMS were more likely to have had reproductive health or sleep-related diagnoses, including premenstrual syndrome, dysmenorrhea, breast cysts, bladder cystitis, sleep apnea, restless leg syndrome, and abnormal leg movements (p < 0.0125). They were calculated to use less than half as many calories per week as control women (689 +/- 1293 vs. 1499 +/- 1584 kcal/week, p < 0.05) and had more sleep pattern difficulties (p < 0.0125), more negative changes in sexual function (greater odds for 5 of 10 indicators at p < 0.005), and lower alcohol use (odds ratio = 0.39, p < 0.05). Patients with FMS deserve careful assessment for reproductive conditions and sleep-related functional disorders. Besides more research into mechanisms underlying symptoms, intervention testing specifically to alleviate sleep problems, low physical activity levels, and sexual dysfunction should be paramount.

In-depth comparison of somatic point mutation callers based on different tumor next-generation sequencing depth data

NASA Astrophysics Data System (ADS)

Cai, Lei; Yuan, Wei; Zhang, Zhou; He, Lin; Chou, Kuo-Chen

2016-11-01

Four popular somatic single nucleotide variant (SNV) calling methods (Varscan, SomaticSniper, Strelka and MuTect2) were carefully evaluated on the real whole exome sequencing (WES, depth of ~50X) and ultra-deep targeted sequencing (UDT-Seq, depth of ~370X) data. The four tools returned poor consensus on candidates (only 20% of calls were with multiple hits by the callers). For both WES and UDT-Seq, MuTect2 and Strelka obtained the largest proportion of COSMIC entries as well as the lowest rate of dbSNP presence and high-alternative-alleles-in-control calls, demonstrating their superior sensitivity and accuracy. Combining different callers does increase reliability of candidates, but narrows the list down to very limited range of tumor read depth and variant allele frequency. Calling SNV on UDT-Seq data, which were of much higher read-depth, discovered additional true-positive variations, despite an even more tremendous growth in false positive predictions. Our findings not only provide valuable benchmark for state-of-the-art SNV calling methods, but also shed light on the access to more accurate SNV identification in the future.

Chronic Stress and Fatigue-Related Quality of Life after Mild-to-Moderate Traumatic Brain Injury (TBI)

PubMed Central

Bay, Esther; de-Leon, Marita B.

2010-01-01

Objective To determine relationships between chronic stress, fatigue-related quality of life (QOL-F) and related covariates after mild-to-moderate traumatic brain injury (TBI). Design Observational and cross-sectional Participants A total of 84 community-dwelling individuals with mild-to-moderate TBI recruited from multiple out-patient rehabilitation clinics assessed on average 15 months after injury. Method Data were collected with self-report surveys and chart abstraction. Measures Neurofunctional Behavioral Inventory, Perceived Stress Scale-14, Impact of Events Scale, McGill Pain Short-form Scale, and modified version of the Fatigue Impact Scale. Results Fatigue-related quality of life was associated with somatic symptoms, perceived situational stress, but not with event-related stress (PTSD symptoms) related to index TBI, pre-injury demographic, or post-injury characteristics. Somatic symptoms and chronic situational stress accounted for 42% of the variance in QOL (F). Conclusions QOL (F) in community-dwelling individuals with mild-to- moderate TBI is associated with chronic situational stress and somatic symptoms. Symptom management strategies may need to include general stress management to reduce fatigue burden and improve quality of life. PMID:21169862

The role of general and specific stressors in the health and well-being of call centre operators.

PubMed

Mellor, David; Moore, Kathleen A; Siong, Zhong Ming Benjamin

2015-01-01

The call centre industry has developed a reputation for generating a highly stressful work environment with high absenteeism and turnover rates. Research has identified role ambiguity, role conflict, role overload, and work-family conflict as common stressors in other settings. Call centre research has additionally identified performance monitoring, job design and job opportunities as call centre specific stressors. This study investigated the impact of the identified stressors on burnout, somatic symptomology, and turnover intent among 126 call centre representatives (CCRs) from 11 call centres in metropolitan Melbourne, Australia. Hierarchical multiple regression analyses found that the common organizational stressors significantly explained between 10% and 53% of the variance in somatic symptomology, burnout (all 3 dimensions) and turnover intent. An additional amount of variance, between 6% and 22% in each of these dependent measures was significantly accounted for by the grouped call centre specific stressors. Overall, common organizational stressors and call centre specific stressors both significantly and independently contributed to burnout, somatic symptomology and turnover intent. These findings are discussed in relation to previous research, and suggestions for improved practice within call centres to safeguard the well-being of workers and for future research are provided.

The landscape of cancer genes and mutational processes in breast cancer

PubMed Central

Stephens, Philip J.; Tarpey, Patrick S.; Davies, Helen; Loo, Peter Van; Greenman, Chris; Wedge, David C.; Nik-Zainal, Serena; Martin, Sancha; Varela, Ignacio; Bignell, Graham R.; Yates, Lucy R.; Papaemmanuil, Elli; Beare, David; Butler, Adam; Cheverton, Angela; Gamble, John; Hinton, Jonathan; Jia, Mingming; Jayakumar, Alagu; Jones, David; Latimer, Calli; Lau, King Wai; McLaren, Stuart; McBride, David J.; Menzies, Andrew; Mudie, Laura; Raine, Keiran; Rad, Roland; Chapman, Michael Spencer; Teague, Jon; Easton, Douglas; Langerød, Anita; OSBREAC; Lee, Ming Ta Michael; Shen, Chen-Yang; Tee, Benita Tan Kiat; Huimin, Bernice Wong; Broeks, Annegien; Vargas, Ana Cristina; Turashvili, Gulisa; Martens, John; Fatima, Aquila; Miron, Penelope; Chin, Suet-Feung; Thomas, Gilles; Boyault, Sandrine; Mariani, Odette; Lakhani, Sunil R.; van de Vijver, Marc; van ’t Veer, Laura; Foekens, John; Desmedt, Christine; Sotiriou, Christos; Tutt, Andrew; Caldas, Carlos; Reis-Filho, Jorge S.; Aparicio, Samuel A. J. R.; Salomon, Anne Vincent; Børresen-Dale, Anne-Lise; Richardson, Andrea L.; Campbell, Peter J.; Futreal, P. Andrew; Stratton, Michael R.

2012-01-01

All cancers carry somatic mutations in their genomes. A subset, known as driver mutations, confer clonal selective advantage on cancer cells and are causally implicated in oncogenesis1, and the remainder are passenger mutations. The driver mutations and mutational processes operative in breast cancer have not yet been comprehensively explored. Here we examine the genomes of 100 tumours for somatic copy number changes and mutations in the coding exons of protein-coding genes. The number of somatic mutations varied markedly between individual tumours. We found strong correlations between mutation number, age at which cancer was diagnosed and cancer histological grade, and observed multiple mutational signatures, including one present in about ten per cent of tumours characterized by numerous mutations of cytosine at TpC dinucleotides. Driver mutations were identified in several new cancer genes including AKT2, ARID1B, CASP8, CDKN1B, MAP3K1, MAP3K13, NCOR1, SMARCD1 and TBX3. Among the 100 tumours, we found driver mutations in at least 40 cancer genes and 73 different combinations of mutated cancer genes. The results highlight the substantial genetic diversity underlying this common disease. PMID:22722201

Psychological characteristics and GoNogo research of patients with functional constipation

PubMed Central

Li, Xiaoyi; Feng, Rui; Wu, Hao; Zhang, Lei; Zhao, Lan; Dai, Ning; Yu, Enyan

2016-01-01

Abstract The emotional state, psychological characteristics, cognitive function, and the relevance among above factors in patients with functional constipation (FC) are complex. This study aimed to investigate whether FC symptoms might be related to implicit processing such as psychological characteristics and emotional somatization. Thirty-five FC patients and 24 normal volunteers were recruited to collect event-related potentials (ERP) behavior and electroencephalogram data when simple digital GoNogo visual tasks were performed. Hamilton Depression Scale (HAMD-17), Hamilton Anxiety Scale (HAMA), Symptom Checklist, and Eysenck Personality Inventory (EPQ) were assessed before the ERP test. There was significant difference in average score, positive index, somatization, obsessive-compulsive disorder, anxiety, depression and psychoticism in HAMD-17, HAMA, Symptom Checklist, and extroversion or introversion and neuroticism in EPQ between the FC patients group and the normal control group (P < 0.05). There was a significant difference in the amplitude of ERP-P300 at site F4, F7, and FZ (P < 0.05). FC patients showed anxiety and depression. The asymmetric forebrain abnormal activities in the 2 hemispheres might initiate implicit automatic processing, such as somatization and obsessive-compulsive disorder, in order to cope with painful experience caused by anxiety and depression in patients with FC. Cognitive dysfunction of implicit processing might be involved in the abnormality of visual communication and information processing. PMID:28033259

The Theobroma cacao B3 domain transcription factor TcLEC2 plays a duel role in control of embryo development and maturation

PubMed Central

2014-01-01

Background The Arabidopsis thaliana LEC2 gene encodes a B3 domain transcription factor, which plays critical roles during both zygotic and somatic embryogenesis. LEC2 exerts significant impacts on determining embryogenic potential and various metabolic processes through a complicated genetic regulatory network. Results An ortholog of the Arabidopsis Leafy Cotyledon 2 gene (AtLEC2) was characterized in Theobroma cacao (TcLEC2). TcLEC2 encodes a B3 domain transcription factor preferentially expressed during early and late zygotic embryo development. The expression of TcLEC2 was higher in dedifferentiated cells competent for somatic embryogenesis (embryogenic calli), compared to non-embryogenic calli. Transient overexpression of TcLEC2 in immature zygotic embryos resulted in changes in gene expression profiles and fatty acid composition. Ectopic expression of TcLEC2 in cacao leaves changed the expression levels of several seed related genes. The overexpression of TcLEC2 in cacao explants greatly increased the frequency of regeneration of stably transformed somatic embryos. TcLEC2 overexpressing cotyledon explants exhibited a very high level of embryogenic competency and when cultured on hormone free medium, exhibited an iterative embryogenic chain-reaction. Conclusions Our study revealed essential roles of TcLEC2 during both zygotic and somatic embryo development. Collectively, our evidence supports the conclusion that TcLEC2 is a functional ortholog of AtLEC2 and that it is involved in similar genetic regulatory networks during cacao somatic embryogenesis. To our knowledge, this is the first detailed report of the functional analysis of a LEC2 ortholog in a species other then Arabidopsis. TcLEC2 could potentially be used as a biomarker for the improvement of the SE process and screen for elite varieties in cacao germplasm. PMID:24758406

MutationAligner: a resource of recurrent mutation hotspots in protein domains in cancer.

PubMed

Gauthier, Nicholas Paul; Reznik, Ed; Gao, Jianjiong; Sumer, Selcuk Onur; Schultz, Nikolaus; Sander, Chris; Miller, Martin L

2016-01-04

The MutationAligner web resource, available at http://www.mutationaligner.org, enables discovery and exploration of somatic mutation hotspots identified in protein domains in currently (mid-2015) more than 5000 cancer patient samples across 22 different tumor types. Using multiple sequence alignments of protein domains in the human genome, we extend the principle of recurrence analysis by aggregating mutations in homologous positions across sets of paralogous genes. Protein domain analysis enhances the statistical power to detect cancer-relevant mutations and links mutations to the specific biological functions encoded in domains. We illustrate how the MutationAligner database and interactive web tool can be used to explore, visualize and analyze mutation hotspots in protein domains across genes and tumor types. We believe that MutationAligner will be an important resource for the cancer research community by providing detailed clues for the functional importance of particular mutations, as well as for the design of functional genomics experiments and for decision support in precision medicine. MutationAligner is slated to be periodically updated to incorporate additional analyses and new data from cancer genomics projects. © The Author(s) 2015. Published by Oxford University Press on behalf of Nucleic Acids Research.

Germline-specific H1 variants: the "sexy" linker histones.

PubMed

Pérez-Montero, Salvador; Carbonell, Albert; Azorín, Fernando

2016-03-01

The eukaryotic genome is packed into chromatin, a nucleoprotein complex mainly formed by the interaction of DNA with the abundant basic histone proteins. The fundamental structural and functional subunit of chromatin is the nucleosome core particle, which is composed by 146 bp of DNA wrapped around an octameric protein complex formed by two copies of each core histone H2A, H2B, H3, and H4. In addition, although not an intrinsic component of the nucleosome core particle, linker histone H1 directly interacts with it in a monomeric form. Histone H1 binds nucleosomes near the exit/entry sites of linker DNA, determines nucleosome repeat length and stabilizes higher-order organization of nucleosomes into the ∼30 nm chromatin fiber. In comparison to core histones, histone H1 is less well conserved through evolution. Furthermore, histone H1 composition in metazoans is generally complex with most species containing multiple variants that play redundant as well as specific functions. In this regard, a characteristic feature is the presence of specific H1 variants that replace somatic H1s in the germline and during early embryogenesis. In this review, we summarize our current knowledge about their structural and functional properties.

Generation of SV40-transformed rabbit tracheal-epithelial-cell-derived blastocyst by somatic cell nuclear transfer

PubMed Central

de Semir, D.; Maurisse, R.; Du, F.; Xu, J.; Yang, X.; Illek, B.; Gruenert, D. C.

2013-01-01

The prospect of developing large animal models for the study of inherited diseases, such as cystic fibrosis (CF), through somatic cell nuclear transfer (SCNT) has opened up new opportunities for enhancing our understanding of disease pathology and for identifying new therapies. Thus, the development of species-specific in vitro cell systems that will provide broader insight into organ- and cell-type-specific functions relevant to the pathology of the disease is crucial. Studies have been undertaken to establish transformed rabbit airway epithelial cell lines that display differentiated features characteristic of the primary airway epithelium. This study describes the successful establishment and characterization of two SV40-transformed rabbit tracheal epithelial cell lines. These cell lines, 5RTEo- and 9RTEo-, express the CF transmembrane conductance regulator (CFTR) gene, retain epithelial-specific differentiated morphology and show CFTR-based cAMP-dependent Cl− ion transport across the apical membrane of a confluent monolayer. Immunocytochemical analysis indicates the presence of airway cytokeratins and tight-junction proteins in the 9RTEo- cell line after multiple generations. However, the tight junctions appear to diminish in their efficacy in both cell lines after at least 100 generations. Initial SCNT studies with the 9RTEo- cells have revealed that SV40-transformed rabbit airway epithelial donor cells can be used to generate blastocysts. These cell systems provide valuable models for studying the developmental and metabolic modulation of CFTR gene expression and rabbit airway epithelial cell biology. PMID:22234514

Accelerated appearance of multiple B cell lymphoma types in NFS/N mice congenic for ecotropic murine leukemia viruses.

PubMed

Hartley, J W; Chattopadhyay, S K; Lander, M R; Taddesse-Heath, L; Naghashfar, Z; Morse, H C; Fredrickson, T N

2000-02-01

Spontaneous lymphomas occur at high frequency in NFS x V+ mice, strains congenic for ecotropic murine leukemia virus (MuLV) proviral genes and expressing virus at high titer. In the present study, a total of 703 NFS x V+ lymphomas were studied by histopathology, immunophenotypic analysis, immunoglobulin heavy chain or T cell receptor beta chain rearrangements, and somatic ecotropic MuLV integrations; 90% of the lymphomas tested were of B cell lineage. Low-grade tumors included small lymphocytic, follicular, and splenic marginal zone lymphomas, while high-grade tumors comprised diffuse large-cell (centroblastic and immunoblastic types), splenic marginal zone, and lymphoblastic lymphomas. Comparison of mice of similar genetic background except for presence (NFS x V+) or absence (NFS x V-) of functional ecotropic MuLV genomes showed that NFS x V-clonal lymphomas developed at about one-half the rate of those occurring in NFS x V+ mice, and most were low-grade B cell lymphomas with extended latent periods. In NFS x V+ mice, clonal outgrowth, defined by Ig gene rearrangements, was associated with acquisition of somatic ecotropic proviral integrations, suggesting that, although generation of B cell clones can be virus independent, ecotropic virus may act to increase the rate of generation of clones and speed their evolution to lymphoma. The mechanism remains undefined, because only rare rearrangements were detected in several cellular loci previously associated with MuLV insertional mutagenesis.

The physiological basis of complementary and alternative medicines for polycystic ovary syndrome.

PubMed

Raja-Khan, Nazia; Stener-Victorin, Elisabet; Wu, XiaoKe; Legro, Richard S

2011-07-01

Polycystic ovary syndrome (PCOS) is a common endocrine disorder that is characterized by chronic hyperandrogenic anovulation leading to symptoms of hirsutism, acne, irregular menses, and infertility. Multiple metabolic and cardiovascular risk factors are associated with PCOS, including insulin resistance, obesity, type 2 diabetes, hypertension, inflammation, and subclinical atherosclerosis. However, current treatments for PCOS are only moderately effective at controlling symptoms and preventing complications. This article describes how the physiological effects of major complementary and alternative medicine (CAM) treatments could reduce the severity of PCOS and its complications. Acupuncture reduces hyperandrogenism and improves menstrual frequency in PCOS. Acupuncture's clinical effects are mediated via activation of somatic afferent nerves innervating the skin and muscle, which, via modulation of the activity in the somatic and autonomic nervous system, may modulate endocrine and metabolic functions in PCOS. Chinese herbal medicines and dietary supplements may also exert beneficial physiological effects in PCOS, but there is minimal evidence that these CAM treatments are safe and effective. Mindfulness has not been investigated in PCOS, but it has been shown to reduce psychological distress and exert positive effects on the central and autonomic nervous systems, hypothalamic-pituitary-adrenal axis, and immune system, leading to reductions in blood pressure, glucose, and inflammation. In conclusion, CAM treatments may have beneficial endocrine, cardiometabolic, and reproductive effects in PCOS. However, most studies of CAM treatments for PCOS are small, nonrandomized, or uncontrolled. Future well-designed studies are needed to further evaluate the safety, effectiveness, and mechanisms of CAM treatments for PCOS.

Access to primary and specialized somatic health care for persons with severe mental illness: a qualitative study of perceived barriers and facilitators in Swedish health care.

PubMed

Björk Brämberg, Elisabeth; Torgerson, Jarl; Norman Kjellström, Anna; Welin, Peder; Rusner, Marie

2018-01-09

Persons with severe mental illness (e.g. schizophrenia, bipolar disorder) have a high prevalence of somatic conditions compared to the general population. Mortality data in the Nordic countries reveal that these persons die 15-20 years earlier than the general population. Some factors explaining this high prevalence may be related to the individuals in question; others arise from the health care system's difficulty in offering somatic health care to these patient groups. The aim of the present study was therefore to explore the experiences and views of patients, relatives and clinicians regarding individual and organizational factors which facilitate or hinder access to somatic health care for persons with severe mental illness. Flexible qualitative design. Data was collected by means of semi-structured individual interviews with patients with severe mental illness, relatives and clinicians representing primary and specialized health care. In all, 50 participants participated. The main barrier to accessing somatic care is the gap between the organization of the health care system and the patients' individual health care needs. This is observed at both individual and organizational level. The health care system seems unable to support patients with severe mental illness and their psychiatric-somatic comorbidity. The main facilitators are the links between severe mental illness patients and medical departments. These links take the form of functions (i.e. systems which ensure that patients receive regular reminders), or persons (i.e. professional contacts who facilitate patients' access the health care). Health care services for patients with severe mental illness need reorganization. Organizational structures and systems that facilitate cooperation between different departments must be put in place, along with training for health care professionals about somatic disease among psychiatric patients. The links between individual and organizational levels could be strengthened by introducing professional contacts, such as liaison physicians and case managers. This is also important to reduce stress and responsibility among relatives.

Psychometric Analysis of the Heart Failure Somatic Perception Scale as a Measure of Patient Symptom Perception.

PubMed

Jurgens, Corrine Y; Lee, Christopher S; Riegel, Barbara

Symptoms are known to predict survival among patients with heart failure (HF), but discrepancies exist between patients' and health providers' perceptions of HF symptom burden. The purpose of this study is to quantify the internal consistency, validity, and prognostic value of patient perception of a broad range of HF symptoms using an HF-specific physical symptom measure, the 18-item HF Somatic Perception Scale v. 3. Factor analysis of the HF Somatic Perception Scale was conducted in a convenience sample of 378 patients with chronic HF. Convergent validity was examined using the Physical Limitation subscale of the Kansas City Cardiomyopathy Questionnaire. Divergent validity was examined using the Self-care of HF Index self-care management score. One-year survival based on HF Somatic Perception Scale scores was quantified using Cox regression controlling for Seattle HF Model scores to account for clinical status, therapeutics, and lab values. The sample was 63% male, 85% white, 67% functionally compromised (New York Heart Association class III-IV) with a mean (SD) age of 63 (12.8) years. Internal consistency of the HF Somatic Perception Scale was α = .90. Convergent (r = -0.54, P < .0001) and divergent (r = 0.18, P > .05) validities were supported. Controlling for Seattle HF scores, HF Somatic Perception Scale was a significant predictor of 1-year survival, with those most symptomatic having worse survival (hazard ratio, 1.012; 95% confidence interval, 1.001-1.024; P = .038). Perception of HF symptom burden as measured by the HF Somatic Perception Scale is a significant predictor of survival, contributing additional prognostic value over and above objective Seattle HF Risk Model scores. This analysis suggests that assessment of a broad range of HF symptoms, or those related to dyspnea or early and subtle symptoms, may be useful in evaluating therapeutic outcomes and predicting event-free survival.

The Aging Lacrimal Gland: Changes in Structure and Function

PubMed Central

Rocha, Eduardo M.; Alves, Monica; Rios, J. David; Dartt, Darlene A.

2014-01-01

The afferent nerves of the cornea and conjunctiva, efferent nerves of the lacrimal gland, and the lacrimal gland are a functional unit that works cooperatively to produce the aqueous component of tears. A decrease in the lacrimal gland secretory function can lead to dry eye disease. Because aging is a risk factor for dry eye disease, study of the changes in the function of the lacrimal gland functional unit with age is important for developing treatments to prevent dry eye disease. No one mechanism is known to induce the changes that occur with aging, although multiple different mechanisms have been associated with aging. These fall into two theoretical categories: programmed theories of aging (immunological, genetic, apoptotic, and neuroendocrine) and error theories of aging (protein alteration, somatic mutation, etc). Lacrimal glands undergo structural and functional alteration with increasing age. In mouse models of aging, it has been shown that neural stimulation of protein secretion is an early target of aging, accompanied by an increase in mast cells and lipofuscin accumulation. Hyperglycemia and increased lymphocytic infiltration can contribute to this loss of function at older ages. These findings suggest that an increase in oxidative stress may play a role in the loss of lacrimal gland function with age. For the afferent and efferent neural components of the lacrimal gland functional unit, immune or inflammatory mediated decrease in nerve function could contribute to loss of lacrimal gland secretion with age. More research in this area is critically needed. PMID:18827949

The aging lacrimal gland: changes in structure and function.

PubMed

Rocha, Eduardo M; Alves, Monica; Rios, J David; Dartt, Darlene A

2008-10-01

The afferent nerves of the cornea and conjunctiva, efferent nerves of the lacrimal gland, and the lacrimal gland are a functional unit that works cooperatively to produce the aqueous component of tears. A decrease in the lacrimal gland secretory function can lead to dry eye disease. Because aging is a risk factor for dry eye disease, study of the changes in the function of the lacrimal gland functional unit with age is important for developing treatments to prevent dry eye disease. No one mechanism is known to induce the changes that occur with aging, although multiple different mechanisms have been associated with aging. These fall into two theoretical categories: programmed theories of aging (immunological, genetic, apoptotic, and neuroendocrine) and error theories of aging (protein alteration, somatic mutation, etc). Lacrimal glands undergo structural and functional alteration with increasing age. In mouse models of aging, it has been shown that neural stimulation of protein secretion is an early target of aging, accompanied by an increase in mast cells and lipofuscin accumulation. Hyperglycemia and increased lymphocytic infiltration can contribute to this loss of function at older ages. These findings suggest that an increase in oxidative stress may play a role in the loss of lacrimal gland function with age. For the afferent and efferent neural components of the lacrimal gland functional unit, immune or inflammatory mediated decrease in nerve function could contribute to loss of lacrimal gland secretion with age. More research in this area is critically needed.

Comment on "Evidence for mesothermy in dinosaurs".

PubMed

Myhrvold, Nathan P

2015-05-29

Grady et al. (Reports, 13 June 2014, p. 1268) studied dinosaur metabolism by comparison of maximum somatic growth rate allometry with groups of known metabolism. They concluded that dinosaurs exhibited mesothermy, a metabolic rate intermediate between endothermy and ectothermy. Multiple statistical and methodological issues call into question the evidence for dinosaur mesothermy. Copyright © 2015, American Association for the Advancement of Science.

Multiplex Droplet Digital PCR Quantification of Recurrent Somatic Mutations in Diffuse Large B-Cell and Follicular Lymphoma.

PubMed

Alcaide, Miguel; Yu, Stephen; Bushell, Kevin; Fornika, Daniel; Nielsen, Julie S; Nelson, Brad H; Mann, Koren K; Assouline, Sarit; Johnson, Nathalie A; Morin, Ryan D

2016-09-01

A plethora of options to detect mutations in tumor-derived DNA currently exist but each suffers limitations in analytical sensitivity, cost, or scalability. Droplet digital PCR (ddPCR) is an appealing technology for detecting the presence of specific mutations based on a priori knowledge and can be applied to tumor biopsies, including formalin-fixed paraffin embedded (FFPE) tissues. More recently, ddPCR has gained popularity in its utility in quantifying circulating tumor DNA. We have developed a suite of novel ddPCR assays for detecting recurrent mutations that are prevalent in common B-cell non-Hodgkin lymphomas (NHLs), including diffuse large B-cell lymphoma, follicular lymphoma, and lymphoplasmacytic lymphoma. These assays allowed the differentiation and counting of mutant and wild-type molecules using one single hydrolysis probe. We also implemented multiplexing that allowed the simultaneous detection of distinct mutations and an "inverted" ddPCR assay design, based on employing probes matching wild-type alleles, capable of detecting the presence of multiple single nucleotide polymorphisms. The assays successfully detected and quantified somatic mutations commonly affecting enhancer of zeste 2 polycomb repressive complex 2 subunit (EZH2) (Y641) and signal transducer and activator of transcription 6 (STAT6) (D419) hotspots in fresh tumor, FFPE, and liquid biopsies. The "inverted" ddPCR approach effectively reported any single nucleotide variant affecting either of these 2 hotspots as well. Finally, we could effectively multiplex hydrolysis probes targeting 2 additional lymphoma-related hotspots: myeloid differentiation primary response 88 (MYD88; L265P) and cyclin D3 (CCND3; I290R). Our suite of ddPCR assays provides sufficient analytical sensitivity and specificity for either the invasive or noninvasive detection of multiple recurrent somatic mutations in B-cell NHLs. © 2016 American Association for Clinical Chemistry.

Restriction of the Xenopus DEADSouth mRNA to the primordial germ cells is ensured by multiple mechanisms.

PubMed

Yamaguchi, Takeshi; Kataoka, Kensuke; Watanabe, Kenji; Orii, Hidefumi

2014-02-01

DEADSouth mRNA encoding the RNA helicase DDX25 is a component of the germ plasm in Xenopus laevis. We investigated the mechanisms underlying its specific mRNA expression in primordial germ cells (PGCs). Based on our previous findings of several microRNA miR-427 recognition elements (MREs) in the 3' untranslated region of the mRNA, we first examined whether DEADSouth mRNA was degraded by miR-427 targeting in somatic cells. Injection of antisense miR-427 oligomer and reporter mRNA for mutated MREs revealed that DEADSouth mRNA was potentially degraded in somatic cells via miR-427 targeting, but not in PGCs after the mid-blastula transition (MBT). The expression level of miR-427 was very low in PGCs, which probably resulted in the lack of miR-427-mediated degradation. In addition, the DEADSouth gene was expressed zygotically after MBT. Thus, the predominant expression of DEADSouth mRNA in the PGCs is ensured by multiple mechanisms including zygotic expression and prohibition from miR-427-mediated degradation. Copyright © 2013 Elsevier Ireland Ltd. All rights reserved.

Has the rolling uterus finally gathered moss? Somatization and malingering of cognitive deficit in six cases of "toxic mold" exposure.

PubMed

Stone, David C; Boone, Kyle B; Back-Madruga, Carla; Lesser, Ira M

2006-12-01

This article reports six cases of litigants claiming neuropsychiatric impairment due to toxic mold exposure. In spite of recent growth in personal injury claims due to mold, numerous reviews of the literature have failed to find an association between environmental exposure to mold and neuropsychiatric and/or neuropsychological damage. We report data on six patients claiming harm, 4 of whom revealed a long history of somatization by history and psychological testing, and 2 of whom were shown to be malingering based on multiple indicators of non-credible performance. Of the 6 patients, only the 2 somatoform patients who were also depressed showed credible evidence of neuropsychological dysfunction. We review two other studies that have examined the link between mold exposure and cognitive impairment and discuss their limitations in view of the presenting behaviors of these 6 patients. Until the literature has established a credible link between mold and neuropsychiatric/neuropsychological impairment, jurists and clinicians must consider the ethics and potential harm of exposing somatoform patients to multiple unwarranted medical evaluations. Principles for forensic evaluations in this special population are reviewed.

Acute myeloid leukaemia genomics.

PubMed

Medinger, Michael; Passweg, Jakob R

2017-11-01

Acute myeloid leukaemia (AML) is a biologically complex, molecularly and clinically heterogeneous disease. Despite major advances in understanding the genetic landscape of AML and its impact on the pathophysiology and biology of the disease, standard treatment options have not significantly changed during the past three decades. AML is characterized by multiple somatically acquired mutations that affect genes of different functional categories. Mutations in genes encoding epigenetic modifiers, such as DNMT3A, ASXL1, TET2, IDH1, and IDH2, are commonly acquired early and are present in the founding clone. By contrast, mutations involving NPM1 or signalling molecules (e.g., FLT3, RAS gene family) are typically secondary events that occur later during leukaemogenesis. This review aims to provide an overview of advances in new prognostic markers, including targetable mutations that will probably guide the development and use of novel molecularly targeted therapies. © 2017 John Wiley & Sons Ltd.

Genetic and epigenetic effects in sex determination.

PubMed

Gunes, Sezgin Ozgur; Metin Mahmutoglu, Asli; Agarwal, Ashok

2016-12-01

Sex determination is a complex and dynamic process with multiple genetic and environmental causes, in which germ and somatic cells receive various sex-specific features. During the fifth week of fetal life, the bipotential embryonic gonad starts to develop in humans. In the bipotential gonadal tissue, certain cell groups start to differentiate to form the ovaries or testes. Despite considerable efforts and advances in identifying the mechanisms playing a role in sex determination and differentiation, the underlying mechanisms of the exact functions of many genes, gene-gene interactions, and epigenetic modifications that are involved in different stages of this cascade are not completely understood. This review aims at discussing current data on the genetic effects via genes and epigenetic mechanisms that affect the regulation of sex determination. Birth Defects Research (Part C) 108:321-336, 2016. © 2016 Wiley Periodicals, Inc. © 2016 Wiley Periodicals, Inc.

Muscle stem cell dysfunction impairs muscle regeneration in a mouse model of Down syndrome.

PubMed

Pawlikowski, Bradley; Betta, Nicole Dalla; Elston, Tiffany; Williams, Darian A; Olwin, Bradley B

2018-03-09

Down syndrome, caused by trisomy 21, is characterized by a variety of medical conditions including intellectual impairments, cardiovascular defects, blood cell disorders and pre-mature aging phenotypes. Several somatic stem cell populations are dysfunctional in Down syndrome and their deficiencies may contribute to multiple Down syndrome phenotypes. Down syndrome is associated with muscle weakness but skeletal muscle stem cells or satellite cells in Down syndrome have not been investigated. We find that a failure in satellite cell expansion impairs muscle regeneration in the Ts65Dn mouse model of Down syndrome. Ts65Dn satellite cells accumulate DNA damage and over express Usp16, a histone de-ubiquitinating enzyme that regulates the DNA damage response. Impairment of satellite cell function, which further declines as Ts65Dn mice age, underscores stem cell deficiencies as an important contributor to Down syndrome pathologies.

Influence of race and crossbreeding on casein micelles size.

PubMed

Freitas, Denise R; Fonseca, Leorges M; Souza, Fernando N; Ladeira, Cristiane V G; Diniz, Soraia A; Haddad, João Paulo A; Ferreira, Diêgo S; Santoro, Marcelo M; Cerqueira, Mônica M O P

2015-05-01

Casein (CN) micelles are colloidal aggregates of protein dispersed in milk, the importance of which in the dairy industry is related to functionality and yield in dairy products. The objective of this work was to investigate the correlation of milk CN micelles diameter from Holstein and Zebu crossbreds with milk composition (protein, fat, lactose, total and nonfat solids and milk urea nitrogen), somatic cell count (SCC), age, lactation stage and production. Average casein micelles diameters of milk samples obtained from 200 cows were measured using photon correlation spectroscopy and multiple regression analysis was used to find relationship between variables. CN micelle diameter, SCC and nonfat solids were different between animals with different Holstein crossbreed ratios, which suggests influence of genetic factors, mammary gland health and milk composition. Overall, results indicate the potential use of CN micelle diameter as a tool to select animals to produce milk more suitable to cheese production. © 2014 Japanese Society of Animal Science.

Functional Organization of Neuronal and Humoral Signals Regulating Feeding Behavior

PubMed Central

Schwartz, Gary J.; Zeltser, Lori M.

2014-01-01

Energy homeostasis- ensuring that energy availability matches energy requirements- is essential for survival. One way that energy balance is achieved is through coordinated action of neural and neuroendocrine feeding circuits, which promote energy intake when energy supply is limited. Feeding behavior engages multiple somatic and visceral tissues distributed throughout the body – contraction of skeletal and smooth muscles in the head and along the upper digestive tract required to consume and digest food, as well as stimulation of endocrine and exocrine secretions from a wide range of organs. Accordingly, neurons that contribute to feeding behaviors are localized to central, peripheral and enteric nervous systems. To promote energy balance, feeding circuits must be able to identify and respond to energy requirements, as well as the amount of energy available from internal and external sources, and then direct appropriate coordinated responses throughout the body. PMID:23642202

Cell therapies: realizing the potential of this new dimension to medical therapeutics.

PubMed

Singh, Pawanbir; Williams, David J

2008-08-01

Stem cells promise to treat conditions poorly served by conventional therapeutics. Cells from both embryonic and somatic tissues are being used to create cell therapies for genetic, traumatic and degenerative conditions. The current human, healthcare and fiscal costs of these conditions are significant. This review summarizes the use of stem cells for neurological and cardiac disorders and diabetes to determine the requirements for generic translational research to assist such therapies to be a reality. While there are multiple strategies in each disease area, with no clear favourite, there are clear opportunities in treatments that use a single cell type. A key requirement is to work with pluripotent progenitor cells to cultivate and differentiate a sufficiently large population of functioning cells. Challenges also arise in determining and achieving timely delivery of the correct dose of cells to where they can most effectively treat the disease and best benefit individual patients. (c) 2008 John Wiley & Sons, Ltd.

EZH2 is required for germinal center formation and somatic EZH2 mutations promote lymphoid transformation

PubMed Central

Béguelin, Wendy; Popovic, Relja; Teater, Matt; Jiang, Yanwen; Bunting, Karen L.; Rosen, Monica; Shen, Hao; Yang, Shao Ning; Wang, Ling; Ezponda, Teresa; Martinez-Garcia, Eva; Zhang, Haikuo; Zhang, Yupeng; Verma, Sharad K.; McCabe, Michael T.; Ott, Heidi M.; Van Aller, Glenn S.; Kruger, Ryan G.; Liu, Yan; McHugh, Charles F.; Scott, David W.; Chung, Young Rock; Kelleher, Neil; Shaknovich, Rita; Creasy, Caretha L.; Gascoyne, Randy D.; Wong, Kwok-Kin; Cerchietti, Leandro C.; Levine, Ross L.; Abdel-Wahab, Omar; Licht, Jonathan D.; Elemento, Olivier; Melnick, Ari M.

2013-01-01

The EZH2 histone methyltransferase is highly expressed in germinal center (GC) B-cells and targeted by somatic mutations in B-cell lymphomas. Here we find that EZH2 deletion or pharmacologic inhibition suppresses GC formation and functions in mice. EZH2 represses proliferation checkpoint genes and helps establish bivalent chromatin domains at key regulatory loci to transiently suppress GC B-cell differentiation. Somatic mutations reinforce these physiological effects through enhanced silencing of EZH2 targets in B-cells, and in human B-cell lymphomas. Conditional expression of mutant EZH2 in mice induces GC hyperplasia and accelerated lymphomagenesis in cooperation with BCL2. GCB-type DLBCLs are mostly addicted to EZH2, regardless of mutation status, but not the more differentiated ABC-type DLBCLs, thus clarifying the therapeutic scope of EZH2 targeting. PMID:23680150

The actin-binding protein profilin is required for germline stem cell maintenance and germ cell enclosure by somatic cyst cells

PubMed Central

Shields, Alicia R.; Spence, Allyson C.; Yamashita, Yukiko M.; Davies, Erin L.; Fuller, Margaret T.

2014-01-01

Specialized microenvironments, or niches, provide signaling cues that regulate stem cell behavior. In the Drosophila testis, the JAK-STAT signaling pathway regulates germline stem cell (GSC) attachment to the apical hub and somatic cyst stem cell (CySC) identity. Here, we demonstrate that chickadee, the Drosophila gene that encodes profilin, is required cell autonomously to maintain GSCs, possibly facilitating localization or maintenance of E-cadherin to the GSC-hub cell interface. Germline specific overexpression of Adenomatous Polyposis Coli 2 (APC2) rescued GSC loss in chic hypomorphs, suggesting an additive role of APC2 and F-actin in maintaining the adherens junctions that anchor GSCs to the niche. In addition, loss of chic function in the soma resulted in failure of somatic cyst cells to maintain germ cell enclosure and overproliferation of transit-amplifying spermatogonia. PMID:24346697

Should general psychiatry ignore somatization and hypochondriasis?

PubMed

Creed, Francis

2006-10-01

This paper examines the tendency for general psychiatry to ignore somatization and hypochondriasis. These disorders are rarely included in national surveys of mental health and are not usually regarded as a concern of general psychiatrists; yet primary care doctors and other physicians often feel let down by psychiatry's failure to offer help in this area of medical practice. Many psychiatrists are unaware of the suffering, impaired function and high costs that can result from these disorders, because these occur mainly within primary care and secondary medical services. Difficulties in diagnosis and a tendency to regard them as purely secondary phenomena of depression, anxiety and related disorders mean that general psychiatry may continue to ignore somatization and hypochondriasis. If general psychiatry embraced these disorders more fully, however, it might lead to better prevention and treatment of depression as well as helping to prevent the severe disability that may arise in association with these disorders.

Should general psychiatry ignore somatization and hypochondriasis?

PubMed Central

CREED, FRANCIS

2006-01-01

This paper examines the tendency for general psychiatry to ignore somatization and hypochondriasis. These disorders are rarely included in national surveys of mental health and are not usually regarded as a concern of general psychiatrists; yet primary care doctors and other physicians often feel let down by psychiatry's failure to offer help in this area of medical practice. Many psychiatrists are unaware of the suffering, impaired function and high costs that can result from these disorders, because these occur mainly within primary care and secondary medical services. Difficulties in diagnosis and a tendency to regard them as purely secondary phenomena of depression, anxiety and related disorders mean that general psychiatry may continue to ignore somatization and hypochondriasis. If general psychiatry embraced these disorders more fully, however, it might lead to better prevention and treatment of depression as well as helping to prevent the severe disability that may arise in association with these disorders. PMID:17139341

The psychophysiology of crying.

PubMed

Gross, J J; Frederickson, B L; Levenson, R W

1994-09-01

Two conflicting views have emerged as to why people cry when they are sad. One suggests that crying serves homeostasis by facilitating recovery; the other suggests that crying produces an aversive high-arousal state that motivates behavior aimed at ending the tears. To test hypotheses drawn from these views, we showed a short film known to elicit sadness to 150 women. During this film, 33 subjects spontaneously cried and 117 did not. Subjects who cried exhibited more expressive behavior and reported feeling more sadness and pain than did subjects who did not cry. Crying also was associated with increases in somatic and autonomic nervous system activity. The increases in autonomic activity could not be accounted for solely by the increases in somatic activity. Crying is thus associated with an aversive state, including negative emotion and a complex mixture of sympathetic, parasympathetic, and somatic activation, and we speculate about the functional implications of these findings.

Combined multiphoton imaging and automated functional enucleation of porcine oocytes using femtosecond laser pulses

NASA Astrophysics Data System (ADS)

Kuetemeyer, Kai; Lucas-Hahn, Andrea; Petersen, Bjoern; Lemme, Erika; Hassel, Petra; Niemann, Heiner; Heisterkamp, Alexander

2010-07-01

Since the birth of ``Dolly'' as the first mammal cloned from a differentiated cell, somatic cell cloning has been successful in several mammalian species, albeit at low success rates. The highly invasive mechanical enucleation step of a cloning protocol requires sophisticated, expensive equipment and considerable micromanipulation skill. We present a novel noninvasive method for combined oocyte imaging and automated functional enucleation using femtosecond (fs) laser pulses. After three-dimensional imaging of Hoechst-labeled porcine oocytes by multiphoton microscopy, our self-developed software automatically identified the metaphase plate. Subsequent irradiation of the metaphase chromosomes with the very same laser at higher pulse energies in the low-density-plasma regime was used for metaphase plate ablation (functional enucleation). We show that fs laser-based functional enucleation of porcine oocytes completely inhibited the parthenogenetic development without affecting the oocyte morphology. In contrast, nonirradiated oocytes were able to develop parthenogenetically to the blastocyst stage without significant differences to controls. Our results indicate that fs laser systems have great potential for oocyte imaging and functional enucleation and may improve the efficiency of somatic cell cloning.

Blastocyst complementation generates exogenic pancreas in vivo in apancreatic cloned pigs

PubMed Central

Matsunari, Hitomi; Nagashima, Hiroshi; Watanabe, Masahito; Umeyama, Kazuhiro; Nakano, Kazuaki; Nagaya, Masaki; Kobayashi, Toshihiro; Yamaguchi, Tomoyuki; Sumazaki, Ryo; Herzenberg, Leonard A.; Nakauchi, Hiromitsu

2013-01-01

In the field of regenerative medicine, one of the ultimate goals is to generate functioning organs from pluripotent cells, such as ES cells or induced pluripotent stem cells (PSCs). We have recently generated functional pancreas and kidney from PSCs in pancreatogenesis- or nephrogenesis-disabled mice, providing proof of principle for organogenesis from PSCs in an embryo unable to form a specific organ. Key when applying the principles of in vivo generation to human organs is compensation for an empty developmental niche in large nonrodent mammals. Here, we show that the blastocyst complementation system can be applied in the pig using somatic cell cloning technology. Transgenic approaches permitted generation of porcine somatic cell cloned embryos with an apancreatic phenotype. Complementation of these embryos with allogenic blastomeres then created functioning pancreata in the vacant niches. These results clearly indicate that a missing organ can be generated from exogenous cells when functionally normal pluripotent cells chimerize a cloned dysorganogenetic embryo. The feasibility of blastocyst complementation using cloned porcine embryos allows experimentation toward the in vivo generation of functional organs from xenogenic PSCs in large animals. PMID:23431169

Blastocyst complementation generates exogenic pancreas in vivo in apancreatic cloned pigs.

PubMed

Matsunari, Hitomi; Nagashima, Hiroshi; Watanabe, Masahito; Umeyama, Kazuhiro; Nakano, Kazuaki; Nagaya, Masaki; Kobayashi, Toshihiro; Yamaguchi, Tomoyuki; Sumazaki, Ryo; Herzenberg, Leonard A; Nakauchi, Hiromitsu

2013-03-19

In the field of regenerative medicine, one of the ultimate goals is to generate functioning organs from pluripotent cells, such as ES cells or induced pluripotent stem cells (PSCs). We have recently generated functional pancreas and kidney from PSCs in pancreatogenesis- or nephrogenesis-disabled mice, providing proof of principle for organogenesis from PSCs in an embryo unable to form a specific organ. Key when applying the principles of in vivo generation to human organs is compensation for an empty developmental niche in large nonrodent mammals. Here, we show that the blastocyst complementation system can be applied in the pig using somatic cell cloning technology. Transgenic approaches permitted generation of porcine somatic cell cloned embryos with an apancreatic phenotype. Complementation of these embryos with allogenic blastomeres then created functioning pancreata in the vacant niches. These results clearly indicate that a missing organ can be generated from exogenous cells when functionally normal pluripotent cells chimerize a cloned dysorganogenetic embryo. The feasibility of blastocyst complementation using cloned porcine embryos allows experimentation toward the in vivo generation of functional organs from xenogenic PSCs in large animals.

DNMT1 Maintains Progenitor Function in Self-Renewing Somatic Tissue

PubMed Central

Sen, George L.; Reuter, Jason A.; Webster, Daniel E.; Zhu, Lilly; Khavari, Paul A.

2010-01-01

Progenitor cells maintain self-renewing tissues throughout life by sustaining their capacity for proliferation while suppressing cell cycle exit and terminal differentiation1,2. DNA methylation3,4,5 provides a potential epigenetic mechanism for the cellular memory needed to preserve the somatic progenitor state through repeated cell divisions. DNA methyltransferase 1 (DNMT1)6,7 maintains DNA methylation patterns after cellular replication. Although dispensable for embryonic stem cell maintenance,8 a clear role for DNMT1 in maintaining the progenitor state in constantly replenished somatic tissues, such as mammalian epidermis, is unknown. Here we show that DNMT1 is essential for epidermal progenitor cell function. DNMT1 protein was found enriched in undifferentiated cells, where it was required to retain proliferative stamina and suppress differentiation. In tissue, DNMT1 depletion led to exit from the progenitor cell compartment, premature differentiation and eventual tissue loss. Genome-wide analysis revealed that a significant portion of epidermal differentiation gene promoters were methylated in self-renewing conditions but were subsequently demethylated during differentiation. Furthermore, we show that UHRF1,9,10 a component of the DNA methylation machinery that targets DNMT1 to hemi-methylated DNA, is also necessary to suppress premature differentiation and sustain proliferation. In contrast, Gadd45A11,12 and B13, which promote active DNA demethylation, are required for full epidermal differentiation gene induction. These data demonstrate that proteins involved in the dynamic regulation of DNA methylation patterns are required for progenitor maintenance and self-renewal in mammalian somatic tissue. PMID:20081831

The impact of physical complaints, social environment, and psychological functioning on IBS patients' health perceptions: looking beyond GI symptom severity.

PubMed

Lackner, Jeffrey M; Gudleski, Gregory D; Thakur, Elyse R; Stewart, Travis J; Iacobucci, Gary J; Spiegel, Brennan Mr

2014-02-01

In the absence of a reliable biomarker, clinical decisions for a functional gastrointestinal (GI) disorder like irritable bowel syndrome (IBS) depend on asking patients to appraise and communicate their health status. Self-ratings of health (SRH) have proven a powerful and consistent predictor of health outcomes, but little is known about how they relate to those relevant to IBS (e.g., quality of life (QOL), IBS symptom severity). This study examined what psychosocial factors, if any, predict SRH among a cohort of more severe IBS patients. Subjects included 234 Rome III-positive IBS patients (mean age=41 years, female=78%) without comorbid organic GI disease. Subjects were administered a test battery that included the IBS Symptom Severity Scale, Screening for Somatoform Symptoms, IBS Medical Comorbidity Inventory, SF-12 Vitality Scale, Perceived Stress Scale, Beck Depression Inventory, Trait Anxiety Inventory, and Negative Interactions Scale. Partial correlations identified somatization, depression, fatigue, stress, anxiety, and medical comorbidities as variables with the strongest correlations with SRH (r values=0.36-0.41, P values <0.05). IBS symptom severity was weakly associated with SRH (r=0.18, P<0.05). The final regression model explained 41.3% of the variance in SRH scores (F=8.49, P<0.001) with significant predictors including fatigue, medical comorbidities, somatization, and negative social interactions. SRH are associated with psychological (anxiety, stress, depression), social (negative interactions), and extraintestinal somatic factors (fatigue, somatization, medical comorbidities). The severity of IBS symptoms appears to have a relatively modest role in how IBS patients describe their health in general.

Bone Metastasis in Prostate Cancer: Recurring Mitochondrial DNA Mutation Reveals Selective Pressure Exerted by the Bone Microenvironment

PubMed Central

Arnold, Rebecca S.; Fedewa, Stacey A.; Goodman, Michael; Osunkoya, Adeboye O.; Kissick, Haydn T.; Morrissey, Colm; True, Lawrence D.; Petros, John A.

2015-01-01

Background Cancer progression and metastasis occurs such that cells with acquired mutations enhancing growth and survival (or inhibiting cell death) increase in number, a concept that has been recognized as analogous to Darwinian evolution of species since Peter C. Nowell’s description in 1976. Selective forces include those intrinsic to the host (including metastatic site) as well as those resulting from anti-cancer therapies. By examining the mutational status of multiple tumor sites within an individual patient some insight may be gained into those genetic variants that enhance site-specific metastasis. By comparing these data across multiple individuals, recurrent patterns may identify alterations that are fundamental to successful site-specific metastasis. Methods We sequenced the mitochondrial genome in 10 prostate cancer patients with bone metastases enrolled in a rapid autopsy program. Patients had late stage disease and received androgen ablation and frequently other systemic therapies. For each of 9 patients, 4 separate tissues were sequenced: the primary prostate cancer, a soft tissue metastasis, a bone metastasis and an uninvolved normal tissue that served as the non-cancerous control. An additional (10th) patient had no primary prostate available for sequencing but had both metastatic sites (and control DNA) sequenced. We then examined the number and location of somatically acquired mitochondrial DNA (mtDNA) mutations in the primary and two metastatic sites in each individual patient. Finally, we compared patients with each other to determine any common patterns of somatic mutation. Results Somatic mutations were significantly more numerous in bone compared to either the primary tumor or soft tissue metastases. A missense mutation at nucleotide position (np) 10398 (A10398G; Thr114Ala) in the respiratory complex I gene ND3 was the most common (7 of 10 patients) and was detected only in bone. Other notable somatic mutations that occurred in more than one patient include a tRNA Arg mutation at np 10436 and a tRNA Thr mutation at np 15928. The tRNA Arg mutation was restricted to bone metastases and occurred in three of 10 patients (30%). Somatic mutation at 15928 was not restricted to bone and also occurred in three patients. Conclusions Mitochondrial genomic variation was greater in metastatic sites than the primary tumor and bone metastases had statistically significantly greater numbers of somatic mutations than either the primary or the soft tissue metastases. The genome was not mutated randomly. At least one mutational “hot-spot” was identified at the individual base level (nucleotide position 10398 in bone metastases) indicating a pervasive selective pressure for bone metastatic cells that had acquired the 10398 mtDNA mutation. Two additional recurrent mutations (tRNA Arg and tRNA Thr) support the concept of bone site-specific “survival of the fittest” as revealed by variation in the mitochondrial genome and selective pressure exerted by the metastatic site. PMID:25952970

Bone metastasis in prostate cancer: Recurring mitochondrial DNA mutation reveals selective pressure exerted by the bone microenvironment.

PubMed

Arnold, Rebecca S; Fedewa, Stacey A; Goodman, Michael; Osunkoya, Adeboye O; Kissick, Haydn T; Morrissey, Colm; True, Lawrence D; Petros, John A

2015-09-01

Cancer progression and metastasis occur such that cells with acquired mutations enhancing growth and survival (or inhibiting cell death) increase in number, a concept that has been recognized as analogous to Darwinian evolution of species since Peter C. Nowell's description in 1976. Selective forces include those intrinsic to the host (including metastatic site) as well as those resulting from anti-cancer therapies. By examining the mutational status of multiple tumor sites within an individual patient some insight may be gained into those genetic variants that enhance site-specific metastasis. By comparing these data across multiple individuals, recurrent patterns may identify alterations that are fundamental to successful site-specific metastasis. We sequenced the mitochondrial genome in 10 prostate cancer patients with bone metastases enrolled in a rapid autopsy program. Patients had late stage disease and received androgen ablation and frequently other systemic therapies. For each of 9 patients, 4 separate tissues were sequenced: the primary prostate cancer, a soft tissue metastasis, a bone metastasis and an uninvolved normal tissue that served as the non-cancerous control. An additional (10th) patient had no primary prostate available for sequencing but had both metastatic sites (and control DNA) sequenced. We then examined the number and location of somatically acquired mitochondrial DNA (mtDNA) mutations in the primary tumor and two metastatic sites in each individual patient. Finally, we compared patients with each other to determine any common patterns of somatic mutation. Somatic mutations were significantly more numerous in the bone compared to either the primary tumor or soft tissue metastases. A missense mutation at nucleotide position (n.p.) 10398 (A10398G; Thr114Ala) in the respiratory complex I gene ND3 was the most common (7 of 10 patients) and was detected only in the bone. Other notable somatic mutations that occurred in more than one patient include a tRNA Arg mutation at n.p. 10436 and a tRNA Thr mutation at n.p. 15928. The tRNA Arg mutation was restricted to bone metastases and occurred in three of 10 patients (30%). Somatic mutation at 15928 was not restricted to the bone and also occurred in three patients. Mitochondrial genomic variation was greater in metastatic sites than in the primary tumor and bone metastases had statistically significantly greater numbers of somatic mutations than either the primary or the soft tissue metastases. The genome was not mutated randomly. At least one mutational "hot-spot" was identified at the individual base level (nucleotide position 10398 in bone metastases) indicating a pervasive selective pressure for bone metastatic cells that had acquired the 10398 mtDNA mutation. Two additional recurrent mutations (tRNA Arg and tRNA Thr) support the concept of bone site-specific "survival of the fittest" as revealed by variation in the mitochondrial genome and selective pressure exerted by the metastatic site. Published by Elsevier Inc.

Somatization: the under-recognized factor in nonspecific eczema. The Hordaland Health Study (HUSK).

PubMed

Klokk, M; Stansfeld, S; Overland, S; Wilhelmsen, I; Gotestam, K G; Steinshamn, S; Mykletun, A

2011-03-01

Psychodermatology has focused primarily on depression and anxiety in eczema. Skin symptoms are listed among many others for the ICD-10 diagnosis of somatization disorder. Somatization (unexplained somatic symptoms) is highly prevalent in the general population, but its association with eczema is yet to be empirically investigated. We therefore explored the association between somatization and eczema by examining the extent of somatization in eczema compared with allergic rhinitis, and by examining if eczema was more strongly associated with somatization than with anxiety and depression. Finally, we aimed to examine the relationship between the site of eczema and somatization for individual somatic symptoms and for somatic symptoms as a whole. For this population-based cross-sectional study we employed data from the Hordaland Health Study (HUSK) with 15,225 participants aged 41-48 years. Information on nonspecific eczema, allergic rhinitis, somatization, anxiety, depression and other covariates was obtained by self-report. The association between nonspecific eczema and somatization was strong and followed a dose-response pattern, as did all somatic symptoms in our index of somatization when analysed separately. The association between nonspecific eczema and somatization was stronger than that between rhinitis and somatization, and also the association between nonspecific eczema and anxiety and depression. In multivariate models, somatization accounted for most of the association between nonspecific eczema and anxiety/depression. In contrast, the association between nonspecific eczema and somatization was robust for adjustment for anxiety/depression. Somatization was strongly associated with nonspecific eczema. This applies to a whole range of somatic symptoms constituting the construct of somatization. There is hardly any mention of somatization in leading dermatological journals, in contrast to anxiety and depression which are frequently reported in eczema. We speculate that this under-recognition of somatization in the dermatological literature may correspond to under-recognition of this factor also in clinical practice. © 2011 The Authors. BJD © 2011 British Association of Dermatologists.

Child behavior check list and Korean personality inventory for children with functional visual loss.

PubMed

Kyung, Sung Eun; Lee, Sang Mi; Lim, Myung Ho

2014-08-01

To investigate the clinical psychiatric characteristics of children with the main complaint of functional visual loss, their behavior and personality were evaluated by the means of the Korean child behavior check list (K-CBCL), and the Korean personality inventory for children (KPI-C). The evaluation was carried out by the K-CBCL and the KPI-C, the domestically standardized tools, with 20 child subjects suspected of functional visual loss, among the patients who visited our hospital, between August, 2005 and December, 2012. The control group included 160 children in general schools of the same region. The 20 patients whose main complaint was functional visual loss were diagnosed as having a functional visual disorder. The child patient group showed a higher score for the K-CBCL and KPI-C sub-scales of somatic complaints, social problems, aggressive behavior, internalizing problems, externalizing problems, total behavioral problems, somatization and hyperactivity, than that of the control group. The results of the K-CBCL and KPI-C tests among children with functional visual loss, were significantly different from those of the normal control group. This result suggested that psychological factors may influence children with a main complaint of functional visual loss.

Ethnic and generational influences on emotional distress and risk behaviors among Chinese and Filipino American adolescents.

PubMed

Willgerodt, Mayumi Anne; Thompson, Elaine Adams

2006-08-01

The purpose of this study was to explore ethnic and generational influences among Chinese, Filipino, and Euro American adolescents on emotional distress and risk behaviors. Hierarchical multiple regression analyses were conducted with 216 Chinese, 387 Filipino, and 400 Euro American adolescents from the National Longitudinal Study on Adolescent Health to investigate the influence of ethnicity on depression, somatic symptoms, delinquency, and substance use; and to examine the influence of generation on the outcome variables among Chinese and Filipino American adolescents. Ethnicity predicted depression and delinquency scores, while generation within ethnic groups predicted somatic symptoms and substance use. The findings diverge from theories using acculturation as an explanatory mechanism for distress and risk behaviors and underscore the importance of examining sub-groups and generations of Asian American youth. Copyright 2006 Wiley Periodicals, Inc.

Cognitive functioning in young children with type 1 diabetes.

PubMed

Cato, M Allison; Mauras, Nelly; Ambrosino, Jodie; Bondurant, Aiden; Conrad, Amy L; Kollman, Craig; Cheng, Peiyao; Beck, Roy W; Ruedy, Katrina J; Aye, Tandy; Reiss, Allan L; White, Neil H; Hershey, Tamara

2014-02-01

The aim of this study was to assess cognitive functioning in children with type 1 diabetes (T1D) and examine whether glycemic history influences cognitive function. Neuropsychological evaluation of 216 children (healthy controls, n = 72; T1D, n = 144) ages 4-10 years across five DirecNet sites. Cognitive domains included IQ, Executive Functions, Learning and Memory, and Processing Speed. Behavioral, mood, parental IQ data, and T1D glycemic history since diagnosis were collected. The cohorts did not differ in age, gender or parent IQ. Median T1D duration was 2.5 years and average onset age was 4 years. After covarying age, gender, and parental IQ, the IQ and the Executive Functions domain scores trended lower (both p = .02, not statistically significant adjusting for multiple comparisons) with T1D relative to controls. Children with T1D were rated by parents as having more depressive and somatic symptoms (p < .001). Learning and memory (p = .46) and processing speed (p = .25) were similar. Trends in the data supported that the degree of hyperglycemia was associated with Executive Functions, and to a lesser extent, Child IQ and Learning and Memory. Differences in cognition are subtle in young children with T1D within 2 years of onset. Longitudinal evaluations will help determine whether these findings change or become more pronounced with time.

Cognitive functioning in young children with type 1 diabetes

PubMed Central

Cato, M. Allison; Mauras, Nelly; Ambrosino, Jodie; Bondurant, Aiden; Conrad, Amy L.; Kollman, Craig; Cheng, Peiyao; Beck, Roy W.; Ruedy, Katrina J.; Aye, Tandy; Reiss, Allan L.; White, Neil H.; Hershey, Tamara

2014-01-01

Objective To assess cognitive functioning in children with type 1 diabetes (T1D) and examine whether glycemic history influences cognitive function. Research Design and Methods Neuropsychological evaluation of 216 children (healthy controls, n = 72; T1D, n = 144) ages 4-10yrs across five DirecNet sites. Cognitive domains included IQ, Executive Functions, Learning and Memory, and Processing Speed. Behavioral, mood, parental IQ data and T1D glycemic history since diagnosis were collected. Results The cohorts did not differ in age, gender or parent IQ. Median T1D duration was 2.5yrs and average onset age was 4yrs. After covarying age, gender, and parental IQ, the IQ and the Executive Functions domain scores trended lower (both p = .02, not statistically significant adjusting for multiple comparisons) with T1D relative to controls. Children with T1D were rated by parents as having more depressive and somatic symptoms (p < 0.001). Learning and memory (p = 0.46) and processing speed (p = 0.25) were similar. Trends in the data supported that the degree of hyperglycemia was associated with Executive Functions, and to a lesser extent, Child IQ and Learning and Memory. Conclusions Differences in cognition are subtle in young children with T1D within 2 years of onset. Longitudinal evaluations will help determine whether these findings change or become more pronounced with time. PMID:24512675

Health costs of reproduction are minimal despite high fertility, mortality and subsistence lifestyle.

PubMed

Gurven, Michael; Costa, Megan; Ben Trumble; Stieglitz, Jonathan; Beheim, Bret; Eid Rodriguez, Daniel; Hooper, Paul L; Kaplan, Hillard

2016-07-20

Women exhibit greater morbidity than men despite higher life expectancy. An evolutionary life history framework predicts that energy invested in reproduction trades-off against investments in maintenance and survival. Direct costs of reproduction may therefore contribute to higher morbidity, especially for women given their greater direct energetic contributions to reproduction. We explore multiple indicators of somatic condition among Tsimane forager-horticulturalist women (Total Fertility Rate = 9.1; n =  592 aged 15-44 years, n = 277 aged 45+). We test whether cumulative live births and the pace of reproduction are associated with nutritional status and immune function using longitudinal data spanning 10 years. Higher parity and faster reproductive pace are associated with lower nutritional status (indicated by weight, body mass index, body fat) in a cross-section, but longitudinal analyses show improvements in women's nutritional status with age. Biomarkers of immune function and anemia vary little with parity or pace of reproduction. Our findings demonstrate that even under energy-limited and infectious conditions, women are buffered from the potential depleting effects of rapid reproduction and compound offspring dependency characteristic of human life histories.

Targeted therapy according to next generation sequencing-based panel sequencing.

PubMed

Saito, Motonobu; Momma, Tomoyuki; Kono, Koji

2018-04-17

Targeted therapy against actionable gene mutations shows a significantly higher response rate as well as longer survival compared to conventional chemotherapy, and has become a standard therapy for many cancers. Recent progress in next-generation sequencing (NGS) has enabled to identify huge number of genetic aberrations. Based on sequencing results, patients recommend to undergo targeted therapy or immunotherapy. In cases where there are no available approved drugs for the genetic mutations detected in the patients, it is recommended to be facilitate the registration for the clinical trials. For that purpose, a NGS-based sequencing panel that can simultaneously target multiple genes in a single investigation has been used in daily clinical practice. To date, various types of sequencing panels have been developed to investigate genetic aberrations with tumor somatic genome variants (gain-of-function or loss-of-function mutations, high-level copy number alterations, and gene fusions) through comprehensive bioinformatics. Because sequencing panels are efficient and cost-effective, they are quickly being adopted outside the lab, in hospitals and clinics, in order to identify personal targeted therapy for individual cancer patients.

Diagnostic criteria for psychosomatic research and somatic symptom disorders.

PubMed

Sirri, Laura; Fava, Giovanni A

2013-02-01

The Diagnostic Criteria for Psychosomatic Research (DCPR) were introduced in 1995 by an international group of investigators to expand the traditional domains of the disease model. The DCPR are a set of 12 'psychosomatic syndromes' which provide operational tools for psychosocial variables with prognostic and therapeutic implications in clinical settings. Eight syndromes concern the main manifestations of abnormal illness behaviour: somatization, hypochondriacal fears and beliefs, and illness denial. The other four syndromes (alexithymia, type A behaviour, demoralization and irritable mood) refer to the domain of psychological factors affecting medical conditions. This review describes the conceptual bases of the DCPR and the main findings concerning their application, with particular reference to the incremental information they added to the customary psychiatric classification. The DCPR were also compared with the provisional DSM-5 somatic symptom disorders. The DCPR were found to be more sensitive than DSM-IV in identifying subthreshold psychological distress and characterizing patients' psychological response to medical illness. DSM-5 somatic symptom disorders seem to neglect important clinical phenomena, such as illness denial, resulting in a narrow view of patients' functioning. The additional information provided by the DCPR may enhance the decision-making process.

Aerobic Exercise Reduces Symptoms of Posttraumatic Stress Disorder: A Randomized Controlled Trial.

PubMed

Fetzner, Mathew G; Asmundson, Gordon J G

2015-01-01

Evidence suggests aerobic exercise has anxiolytic effects; yet, the treatment potential for posttraumatic stress disorder (PTSD) and responsible anxiolytic mechanisms have received little attention. Emerging evidence indicates that attentional focus during exercise may dictate the extent of therapeutic benefit. Whether benefits are a function of attentional focus toward or away from somatic arousal during exercise remains untested. Thirty-three PTSD-affected participants completed two weeks of stationary biking aerobic exercise (six sessions). To assess the effect of attentional focus, participants were randomized into three exercise groups: group 1 (attention to somatic arousal) received prompts directing their attention to the interoceptive effects of exercise, group 2 (distraction from somatic arousal) watched a nature documentary, and group 3 exercised with no distractions or interoceptive prompts. Hierarchal linear modeling showed all groups reported reduced PTSD and anxiety sensitivity (AS; i.e., fear of arousal-related somatic sensations) during treatment. Interaction effects between group and time were found for PTSD hyperarousal and AS physical and social scores, wherein group 1, receiving interoceptive prompts, experienced significantly less symptom reduction than other groups. Most participants (89%) reported clinically significant reductions in PTSD severity after the two-week intervention. Findings suggest, regardless of attentional focus, aerobic exercise reduces PTSD symptoms.

The critical role of psychosomatics in promoting a new perspective upon health and disease.

PubMed

Dragoş, Dorin; Tănăsescu, Maria Daniela

2009-01-01

In an evolutionary model, health and disease are regarded as successful and respectively failed adaptation to the demands of the environment. The social factors are critical for a successful adaptation, while emotions are means of both signaling the organism's state and of adapting the physiological responses to environmental challenges. Hence the importance of a biopsychosocial model of health and disease. Psychoemotional distress generates and/or amplifies somatic symptoms. Somatization may be viewed as an altered cognitive process, inclining the individual to an augmented perception of bodily sensations and to an increased degree of complexity in reporting negative experiences (hence the greater cognitive effort allocated thereto). Somatosensory amplification and alexithymia are key elements in this process. The brain's right hemisphere is more involved in the generation of emotionally conditioned somatization symptoms. Somatic symptoms have various psychological and social functions and are strongly influenced by the particular belief system of the individual. Inappropriately perceiving the environment as an aggressor and excessively responding to it (by activating the cytokine system in correlation with the arousal of the psychic, nervous, and endocrine systems) may be a key element in the altered cognition conducive to ill health.

[The correlations of somatic, dermatoglyphic and psychological characteristics in the structure of general human constitution from the standpoint of systemic approach].

PubMed

Negasheva, M A

2008-01-01

669 young men and women aged 16-23 years were examined using a program including the measurements of 40 body, head and face parameters, fingerprinting and determination of personal psychological characteristics. On the basis of the study of the correlations between the different groups of characteristics, the evidence was obtained that supports the concept of a relative autonomy of the morpho-functional systems as an essential condition for the integrity of the organism as a whole. The coefficients of canonical correlation were calculated between the somatic and dermatoglyphic features (R=0.3), somatic sizes and psychological personality characteristics (R=0.4), psychological characteristics and the dermatoglyphic indices (R=0.4). An original model is suggested that describes the correlations of somatic, dermatoglyphic and psychological features in the structure of general human constitution on the basis of statistically significant canonical correlations (revealed by the author) and that takes in consideration the degree of the influence of genetic and social-economic complex of factors (on the basis of the literature data) on the development and formation of the investigated systems of characteristics.

Brief Report: Late-Onset Cryopyrin-Associated Periodic Syndrome Due to Myeloid-Restricted Somatic NLRP3 Mosaicism.

PubMed

Mensa-Vilaro, Anna; Teresa Bosque, María; Magri, Giuliana; Honda, Yoshitaka; Martínez-Banaclocha, Helios; Casorran-Berges, Marta; Sintes, Jordi; González-Roca, Eva; Ruiz-Ortiz, Estibaliz; Heike, Toshio; Martínez-Garcia, Juan J; Baroja-Mazo, Alberto; Cerutti, Andrea; Nishikomori, Ryuta; Yagüe, Jordi; Pelegrín, Pablo; Delgado-Beltran, Concha; Aróstegui, Juan I

2016-12-01

Gain-of-function NLRP3 mutations cause cryopyrin-associated periodic syndrome (CAPS), with gene mosaicism playing a relevant role in the pathogenesis. This study was undertaken to characterize the genetic cause underlying late-onset but otherwise typical CAPS. We studied a 64-year-old patient who presented with recurrent episodes of urticaria-like rash, fever, conjunctivitis, and oligoarthritis at age 56 years. DNA was extracted from both unfractionated blood and isolated leukocyte and CD34+ subpopulations. Genetic studies were performed using both the Sanger method of DNA sequencing and next-generation sequencing (NGS) methods. In vitro and ex vivo analyses were performed to determine the consequences that the presence of the variant have in the normal structure or function of the protein of the detected variant. NGS analyses revealed the novel p.Gln636Glu NLRP3 variant in unfractionated blood, with an allele frequency (18.4%) compatible with gene mosaicism. Sanger sequence chromatograms revealed a small peak corresponding to the variant allele. Amplicon-based deep sequencing revealed somatic NLRP3 mosaicism restricted to myeloid cells (31.8% in monocytes, 24.6% in neutrophils, and 11.2% in circulating CD34+ common myeloid progenitor cells) and its complete absence in lymphoid cells. Functional analyses confirmed the gain-of-function behavior of the gene variant and hyperactivity of the NLRP3 inflammasome in the patient. Treatment with anakinra resulted in good control of the disease. We identified the novel gain-of-function p.Gln636Glu NLRP3 mutation, which was detected as a somatic mutation restricted to myeloid cells, as the cause of late-onset but otherwise typical CAPS. Our results expand the diversity of CAPS toward milder phenotypes than previously reported, including those starting during adulthood. © 2016, American College of Rheumatology.

Are Anxiety Disorders Associated with Accelerated Aging? A Focus on Neuroprogression

PubMed Central

Perna, Giampaolo; Iannone, Giuseppe; Alciati, Alessandra; Caldirola, Daniela

2016-01-01

Anxiety disorders (AnxDs) are highly prevalent throughout the lifespan, with detrimental effects on daily-life functioning, somatic health, and quality of life. An emerging perspective suggested that AnxDs may be associated with accelerated aging. In this paper, we explored the association between AnxDs and hallmarks of accelerated aging, with a specific focus on neuroprogression. We reviewed animal and human findings that suggest an overlap between processes of impaired neurogenesis, neurodegeneration, structural, functional, molecular, and cellular modifications in AnxDs, and aging. Although this research is at an early stage, our review suggests a link between anxiety and accelerated aging across multiple processes involved in neuroprogression. Brain structural and functional changes that accompany normal aging were more pronounced in subjects with AnxDs than in coevals without AnxDs, including reduced grey matter density, white matter alterations, impaired functional connectivity of large-scale brain networks, and poorer cognitive performance. Similarly, molecular correlates of brain aging, including telomere shortening, Aβ accumulation, and immune-inflammatory and oxidative/nitrosative stress, were overrepresented in anxious subjects. No conclusions about causality or directionality between anxiety and accelerated aging can be drawn. Potential mechanisms of this association, limitations of the current research, and implications for treatments and future studies are discussed. PMID:26881136

Functional Nausea in Children: A Review of the Literature and Need for Diagnostic Criteria

PubMed Central

Russell, Alexandra C.; Stone, Amanda L.; Walker, Lynn S.

2016-01-01

Nausea is common amongst children with functional gastrointestinal disorders and is associated with a high burden of somatic and psychosocial comorbidities in both the short and long-term. Current treatments including medications, phytotherapy, stress-reduction techniques, and gastric electrical stimulation for recalcitrant cases, are reviewed. Functional nausea merits its own diagnostic criteria as a pediatric functional gastrointestinal disorder. PMID:27417243

Somatic and Reinforcement-Based Plasticity in the Initial Stages of Human Motor Learning.

PubMed

Sidarta, Ananda; Vahdat, Shahabeddin; Bernardi, Nicolò F; Ostry, David J

2016-11-16

As one learns to dance or play tennis, the desired somatosensory state is typically unknown. Trial and error is important as motor behavior is shaped by successful and unsuccessful movements. As an experimental model, we designed a task in which human participants make reaching movements to a hidden target and receive positive reinforcement when successful. We identified somatic and reinforcement-based sources of plasticity on the basis of changes in functional connectivity using resting-state fMRI before and after learning. The neuroimaging data revealed reinforcement-related changes in both motor and somatosensory brain areas in which a strengthening of connectivity was related to the amount of positive reinforcement during learning. Areas of prefrontal cortex were similarly altered in relation to reinforcement, with connectivity between sensorimotor areas of putamen and the reward-related ventromedial prefrontal cortex strengthened in relation to the amount of successful feedback received. In other analyses, we assessed connectivity related to changes in movement direction between trials, a type of variability that presumably reflects exploratory strategies during learning. We found that connectivity in a network linking motor and somatosensory cortices increased with trial-to-trial changes in direction. Connectivity varied as well with the change in movement direction following incorrect movements. Here the changes were observed in a somatic memory and decision making network involving ventrolateral prefrontal cortex and second somatosensory cortex. Our results point to the idea that the initial stages of motor learning are not wholly motor but rather involve plasticity in somatic and prefrontal networks related both to reward and exploration. In the initial stages of motor learning, the placement of the limbs is learned primarily through trial and error. In an experimental analog, participants make reaching movements to a hidden target and receive positive feedback when successful. We identified sources of plasticity based on changes in functional connectivity using resting-state fMRI. The main finding is that there is a strengthening of connectivity between reward-related prefrontal areas and sensorimotor areas in the basal ganglia and frontal cortex. There is also a strengthening of connectivity related to movement exploration in sensorimotor circuits involved in somatic memory and decision making. The results indicate that initial stages of motor learning depend on plasticity in somatic and prefrontal networks related to reward and exploration. Copyright © 2016 the authors 0270-6474/16/3611682-11$15.00/0.

Somatic and Reinforcement-Based Plasticity in the Initial Stages of Human Motor Learning

PubMed Central

Sidarta, Ananda; Vahdat, Shahabeddin; Bernardi, Nicolò F.

2016-01-01

As one learns to dance or play tennis, the desired somatosensory state is typically unknown. Trial and error is important as motor behavior is shaped by successful and unsuccessful movements. As an experimental model, we designed a task in which human participants make reaching movements to a hidden target and receive positive reinforcement when successful. We identified somatic and reinforcement-based sources of plasticity on the basis of changes in functional connectivity using resting-state fMRI before and after learning. The neuroimaging data revealed reinforcement-related changes in both motor and somatosensory brain areas in which a strengthening of connectivity was related to the amount of positive reinforcement during learning. Areas of prefrontal cortex were similarly altered in relation to reinforcement, with connectivity between sensorimotor areas of putamen and the reward-related ventromedial prefrontal cortex strengthened in relation to the amount of successful feedback received. In other analyses, we assessed connectivity related to changes in movement direction between trials, a type of variability that presumably reflects exploratory strategies during learning. We found that connectivity in a network linking motor and somatosensory cortices increased with trial-to-trial changes in direction. Connectivity varied as well with the change in movement direction following incorrect movements. Here the changes were observed in a somatic memory and decision making network involving ventrolateral prefrontal cortex and second somatosensory cortex. Our results point to the idea that the initial stages of motor learning are not wholly motor but rather involve plasticity in somatic and prefrontal networks related both to reward and exploration. SIGNIFICANCE STATEMENT In the initial stages of motor learning, the placement of the limbs is learned primarily through trial and error. In an experimental analog, participants make reaching movements to a hidden target and receive positive feedback when successful. We identified sources of plasticity based on changes in functional connectivity using resting-state fMRI. The main finding is that there is a strengthening of connectivity between reward-related prefrontal areas and sensorimotor areas in the basal ganglia and frontal cortex. There is also a strengthening of connectivity related to movement exploration in sensorimotor circuits involved in somatic memory and decision making. The results indicate that initial stages of motor learning depend on plasticity in somatic and prefrontal networks related to reward and exploration. PMID:27852776

Clonal hematopoiesis as determined by the HUMARA assay is a marker for acquired mutations in epigenetic regulators in older women.

PubMed

Wiedmeier, Julia Erin; Kato, Catherine; Zhang, Zhenzhen; Lee, Hyunjung; Dunlap, Jennifer; Nutt, Eric; Rattray, Rogan; McKay, Sarah; Eide, Christopher; Press, Richard; Mori, Motomi; Druker, Brian; Dao, Kim-Hien

2016-09-01

Recent large cohort studies revealed that healthy older individuals harbor somatic mutations that increase their risk for hematologic malignancy and all-cause cardiovascular deaths. The majority of these mutations are in chromatin and epigenetic regulatory genes (CERGs). CERGs play a key role in regulation of DNA methylation (DNMT3A and TET2) and histone function (ASXL1) and in clonal proliferation of hematopoietic stem cells. We hypothesize that older women manifesting clonal hematopoiesis, defined here as a functional phenomenon in which a hematopoietic stem cell has acquired a survival and proliferative advantage, harbor a higher frequency of somatic mutations in CERGs. The human androgen receptor gene (HUMARA) assay was used in our study to detect the presence of nonrandom X inactivation in women, a marker for clonal hematopoiesis. In our pilot study, we tested 127 blood samples from women ≥65 years old without a history of invasive cancer or hematologic malignancies. Applying stringent qualitative criteria, we found that 26% displayed clonal hematopoiesis; 52.8% displayed polyclonal hematopoiesis; and 21.3% had indeterminate patterns (too close to call by qualitative assessment). Using Illumina MiSeq next-generation sequencing, we identified somatic mutations in CERGs in 15.2% of subjects displaying clonal hematopoiesis (three ASXL1 and two DNMT3A mutations with an average variant allele frequency of 15.7%, range: 6.3%-23.3%). In a more limited sequencing analysis, we evaluated the frequency of ASXL1 mutations by Sanger sequencing and found mutations in 9.7% of the clonal samples and 0% of the polyclonal samples. By comparing several recent studies (with some caveats as described), we determined the fold enrichment of detecting CERG mutations by using the HUMARA assay as a functional screen for clonal hematopoiesis. We conclude that a functional assay of clonal hematopoiesis is enriching for older women with somatic mutations in CERGs, particularly for ASXL1 and TET2 mutations and less so for DNMT3A mutations. Copyright © 2016 ISEH - International Society for Experimental Hematology. Published by Elsevier Inc. All rights reserved.

International Cancer Genome Consortium Data Portal--a one-stop shop for cancer genomics data.

PubMed

Zhang, Junjun; Baran, Joachim; Cros, A; Guberman, Jonathan M; Haider, Syed; Hsu, Jack; Liang, Yong; Rivkin, Elena; Wang, Jianxin; Whitty, Brett; Wong-Erasmus, Marie; Yao, Long; Kasprzyk, Arek

2011-01-01

The International Cancer Genome Consortium (ICGC) is a collaborative effort to characterize genomic abnormalities in 50 different cancer types. To make this data available, the ICGC has created the ICGC Data Portal. Powered by the BioMart software, the Data Portal allows each ICGC member institution to manage and maintain its own databases locally, while seamlessly presenting all the data in a single access point for users. The Data Portal currently contains data from 24 cancer projects, including ICGC, The Cancer Genome Atlas (TCGA), Johns Hopkins University, and the Tumor Sequencing Project. It consists of 3478 genomes and 13 cancer types and subtypes. Available open access data types include simple somatic mutations, copy number alterations, structural rearrangements, gene expression, microRNAs, DNA methylation and exon junctions. Additionally, simple germline variations are available as controlled access data. The Data Portal uses a web-based graphical user interface (GUI) to offer researchers multiple ways to quickly and easily search and analyze the available data. The web interface can assist in constructing complicated queries across multiple data sets. Several application programming interfaces are also available for programmatic access. Here we describe the organization, functionality, and capabilities of the ICGC Data Portal.

Dysfunction of the hypothalamic-pituitary-adrenal axis and functional somatic symptoms: a longitudinal cohort study in the general population.

PubMed

Tak, Lineke M; Bakker, Stephan J L; Rosmalen, Judith G M

2009-07-01

In persons with functional somatic symptoms (FSS), no conventionally defined organic pathology is apparent. It has been suggested that complex interactions of psychological, physiological, and social factors are involved in the etiology of FSS. One of the physiological mechanisms that may contribute to FSS is the function of the hypothalamic-pituitary-adrenal (HPA)-axis. This study investigates the association of HPA-axis function with cross-sectional presence and prospective development of FSS in the general population. This study was performed in a population-based cohort of 741 male and female adults (mean age 53.1, S.D. 10.9). Participants completed the somatization section of the Composite International Diagnostic Interview (CIDI) in which the presence of 43 FSS is surveyed. In addition to the total number of FSS, bodily system FSS clusters with musculoskeletal, gastrointestinal, cardiorespiratory, and general symptoms were constructed. HPA-axis function was assessed by measuring 24-h urinary free cortisol (24-h UFC) excretion. Follow-up measurements were performed approximately 2 years later. All analyses were adjusted for age, gender, body mass index, smoking, alcohol use, depression, exercise frequency, and urinary volume. Regression analysis detected no cross-sectional association between 24-h UFC excretion and the number of FSS (beta=-0.021, t=-0.521, p=0.603). In addition, 24-h UFC excretion was not associated with any of the bodily system FSS clusters (all p>0.050). Furthermore, 24-h UFC excretion did not predict new-onset FSS in the 2-year follow-up period (beta=0.021, t=0.566, p=0.572). We conclude that this study does not provide evidence for an association between altered HPA-axis function, as indexed by 24-h UFC, and FSS in the general population. We conclude that this study does not provide evidence for an association between altered HPA-axis function, as indexed by 24-h UFC, and FSS in the general population.

Somatic expansion behaviour of the (CTG)n repeat in myotonic dystrophy knock-in mice is differentially affected by Msh3 and Msh6 mismatch-repair proteins.

PubMed

van den Broek, Walther J A A; Nelen, Marcel R; Wansink, Derick G; Coerwinkel, Marga M; te Riele, Hein; Groenen, Patricia J T A; Wieringa, Bé

2002-01-15

The mechanism of expansion of the (CTG)n repeat in myotonic dystrophy (DM1) patients and the cause of its pathobiological effects are still largely unknown. Most likely, long repeats exert toxicity at the level of nuclear RNA transport or splicing. Here, we analyse cis- and trans-acting parameters that determine repeat behaviour in novel mouse models for DM1. Our mice carry 'humanized' myotonic dystrophy protein kinase (Dmpk) allele(s) with either a (CTG)84 or a (CTG)11 repeat, inserted at the correct position into the endogenous DM locus. Unlike in the human situation, the (CTG)84 repeat in the syntenic mouse environment was relatively stable during intergenerational segregation. However, somatic tissues showed substantial repeat expansions which were progressive upon aging and prominent in kidney, and in stomach and small intestine, where it was cell-type restricted. Other tissues examined showed only marginal size changes. The (CTG)11 allele was completely stable, as anticipated. Introducing the (CTG)84 allele into an Msh3-deficient background completely blocked the somatic repeat instability. In contrast, Msh6 deficiency resulted in a significant increase in the frequency of somatic expansions. Competition of Msh3 and Msh6 for binding to Msh2 in functional complexes with different DNA mismatch-recognition specificity may explain why the somatic (CTG)n expansion rate is differentially affected by ablation of Msh3 and Msh6.

Brief Cognitive-Behavioral Treatment for TMD Pain: Long-Term Outcomes and Moderators of Treatment

PubMed Central

Litt, Mark D.; Shafer, David M.; Kreutzer, Donald L.

2010-01-01

The purpose of this study was to determine whether a brief (6–8 sessions) cognitive-behavioral treatment for temporomandibular dysfunction-related pain could be efficacious in reducing pain, pain-related interference with lifestyle and depressive symptoms. The patients were 101 men and women with pain in the area of the temporomandibular joint of at least 3 months duration, randomly assigned to either Standard Treatment (STD; n=49) or to Standard Treatment + Cognitive-Behavioral skills training (STD+CBT; n=52). Patients were assessed at posttreatment (6 weeks), 12 weeks, 24 weeks, 36 weeks, and 52 weeks. Linear mixed model analyses of reported pain indicated that both treatments yielded significant decreases in pain, with the STD+CBT condition resulting in steeper decreases in pain over time compared to the STD condition. Somatization, self-efficacy and readiness for treatment emerged as significant moderators of outcome, such that those low in somatization, or higher in self-efficacy or readiness, and treated with STD+CBT reported lower pain over time. Somatization was also a significant moderator of treatment effects on pain-related interference with functioning, with those low on somatization reporting less pain interference over time when treated in the STD+CBT condition. It was concluded that brief treatments can yield significant reductions in pain, life interference and depressive symptoms in TMD sufferers, and that the addition of cognitive-behavioral coping skills will add to efficacy, especially for those low in somatization, or high in readiness or self-efficacy. PMID:20655662

Pulmonary Neoplasms in Patients with Birt-Hogg-Dubé Syndrome: Histopathological Features and Genetic and Somatic Events.

PubMed

Furuya, Mitsuko; Tanaka, Reiko; Okudela, Koji; Nakamura, Satoko; Yoshioka, Hiromu; Tsuzuki, Toyonori; Shibuya, Ryo; Yatera, Kazuhiro; Shirasaki, Hiroki; Sudo, Yoshiko; Kimura, Naoko; Yamada, Kazuaki; Uematsu, Shugo; Kunimura, Toshiaki; Kato, Ikuma; Nakatani, Yukio

2016-01-01

Birt-Hogg-Dubé syndrome (BHD) is an inherited disorder caused by genetic mutations in the folliculin (FLCN) gene. Individuals with BHD have multiple pulmonary cysts and are at a high risk for developing renal cell carcinomas (RCCs). Currently, little information is available about whether pulmonary cysts are absolutely benign or if the lungs are at an increased risk for developing neoplasms. Herein, we describe 14 pulmonary neoplastic lesions in 7 patients with BHD. All patients were confirmed to have germline FLCN mutations. Neoplasm histologies included adenocarcinoma in situ (n = 2), minimally invasive adenocarcinoma (n = 1), papillary adenocarcinoma (n = 1), micropapillary adenocarcinoma (n = 1), atypical adenomatous hyperplasia (n = 8), and micronodular pneumocyte hyperplasia (MPH)-like lesion (n = 1). Five of the six adenocarcinoma/MPH-like lesions (83.3%) demonstrated a loss of heterozygosity (LOH) of FLCN. All of these lesions lacked mutant alleles and preserved wild-type alleles. Three invasive adenocarcinomas possessed additional somatic events: 2 had a somatic mutation in the epidermal growth factor receptor gene (EGFR) and another had a somatic mutation in KRAS. Immunohistochemical analysis revealed that most of the lesions were immunostained for phospho-mammalian target of rapamycin (p-mTOR) and phospho-S6. Collective data indicated that pulmonary neoplasms of peripheral adenocarcinomatous lineage in BHD patients frequently exhibit LOH of FLCN with mTOR pathway signaling. Additional driver gene mutations were detected only in invasive cases, suggesting that FLCN LOH may be an underlying abnormality that cooperates with major driver gene mutations in the progression of pulmonary adenocarcinomas in BHD patients.

Germline Proliferation Is Regulated by Somatic Endocytic Genes via JNK and BMP Signaling in Drosophila.

PubMed

Tang, Yaning; Geng, Qing; Chen, Di; Zhao, Shaowei; Liu, Xian; Wang, Zhaohui

2017-05-01

Signals derived from the microenvironment contribute greatly to tumorigenesis . The underlying mechanism requires thorough investigation. Here, we use Drosophila testis as a model system to address this question, taking the advantage of the ease to distinguish germline and somatic cells and to track the cell numbers. In an EMS mutagenesis screen, we identified Rab5 , a key factor in endocytosis, for its nonautonomous role in germline proliferation. The disruption of Rab5 in somatic cyst cells, which escort the development of germline lineage, induced the overproliferation of underdifferentiated but genetically wild-type germ cells. We demonstrated that this nonautonomous effect was mediated by the transcriptional activation of Dpp [the fly homolog of bone morphogenetic protein (BMP)] by examining the Dpp-reporter expression and knocking down Dpp to block germline overgrowth. Consistently, the protein levels of Bam, the germline prodifferentiation factor normally accumulated in the absence of BMP/Dpp signaling, decreased in the overproliferating germ cells. Further, we discovered that the JNK signaling pathway operated between Rab5 and Dpp, because simultaneously inhibiting the JNK pathway and Rab5 in cyst cells prevented both dpp transcription and germline tumor growth. Additionally, we found that multiple endocytic genes, such as avl , TSG101 , Vps25 , or Cdc42 , were required in the somatic cyst cells to restrict germline amplification. These findings indicate that when the endocytic state of the surrounding cells is impaired, genetically wild-type germ cells overgrow. This nonautonomous model of tumorigenesis provides a simple system to dissect the relation between tumor and its niche. Copyright © 2017 by the Genetics Society of America.

Mental health of newly arrived Burmese refugees in Australia: contributions of pre-migration and post-migration experience.

PubMed

Schweitzer, Robert D; Brough, Mark; Vromans, Lyn; Asic-Kobe, Mary

2011-04-01

This study documents the mental health status of people from Burmese refugee backgrounds recently arrived in Australia, then examines the contributions of gender, pre-migration and post-migration factors in predicting mental health. Structured interviews, including a demographic questionnaire, the Harvard Trauma Questionnaire, the Post-migration Living Difficulties Checklist and Hopkins Symptom Checklist assessed pre-migration trauma, post-migration living difficulties, depression, anxiety, somatization and traumatization symptoms in a sample of 70 adults across five Burmese ethnic groups. Substantial proportions of participants reported psychological distress in symptomatic ranges including: post-traumatic stress disorder (9%), anxiety (20%) and depression (36%), as well as significant symptoms of somatization (37%). Participants reported multiple and severe pre-migration traumas. Post-migration living difficulties of greatest concern included communication problems and worry about family not in Australia. Gender did not predict mental health. Level of exposure to traumatic events and post-migration living difficulties each made unique and relatively equal contributions to traumatization symptoms. Post-migration living difficulties made unique contributions to depression, anxiety and somatization symptoms. While exposure to traumatic events impacted on participants' mental well-being, post-migration living difficulties had greater salience in predicting mental health outcomes of people from Burmese refugee backgrounds. Reported rates of post-traumatic stress disorder symptoms were consistent with a large review of adults across seven western countries. High levels of somatization point to a nuanced expression of distress. Findings have implications for service provision in terms of implementing appropriate interventions to effectively meet the needs of this newly arrived group in Australia.

Children's well-being 11 years after the Chornobyl catastrophe.

PubMed

Bromet, E J; Goldgaber, D; Carlson, G; Panina, N; Golovakha, E; Gluzman, S F; Gilbert, T; Gluzman, D; Lyubsky, S; Schwartz, J E

2000-06-01

The psychological effects of technological disasters have rarely been studied in children. This study assessed the aftermath of the 1986 Chornobyl disaster in children evacuated to Kyiv from the contaminated zone surrounding the nuclear power facility. In 1997, we evaluated three hundred 10- to 12-year-old children in Kyiv who were in utero or infants at the time of the disaster and who had resided near Chornobyl (evacuees) and 300 sex-matched homeroom classmates who had never lived in a radiation-contaminated area. Response rates were 92% (evacuees) and 85% (classmates). Data were obtained from children, mothers, and teachers using standard measures of well-being and risk factors for childhood psychopathology. The children also received physical examinations and basic blood tests. The evacuees and classmates perceived their mental health similarly except for Chornobyl-related anxiety symptoms and perceived scholastic competence. No differences were found on the Iowa Conners' Teacher Rating Scale. Although the physical examination and blood test results were normal, the evacuee mothers rated their children's well-being as significantly worse, especially with respect to somatic symptoms on the Children's Somatization Inventory and Child Behavior Checklist. The most important risk factors for these ratings were maternal somatization and Chornobyl-related stress. Given the multiple stressful experiences to which evacuee families were exposed, the small differences in the children's self-reports suggest that there are protective factors in the lives of these children. The trauma experienced by the mothers was reflected in their perceptions of their children's well-being, particularly somatic symptoms, but was not transmitted to the children themselves.

Two Classes of Gap Junction Channels Mediate Soma-Germline Interactions Essential for Germline Proliferation and Gametogenesis in Caenorhabditis elegans

PubMed Central

Starich, Todd A.; Hall, David H.; Greenstein, David

2014-01-01

In all animals examined, somatic cells of the gonad control multiple biological processes essential for germline development. Gap junction channels, composed of connexins in vertebrates and innexins in invertebrates, permit direct intercellular communication between cells and frequently form between somatic gonadal cells and germ cells. Gap junctions comprise hexameric hemichannels in apposing cells that dock to form channels for the exchange of small molecules. Here we report essential roles for two classes of gap junction channels, composed of five innexin proteins, in supporting the proliferation of germline stem cells and gametogenesis in the nematode Caenorhabditis elegans. Transmission electron microscopy of freeze-fracture replicas and fluorescence microscopy show that gap junctions between somatic cells and germ cells are more extensive than previously appreciated and are found throughout the gonad. One class of gap junctions, composed of INX-8 and INX-9 in the soma and INX-14 and INX-21 in the germ line, is required for the proliferation and differentiation of germline stem cells. Genetic epistasis experiments establish a role for these gap junction channels in germline proliferation independent of the glp-1/Notch pathway. A second class of gap junctions, composed of somatic INX-8 and INX-9 and germline INX-14 and INX-22, is required for the negative regulation of oocyte meiotic maturation. Rescue of gap junction channel formation in the stem cell niche rescues germline proliferation and uncovers a later channel requirement for embryonic viability. This analysis reveals gap junctions as a central organizing feature of many soma–germline interactions in C. elegans. PMID:25195067

Epitranscriptomics: A New Regulatory Mechanism of Brain Development and Function

PubMed Central

Noack, Florian; Calegari, Federico

2018-01-01

Epigenetic modifications of DNA and chromatin are long known to control stem cell differentiation and organ function but the role of similar modifications at the level or regulatory RNAs is just beginning to emerge. Over 160 RNA modifications have been identified but their abundance, distribution and functional significance are not known. The few available maps of RNA modifications indicated their dynamic regulation during somatic stem cell differentiation, brain development and function in adulthood suggesting a hitherto unsuspected layer of regulation both at the level of RNA metabolism and post-transcriptional control of gene expression. The advent of programmable, RNA-specific CRISPR-Cas editing platforms together with the identification of RNA modifying enzymes now offers the opportunity to investigate the functional role of these elusive epitranscriptome changes. Here, we discuss recent insights in studying the most abundant modifications in functional mRNAs and lncRNAs, N6-methyladenosine and 5-(hydroxy-)methylcytosine, and their role in regulating somatic stem cell differentiation with particular attention to neural stem cells during mammalian corticogenesis. An outlook on novel CRISPR-Cas based systems that allow stem cell reprogramming by epitranscriptome-editing will also be discussed. PMID:29515357

Is somatic comorbidity associated with more somatic symptoms, mental distress, or unhealthy lifestyle in elderly cancer survivors?

PubMed

Grov, Ellen Karine; Fosså, Sophie D; Dahl, Alv A

2009-06-01

The associations of lifestyle factors, somatic symptoms, mental distress, and somatic comorbidity in elderly cancer survivors have not been well studied. This study examines these associations among elderly cancer survivors (age >or=65 years) in a population-based sample. A cross-sectional comparative study of Norwegian elderly cancer survivors. Combining information from The Norwegian Cancer Registry, and by self-reporting, 972 elderly cancer survivors were identified, of whom 632 (65%) had somatic comorbidity and 340 did not. Elderly cancer survivors with somatic comorbidity had significantly higher BMI, more performed minimal physical activity, had more somatic symptoms, used more medication, and had more frequently seen a medical doctor than survivors without somatic comorbidity. In multivariable analyses, unhealthy lifestyle and higher somatic symptoms scores were significantly associated with cancer cases with somatic comorbidity. In univariate analyses those with somatic comorbidity were significantly older, had lower levels of education, higher proportions of BMI >or= 30, less physical activity, poorer self-rated health, higher somatic symptoms score, more mental distress, had more frequently seen a medical doctor last year, and more frequently used daily medication. Our outcome measures of lifestyle, somatic symptoms and mental distress were all significantly associated with somatic comorbidity in elderly cancer survivors, however only lifestyle and somatic symptoms were significant in multivariable analyses. In elderly cancer survivors not only cancer, but also somatic comorbidity, deserve attention. Such comorbidity is associated with unhealthy lifestyles, more somatic symptoms and mental distress which should be evaluated and eventually treated.

Genetic relationships between detailed reproductive traits and performance traits in Holstein-Friesian dairy cattle.

PubMed

Carthy, T R; Ryan, D P; Fitzgerald, A M; Evans, R D; Berry, D P

2016-02-01

The objective of the study was to estimate the genetic relationships between detailed reproductive traits derived from ultrasound examination of the reproductive tract and a range of performance traits in Holstein-Friesian dairy cows. The performance traits investigated included calving performance, milk production, somatic cell score (i.e., logarithm transformation of somatic cell count), carcass traits, and body-related linear type traits. Detailed reproductive traits included (1) resumed cyclicity at the time of examination, (2) multiple ovulations, (3) early ovulation, (4) heat detection, (5) ovarian cystic structures, (6) embryo loss, and (7) uterine score, measured on a 1 (little or no fluid with normal tone) to 4 (large quantity of fluid with a flaccid tone) scale, based on the tone of the uterine wall and the quantity of fluid present in the uterus. (Co)variance components were estimated using a repeatability animal linear mixed model. Genetic merit for greater milk, fat, and protein yield was associated with a reduced ability to resume cyclicity postpartum (genetic correlations ranged from -0.25 to -0.15). Higher genetic merit for milk yield was also associated with a greater genetic susceptibility to multiple ovulations. Genetic predisposition to elevated somatic cell score was associated with a decreased likelihood of cyclicity postpartum (genetic correlation of -0.32) and a greater risk of both multiple ovulations (genetic correlation of 0.25) and embryo loss (genetic correlation of 0.32). Greater body condition score was genetically associated with an increased likelihood of resumption of cyclicity postpartum (genetic correlation of 0.52). Genetically heavier, fatter carcasses with better conformation were also associated with an increased likelihood of resumed cyclicity by the time of examination (genetic correlations ranged from 0.24 to 0.41). Genetically heavier carcasses were associated with an inferior uterine score as well as a greater predisposition to embryo loss. Despite the overall antagonistic relationship between reproductive performance and both milk and carcass traits, not all detailed aspects of reproduction performance exhibited an antagonistic relationship. Copyright © 2016 American Dairy Science Association. Published by Elsevier Inc. All rights reserved.

Fluorescence-based detection and quantification of features of cellular senescence.

PubMed

Cho, Sohee; Hwang, Eun Seong

2011-01-01

Cellular senescence is a spontaneous organismal defense mechanism against tumor progression which is raised upon the activation of oncoproteins or other cellular environmental stresses that must be circumvented for tumorigenesis to occur. It involves growth-arrest state of normal cells after a number of active divisions. There are multiple experimental routes that can drive cells into a state of senescence. Normal somatic cells and cancer cells enter a state of senescence upon overexpression of oncogenic Ras or Raf protein or by imposing certain kinds of stress such as cellular tumor suppressor function. Both flow cytometry and confocal imaging analysis techniques are very useful in quantitative analysis of cellular senescence phenomenon. They allow quantitative estimates of multiple different phenotypes expressed in multiple cell populations simultaneously. Here we review the various types of fluorescence methodologies including confocal imaging and flow cytometry that are frequently utilized to study a variety of senescence. First, we discuss key cell biological changes occurring during senescence and review the current understanding on the mechanisms of these changes with the goal of improving existing protocols and further developing new ones. Next, we list specific senescence phenotypes associated with each cellular trait along with the principles of their assay methods and the significance of the assay outcomes. We conclude by selecting appropriate references that demonstrate a typical example of each method. Copyright © 2011 Elsevier Inc. All rights reserved.

Experiences of patients with multiple sclerosis from group counseling.

PubMed

Mazaheri, Mina; Fanian, Nasrin; Zargham-Boroujeni, Ali

2011-01-01

Group counseling is one of the most important methods in somatic and psychological rehabilitation of the multiple sclerosis (M.S.) patients. Knowing these patients' experiences, feelings, believes and emotion based on learning in group is necessary to indicate the importance of group discussion on quality of life of the patients. This study was done to achieve experiences of M.S. patients from group training. This was a qualitative study using phenomenological method. The samples were selected using purposeful sampling. Ten patients from M.S. society who had passed group training were included in the study. The group training was done through seven sessions weekly and voluntarily. The participants were interviewed using in-depth interview. The average time of each interview was between 30-50 minutes which has been recorded digitally and moved to a compact disc to transcribe and analysis. The data analyzed using 7-step Colaizzi method. The data were transformed into 158 codes, 12 sub-concepts and 4 main concepts including emotional consequences, communication, quality of life and needs. M.S can lead to multiple problems in patients such as somatic, behavioral, emotional and social disorders. Group psychotherapy is one of the methods which can decrease these problems and improve rehabilitation of the patients. Group discussion helps patients to overcome adverse feelings, behaviors and thoughts and guides them to move in a meaningful life. It also can improve quality of life and mental health of the patients.

A pilot study of Trabajadora de salud, a lay health worker intervention for Latinas/os with traumatic brain injuries and their caregivers.

PubMed

Linton, Kristen F; Kim, Bum Jung

2018-01-01

Latinas/os with traumatic brain injuries (TBIs) and their caregivers experience worse outcomes than others. The study aimed to assess the acceptability and promise of Trabajadora de Salud on the functional abilities, hospital readmission, rehabilitation, employment, depression, somatic symptoms, and caregiver burden among Latinas/os with TBIs and their caregivers. A pre-posttest experimental pilot study was conducted. A total of eight Latina/o adult patients (50% female) with mild or moderate TBI and six of their caregivers (66.7% female) were randomized to receive Trabajadora de Salud or a telephone only control group. Trabajadora de Salud, a three-month, in-home intervention administered by bilingual lay health workers, focused on: 1) providing empathy and validation of TBI symptoms, 2) addressing basic needs, 3) goal setting, and 4) improving communication with healthcare providers. Trabajadora de Salud was widely accepted by patients, caregivers, and health professionals. The functional, depression, and somatic symptoms of the patients as well as the somatic symptoms and caregiver burden of the caregivers improved more for participants in the intervention group than the control group. Trabajadora de Salud demonstrated promise in improving outcomes of Latinas/os with TBIs and their caregivers and should be further studied. Copyright © 2017 Elsevier Inc. All rights reserved.

Parental overprotection predicts the development of functional somatic symptoms in young adolescents.

PubMed

Janssens, Karin A M; Oldehinkel, Albertine J; Rosmalen, Judith G M

2009-06-01

To examine whether parental overprotection contributes to the development of functional somatic symptoms (FSS) in young adolescents. In addition, we aimed to study whether this potential effect of parental overprotection is mediated by parenting distress and/or moderated by the adolescent's sex. FSS were measured in 2230 adolescents (ages 10 to 12 years from the Tracking Adolescents' Individual Lives Survey) by the Somatic Complaints subscale of the Youth Self Report at baseline and at follow-up 2 1/2 years later. Parental overprotection as perceived by the child was assessed by means of the EMBU-C (Swedish acronym for my memories of upbringing-child version). Parents completed the Parenting Stress Index. Linear regression analyses were performed adjusted for FSS at baseline and sex. Parental overprotection was a predictor of the development of FSS in young adolescents (beta = 0.055, P < .01). Stratified analyses revealed that maternal overprotection was a predictor of the development of FSS in girls (beta = 0.085, P < .02), whereas paternal overprotection was a predictor of the development of FSS in boys (beta = 0.072, P < .01). A small (5.7%) but significant mediating effect of maternal parenting stress in the relationship between parental overprotection and FSS was found. Parental overprotection may play a role in the development of FSS in young adolescents.

Mice deficient in carbonic anhydrase type 8 exhibit motor dysfunctions and abnormal calcium dynamics in the somatic region of cerebellar granule cells.

PubMed

Lamont, Matthew G; Weber, John T

2015-06-01

The waddles (wdl) mouse is characterized by a namesake "side-to-side" waddling gait due to a homozygous mutation of the Car8 gene. This mutation results in non-functional copies of the protein carbonic anhydrase type 8. Rota-rod testing was conducted to characterize the wdl mutations' effect on motor output. Results indicated that younger homozygotes outperformed their older cohorts, an effect not seen in previous studies. Heterozygotes, which were thought to be free of motor impairment, displayed motor learning deficiencies when compared with wild type performance. Acute cerebellar slices were then utilized for fluorescent calcium imaging experiments, which revealed significant alterations in cerebellar granule cell somatic calcium signaling when exposed to glutamate. The contribution of GABAergic signaling to these alterations was also verified using bath application of bicuculline. Changes in somatic calcium signals were found to be applicable to an in vivo scenario by comparing group responses to electrical stimulation of afferent mossy fiber projections. Finally, intracellular calcium store function was also found to be altered by the wdl mutation when slices were treated with thapsigargin. These findings, taken together with previous work on the wdl mouse, indicate a widespread disruption in cerebellar circuitry hampering proper neuronal communication. Copyright © 2015 Elsevier B.V. All rights reserved.

Sleeping Beauty transposon system for genetic etiological research and gene therapy of cancers.

PubMed

Hou, Xiaomei; Du, Yan; Deng, Yang; Wu, Jianfeng; Cao, Guangwen

2015-01-01

Carcinogenesis is etiologically associated with somatic mutations of critical genes. Recently, a number of somatic mutations and key molecules have been found to be involved in functional networks affecting cancer progression. Suitable animal models are required to validate cancer-promoting or -inhibiting capacities of these mutants and molecules. Sleeping Beauty transposon system consists of a transposon that carries gene(s) of interest and a transposase that recognizes, excises, and reinserts genes in given location of the genome. It can create both gain-of-function and loss-of-function mutations, thus being frequently chosen to investigate the etiological mechanisms and gene therapy for cancers in animal models. In this review, we summarized current advances of Sleeping Beauty transposon system in revealing molecular mechanism of cancers and improving gene therapy. Understanding molecular mechanisms by which driver mutations contribute to carcinogenesis and metastasis may pave the way for the development of innovative prophylactic and therapeutic strategies against malignant diseases.

Neural pathways for colorectal control, relevance to spinal cord injury and treatment: a narrative review.

PubMed

Callaghan, Brid; Furness, John B; Pustovit, Ruslan V

2018-03-01

Narrative review. The purpose is to review the organisation of the nerve pathways that control defecation and to relate this knowledge to the deficits in colorectal function after SCI. A literature review was conducted to identify salient features of defecation control pathways and the functional consequences of damage to these pathways in SCI. The control pathways for defecation have separate pontine centres under cortical control that influence defecation. The pontine centres connect, separately, with autonomic preganglionic neurons of the spinal defecation centres and somatic motor neurons of Onuf's nucleus in the sacral spinal cord. Organised propulsive motor patterns can be generated by stimulation of the spinal defecation centres. Activation of the somatic neurons contracts the external sphincter. The analysis aids in interpreting the consequences of SCI and predicts therapeutic strategies. Analysis of the bowel control circuits identifies sites at which bowel function may be modulated after SCI. Colokinetic drugs that elicit propulsive contractions of the colorectum may provide valuable augmentation of non-pharmacological bowel management procedures.

The Cognitive Processing of Somatic Anxiety: Using Functional Measurement to Understand and Address the Fear of Pain

ERIC Educational Resources Information Center

Moore, Philip J.; Chrabaszcz, Jeffrey S.; Peterson, Rolf A.

2010-01-01

Although anxiety has both dispositional and situational determinants, little is known about how individuals' anxiety-related sensitivities and their expectations about stressful events combine to determine anxiety. This research used Information Integration Theory and Functional Measurement to assess how participants' anxiety sensitivity and event…

Development and Validation of a Nausea Severity Scale for Assessment of Nausea in Children with Abdominal Pain-Related Functional Gastrointestinal Disorders.

PubMed

Russell, Alexandra C; Stone, Amanda L; Wang, Andi; Walker, Lynn S

2018-06-01

The objective of this study was to develop a pediatric measure of chronic nausea severity, the Nausea Severity Scale (NSS), and evaluate its reliability and validity in youth with abdominal pain-related functional gastrointestinal disorders (AP-FGID). Pediatric patients (aged 11⁻17 years-old, n = 236) presenting to an outpatient clinic for evaluation of abdominal pain completed the NSS, Children's Somatization Inventory (CSI), Functional Disability Inventory (FDI), Abdominal Pain Index (API), Patient-Report Outcomes Measurement Information System (PROMIS), Anxiety and Depression Scales and the Pediatric Rome III Questionnaire for FGIDs. The NSS demonstrated good concurrent, discriminant, and construct validity, as well as good internal consistency. One-third (34%) of AP-FGID patients reported experiencing nausea "most" or "every day" in the previous two weeks. The severity of nausea was higher in females than males and correlated significantly with the severity of somatic symptoms, functional disability, anxiety, and depression. The NSS is a valid and reliable measure of nausea in children with AP-FGID.

Micropropagation of Dalbergia sissoo Roxb. through tissue culture technique.

PubMed

Sahu, Jyoti; Khan, Shagufta; Sahu, Ram Kumar; Roy, Amit

2014-04-01

Multiple shoots of Dalbergia sissoo Roxb. (Sissoo) were incited from seeds through indirect somatic embryogenesis method. Seeds were inoculated in Murashige and Skoog's medium without any growth hormone. Than cotyledonary leaves were struck and used for callus induction on MS medium amplified with 2, 4-dichlorophenoxyacetic acid (0.5 to 4 mg mL(-1)). After 3 to 4 weeks the embryogenic callus clumps was transferred to medium supplemented with cytokinin (BAP 1 to 5 mg L(-1), kinetin 1-5.0 mg L(-1)) for embryo maturation and germination. The high-frequency shoot proliferation (82%) and maximum number of shoots per explants were recorded in MS medium containing NAA (0.5)+BAP (0.5). The findings of recent investigations have shown that, it is possible to induce indirect somatic embryogenesis in Dalbergia sissoo and plant regeneration from callus cultures derived from cotyledonary leaves as explants.

Mutational signatures associated with tobacco smoking in human cancer

DOE PAGES

Alexandrov, Ludmil B.; Ju, Young Seok; Haase, Kerstin; ...

2016-11-04

Tobacco smoking increases the risk of at least 17 classes of cancer. Here, we analyzed somatic mutations and DNA methylation in 5,243 cancers of types for which tobacco smoking confers an elevated risk. Smoking is associated with increased mutation burdens of multiple distinct mutational signatures, which contribute to different extents in different cancers. One of these signatures, mainly found in cancers derived from tissues directly exposed to tobacco smoke, is attributable to misreplication of DNA damage caused by tobacco carcinogens. Others likely reflect indirect activation of DNA edi ting by APOBEC cytidine deaminases and of an endogenous clock-like mutational process.more » Smoking is associated with limited differences in methylation. The results are consistent with the proposition that smoking increases cancer risk by increasing the somatic mutation load, although direct evidence for this mechanism is lacking in some smoking-related cancer types.« less

Dynamics of cortical dendritic membrane potential and spikes in freely behaving rats.

PubMed

Moore, Jason J; Ravassard, Pascal M; Ho, David; Acharya, Lavanya; Kees, Ashley L; Vuong, Cliff; Mehta, Mayank R

2017-03-24

Neural activity in vivo is primarily measured using extracellular somatic spikes, which provide limited information about neural computation. Hence, it is necessary to record from neuronal dendrites, which can generate dendritic action potentials (DAPs) in vitro, which can profoundly influence neural computation and plasticity. We measured neocortical sub- and suprathreshold dendritic membrane potential (DMP) from putative distal-most dendrites using tetrodes in freely behaving rats over multiple days with a high degree of stability and submillisecond temporal resolution. DAP firing rates were several-fold larger than somatic rates. DAP rates were also modulated by subthreshold DMP fluctuations, which were far larger than DAP amplitude, indicating hybrid, analog-digital coding in the dendrites. Parietal DAP and DMP exhibited egocentric spatial maps comparable to pyramidal neurons. These results have important implications for neural coding and plasticity. Copyright © 2017, American Association for the Advancement of Science.

Cloning higher plants from aseptically cultured tissues and cells

NASA Technical Reports Server (NTRS)

Krikorian, A. D.

1982-01-01

A review of aseptic culture methods for higher plants is presented, which focuses on the existing problems that limit or prevent the full realization of cloning plants from free cells. It is shown that substantial progress in clonal multiplication has been made with explanted stem tips or lateral buds which can be stimulated to produce numerous precocious axillary branches. These branches can then be separated or subdivided and induced to root in order to yield populations of genetically and phenotypically uniorm plantlets. Similarly, undifferentiated calluses can sometimes be induced to form shoots and/or roots adventitiously. Although the cell culture techniques required to produce somatic embryos are presently rudimentary, steady advances are being made in learning how to stimulate formation of somatic or adventive embryos from totipotent cells grown in suspension cultures. It is concluded that many problems exist in the producing and growing of totipotent or morphogenetically competent cell suspensions, but the potential benefits are great.

Mutational signatures associated with tobacco smoking in human cancer

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

Alexandrov, Ludmil B.; Ju, Young Seok; Haase, Kerstin

Tobacco smoking increases the risk of at least 17 classes of cancer. Here, we analyzed somatic mutations and DNA methylation in 5,243 cancers of types for which tobacco smoking confers an elevated risk. Smoking is associated with increased mutation burdens of multiple distinct mutational signatures, which contribute to different extents in different cancers. One of these signatures, mainly found in cancers derived from tissues directly exposed to tobacco smoke, is attributable to misreplication of DNA damage caused by tobacco carcinogens. Others likely reflect indirect activation of DNA edi ting by APOBEC cytidine deaminases and of an endogenous clock-like mutational process.more » Smoking is associated with limited differences in methylation. The results are consistent with the proposition that smoking increases cancer risk by increasing the somatic mutation load, although direct evidence for this mechanism is lacking in some smoking-related cancer types.« less

Cost-utility of a specific collaborative group intervention for patients with functional somatic syndromes.

PubMed

Konnopka, Alexander; König, Hans-Helmut; Kaufmann, Claudia; Egger, Nina; Wild, Beate; Szecsenyi, Joachim; Herzog, Wolfgang; Schellberg, Dieter; Schaefert, Rainer

2016-11-01

Collaborative group intervention (CGI) in patients with functional somatic syndromes (FSS) has been shown to improve mental quality of life. To analyse incremental cost-utility of CGI compared to enhanced medical care in patients with FSS. An economic evaluation alongside a cluster-randomised controlled trial was performed. 35 general practitioners (GPs) recruited 300 FSS patients. Patients in the CGI arm were offered 10 group sessions within 3months and 2 booster sessions 6 and 12months after baseline. Costs were assessed via questionnaire. Quality adjusted life years (QALYs) were calculated using the SF-6D index, derived from the 36-item short-form health survey (SF-36). We calculated patients' net-monetary-benefit (NMB), estimated the treatment effect via regression, and generated cost-effectiveness acceptability curves. Using intention-to-treat analysis, total costs during the 12-month study period were 5777EUR in the intervention, and 6858EUR in the control group. Controlling for possible confounders, we found a small, but significant positive intervention effect on QALYs (+0.017; p=0.019) and an insignificant cost saving resulting from a cost-increase in the control group (-10.5%; p=0.278). NMB regression showed that the probability of CGI to be cost-effective was 69% for a willingness to pay (WTP) of 0EUR/QALY, increased to 92% for a WTP of 50,000EUR/QALY and reached the level of 95% at a WTP of 70,375EUR/QALY. Subgroup analyses yielded that CGI was only cost-effective in severe somatic symptom severity (PHQ-15≥15). CGI has a high probability to be a cost-effective treatment for FSS, in particular for patients with severe somatic symptom severity. Copyright © 2016 Elsevier Inc. All rights reserved.

Functional impairment due to bereavement after the death of adolescent or young adult offspring in a national population study of 1,051,515 parents.

PubMed

Wilcox, Holly C; Mittendorfer-Rutz, Ellenor; Kjeldgård, Linnea; Alexanderson, Kristina; Runeson, Bo

2015-08-01

This study addresses the burden of grief after the death of an adolescent or young adult offspring. Parental bereavement following the death of an adolescent or young adult offspring is associated with considerable psychiatric and somatic impairment. Our aim is to fill a research gap by examining offspring death due to suicide, accidents, or natural causes in relation to risk of parental sickness absence with psychiatric or somatic disorders. This whole population-based prospective study included mothers and fathers of all offspring aged 16-24 years in Sweden on December 31, 2004 (n = 1,051,515). This study had no loss to follow-up and exposure, confounders, and the outcome were recorded independently of each other. Cox survival analysis was used to model time to sickness absence exceeding 30 days, adjusting for parental demographic characteristics, previous parental sickness absence and disability pension, and inpatient and outpatient psychiatric and somatic healthcare prior to offspring death in 2001-2004. This large study population provided satisfactory statistical power for stratification by parents' sex and adolescent and young adults' cause of death. Mothers and fathers of offspring suicide and accident decedents both had over tenfold higher risk for psychiatric sickness absence exceeding 30 days as compared to parents of live offspring. Fathers of suicide decedents were at 40 % higher risk for somatic sickness absence. This is the largest study to date of parents who survived their offspring's death and the first study of work-related outcomes in bereaved parents. This study uses a broad metric of work-related functional impairment, sickness absence, for capturing the burden of sudden offspring death.

The relationship between salivary amylase and the physical and psychological changes elicited by continuation of autogenic training in patients with functional somatic syndrome.

PubMed

Kiba, Tadashi; Abe, Tetsuya; Kanbara, Kenji; Kato, Fumie; Kawashima, Sadanobu; Saka, Yukie; Yamamoto, Kazumi; Mizuno, Yasuyuki; Nishiyama, Junji; Fukunaga, Mikihiko

2017-01-01

The aim of this study was to clarify the changes in biological measures during autogenic training (AT) sessions and the relationship between these biological measures and the changes in physical and psychological measures induced by continuation of AT in patients with functional somatic syndrome (FSS). We used the salivary amylase (SAMY) level, skin temperature of the finger (TEMP), subjective symptom scores, and psychological characteristics to assess these changes. We assessed 24 patients with FSS and 23 healthy controls before and after AT. We then conducted the same tests after the participants had practiced AT at home 1 and 2 months later. The baseline SAMY levels in the first session were significantly higher in the FSS group than in the control group. However, this difference was not significant in the second and third sessions. The pattern of changes in TEMP induced by AT was not different between the FSS and control groups. Tension-anxiety and somatic symptoms in patients with FSS were improved by AT. In the FSS group, the baseline SAMY levels in the first session showed a significant negative correlation with the changes in the subjective symptom score and tension-anxiety score at baseline. The practice of AT, both during the first session and after 1 month of continuation, eased the dysregulation of the autonomic nervous system that is reflected in SAMY in patients with FSS. AT also contributed to decreases in the tension-anxiety and somatic symptoms in patients with FSS. We suggest that SAMY is related to both physical and psychological effects of AT in patients with FSS.

Analytic validation and real-time clinical application of an amplicon-based targeted gene panel for advanced cancer

PubMed Central

Wing, Michele R.; Reeser, Julie W.; Smith, Amy M.; Reeder, Matthew; Martin, Dorrelyn; Jewell, Benjamin M.; Datta, Jharna; Miya, Jharna; Monk, J. Paul; Mortazavi, Amir; Otterson, Gregory A.; Goldberg, Richard M.; VanDeusen, Jeffrey B.; Cole, Sharon; Dittmar, Kristin; Jaiswal, Sunny; Kinzie, Matthew; Waikhom, Suraj; Freud, Aharon G.; Zhou, Xiao-Ping; Chen, Wei; Bhatt, Darshna; Roychowdhury, Sameek

2017-01-01

Multiplex somatic testing has emerged as a strategy to test patients with advanced cancer. We demonstrate our analytic validation approach for a gene hotspot panel and real-time prospective clinical application for any cancer type. The TruSight Tumor 26 assay amplifies 85 somatic hotspot regions across 26 genes. Using cell line and tumor mixes, we observed that 100% of the 14,715 targeted bases had at least 1000x raw coverage. We determined the sensitivity (100%, 95% CI: 96-100%), positive predictive value (100%, 95% CI: 96-100%), reproducibility (100% concordance), and limit of detection (3% variant allele frequency at 1000x read depth) of this assay to detect single nucleotide variants and small insertions and deletions. Next, we applied the assay prospectively in a clinical tumor sequencing study to evaluate 174 patients with metastatic or advanced cancer, including frozen tumors, formalin-fixed tumors, and enriched peripheral blood mononuclear cells in hematologic cancers. We reported one or more somatic mutations in 89 (53%) of the sequenced tumors (167 passing quality filters). Forty-three of these patients (26%) had mutations that would enable eligibility for targeted therapies. This study demonstrates the validity and feasibility of applying TruSight Tumor 26 for pan-cancer testing using multiple specimen types. PMID:29100271

Relationship between endogenous hormonal content and somatic organogenesis in callus of peach (Prunus persica L. Batsch) cultivars and Prunus persica×Prunus dulcis rootstocks.

PubMed

Pérez-Jiménez, Margarita; Cantero-Navarro, Elena; Pérez-Alfocea, Francisco; Le-Disquet, Isabel; Guivarc'h, Anne; Cos-Terrer, José

2014-05-01

The relationship between endogenous hormones content and the induction of somatic peach plant was studied. To induce multiple shoots from callus derived from the base of stem explants of the scion cultivars 'UFO-3', 'Flariba' and 'Alice Bigi', and the peach×almond rootstocks 'Garnem' and 'GF677', propagated plants were cultured on Murashige and Skoog salts augmented with 0.1mgL(-1) of indolebutyric acid, 1mgL(-1) of 6-benzylaminopurine and 3% sucrose. The highest regeneration rate was obtained with the peach×almond rootstocks. Endogenous levels of abscisic acid (ABA), indole-3-acetic acid (IAA), zeatin (Z), zeatin riboside (ZR), ethylene precursor 1-aminocyclopropane-1-carboxylic acid (ACC), salicylic acid (SA), and jasmonic acid (JA) were analyzed in the organogenic callus. Lower levels of several hormones, namely Z, ZR, ABA, and ACC were found in the peach×almond rootstock compared to peach cultivars, while IAA and SA presented inconclusive returns. These results suggest that the difference in somatic organogenesis capacity observed in peach and peach×almond hybrids is markedly affected by the endogenous hormonal content of the studied genotypes. Copyright © 2014 Elsevier GmbH. All rights reserved.

Genetic analysis of fat-to-protein ratio, milk yield and somatic cell score of Holstein cows in Japan in the first three lactations by using a random regression model.

PubMed

Nishiura, Akiko; Sasaki, Osamu; Aihara, Mitsuo; Takeda, Hisato; Satoh, Masahiro

2015-12-01

We estimated the genetic parameters of fat-to-protein ratio (FPR) and the genetic correlations between FPR and milk yield or somatic cell score in the first three lactations in dairy cows. Data included 3,079,517 test-day records of 201,138 Holstein cows in Japan from 2006 to 2011. Genetic parameters were estimated with a multiple-trait random regression model in which the records within and between parities were treated as separate traits. The phenotypic values of FPR increased soon after parturition and peaked at 10 to 20 days in milk, then decreased slowly in mid- and late lactation. Heritability estimates for FPR yielded moderate values. Genetic correlations of FPR among parities were low in early lactation. Genetic correlations between FPR and milk yield were positive and low in early lactation, but only in the first lactation. Genetic correlations between FPR and somatic cell score were positive in early lactation and decreased to become negative in mid- to late lactation. By using these results for genetic evaluation it should be possible to improve energy balance in dairy cows. © 2015 Japanese Society of Animal Science.

Sisters in hereditary breast and ovarian cancer families: communal coping, social integration, and psychological well-being.

PubMed

Koehly, Laura M; Peters, June A; Kuhn, Natalia; Hoskins, Lindsey; Letocha, Anne; Kenen, Regina; Loud, Jennifer; Greene, Mark H

2008-08-01

We investigated the association between psychological distress and indices of social integration and communal coping among sisters from hereditary breast and ovarian cancer (HBOC) families. Sixty-five sisters from 31 HBOC families completed the Brief Symptom Inventory-18 and the Colored Eco-Genetic Relationship Map, which identified members of participants' social support networks. Hierarchical linear models were used for all analyses to account for the clustering of sisters within families. Intra-family correlation coefficients suggested that sisters shared perceptions of breast cancer risk and worry, but not ovarian cancer risk and worry. Further, sisters demonstrated shared levels of anxiety and somatization, but not depressive symptoms. Communal coping indices quantifying shared support resources were negatively related to anxiety and somatization. The number of persons with whom cancer risk information was shared exhibited a positive trend with somatization. Social integration, as measured by the size of participants' emotional support network, was negatively associated with anxiety. Lower depression scores were observed among participants with more persons playing multiple support roles and fewer persons providing tangible assistance. Understanding how support relationships impact well-being among persons adjusting to HBOC risk, and the particular role of family in that process, will facilitate developing appropriate management approaches to help cancer-prone families adjust to their cancer risk.

The relationship between flesh quality and numbers of Kudoa thyrsites plasmodia and spores in farmed Atlantic salmon, Salmo salar L.

PubMed

Dawson-Coates, J A; Chase, J C; Funk, V; Booy, M H; Haines, L R; Falkenberg, C L; Whitaker, D J; Olafson, R W; Pearson, T W

2003-08-01

Atlantic salmon, Salmo salar L., were exposed to Kudoa thyrsites (Myxozoa, Myxosporea)-containing sea water for 15 months, and then harvested and assessed for parasite burden and fillet quality. At harvest, parasites were enumerated in muscle samples from a variety of somatic and opercular sites, and mean counts were determined for each fish. After 6 days storage at 4 degrees C, fillet quality was determined by visual assessment and by analysis of muscle firmness using a texture analyzer. Fillet quality could best be predicted by determining mean parasite numbers and spore counts in all eight tissue samples (somatic and opercular) or in four fillet samples, as the counts from opercular samples alone showed greater variability and thus decreased reliability. The variability in both plasmodia and spore numbers between tissue samples taken from an individual fish indicated that the parasites were not uniformly distributed in the somatic musculature. Therefore, to best predict the probable level of fillet degradation caused by K. thyrsites infections, multiple samples must be taken from each fish. If this is performed, a mean plasmodia count of 0.3 mm(-2) or a mean spore count of 4.0 x 10(5) g(-1) of tissue are the levels where the probability of severe myoliquefaction becomes a significant risk.

Dana-Farber Cancer Institute: Mapping the Function of Rare Oncogenic Variants | Office of Cancer Genomics

Cancer.gov

Although some oncogenes and tumor suppressor genes are recurrently mutated at high frequency, the majority of somatic sequence alterations found in cancers occur at low frequency, and the functional consequences of the majority of these mutated alleles remain unknown. We are developing a scalable systematic approach to interrogate the function of cancer-associated gene variants. Read the abstract

Children and adolescents with complex regional pain syndrome: More psychologically distressed than other children in pain?

PubMed Central

Logan, Deirdre E; Williams, Sara E; Carullo, Veronica P; Claar, Robyn Lewis; Bruehl, Stephen; Berde, Charles B

2013-01-01

BACKGROUND Historically, in both adult and pediatric populations, a lack of knowledge regarding complex regional pain syndrome (CRPS) and absence of clear diagnostic criteria have contributed to the view that this is a primarily psychiatric condition. OBJECTIVE: To test the hypothesis that children with CRPS are more functionally disabled, have more pain and are more psychologically distressed than children with other pain conditions. METHODS: A total of 101 children evaluated in a tertiary care pediatric pain clinic who met the International Association for the Study of Pain consensus diagnostic criteria for CRPS participated in the present retrospective study. Comparison groups included 103 children with abdominal pain, 291 with headache and 119 with back pain. Children and parents completed self-report questionnaires assessing disability, somatization, pain coping, depression, anxiety and school attendance. RESULTS: Children with CRPS reported higher pain intensity and more recent onset of pain at the initial tertiary pain clinic evaluation compared with children with other chronic pain conditions. They reported greater functional disability and more somatic symptoms than children with headaches or back pain. Scores on measures of depression and anxiety were within normal limits and similar to those of children in other pain diagnostic groups. CONCLUSIONS: As a group, clinic-referred children with CRPS may be more functionally impaired and experience more somatic symptoms compared with children with other pain conditions. However, overall psychological functioning as assessed by self-report appears to be similar to that of children with other chronic pain diagnoses. Comprehensive assessment using a biopsychosocial framework is essential to understanding and appropriately treating children with symptoms of CRPS. PMID:23662291

Age-specific associations between cardiac vagal activity and functional somatic symptoms: a population-based study.

PubMed

Tak, Lineke M; Janssens, Karin A M; Dietrich, Andrea; Slaets, Joris P J; Rosmalen, Judith G M

2010-01-01

Functional somatic symptoms (FSS) are symptoms not explained by underlying organic pathology. It has frequently been suggested that dysfunction of the autonomic nervous system (ANS) contributes to the development of FSS. We hypothesized that decreased cardiac vagal activity is cross-sectionally and prospectively associated with the number of FSS in the general population. This study was performed in a population-based cohort of 774 adults (45.1% male, mean age +/- SD 53.5 +/- 10.7 years). Participants completed the somatization section of the Composite International Diagnostic Interview surveying the presence of 43 FSS. ANS function was assessed by spectral analysis of heart rate variability in the high-frequency band (HRV-HF), reflecting cardiac vagal activity. Follow-up measurements of HRV-HF and FSS were performed approximately 2 years later. Linear regression analyses, with adjustments for gender, age, body mass index, anxiety, depression, smoking, alcohol use, and frequency of exercise, revealed an interaction of cardiac vagal activity with age: HRV-HF was negatively associated with FSS in adults 52 years (beta = 0.13, t = 2.51, p = 0.012). Longitudinal analysis demonstrated a similar pattern. Decreased cardiac vagal activity is associated with a higher number of FSS in adults aged 52 years needs further exploration. The role of age should be acknowledged in future studies on ANS function in the etiology of FSS. (c) 2010 S. Karger AG, Basel.

Is high-sensitive C-reactive protein a biomarker for functional somatic symptoms? A population-based study.

PubMed

Tak, Lineke M; Bakker, Stephan J L; Slaets, Joris P J; Rosmalen, Judith G M

2009-10-01

Functional somatic symptoms (FSS) are symptoms unexplained in terms of underlying organic pathology. Alterations in the immune system function may be associated with FSS via induction of sickness behavior. We aimed to investigate whether low-grade immune system activation is positively associated with FSS in a population-based cohort of 881 adults (46% male, mean age 53.0, SD 11.4). Participants completed the somatization section of the Composite International Diagnostic Interview surveying the presence of 43 FSS. Innate immune function was assessed by measuring high-sensitive C-reactive protein (hs-CRP). Follow-up measurements of hs-CRP and FSS were performed approximately 2years later. Regression analyses, with adjustments for gender, age, body mass index, anxiety, depression, smoking, alcohol use, and frequency of exercise, did not reveal a cross-sectional association (beta=0.01, t=0.40, p=0.693) or longitudinal association (beta=-0.03, t=-0.93, p=0.352) between hs-CRP and the total number of FSS. When examining different bodily clusters of FSS, hs-CRP was not associated with the gastrointestinal FSS cluster, but the association approached statistical significance for the general FSS cluster (OR 1.08, 95% CI 0.98-1.18) and musculoskeletal FSS cluster (OR 1.08, 95% CI 0.99-1.17). For the latter association, exploratory analyses revealed that mainly the pure musculoskeletal complaints were responsible (OR 1.12, 95% CI 1.03-1.21). We conclude that the level of hs-CRP is not a biomarker for the total number of FSS in the general population. The association between hs-CRP and musculoskeletal and general FSS needs further study.

A switch in the mode of Wnt signaling orchestrates the formation of germline stem cell differentiation niche in Drosophila

PubMed Central

Upadhyay, Maitreyi; Kuna, Michael; Tudor, Sara; Martino Cortez, Yesenia

2018-01-01

Germline stem cell (GSC) self-renewal and differentiation into gametes is regulated by both intrinsic factors in the germ line as well as extrinsic factors from the surrounding somatic niche. dWnt4, in the escort cells of the adult somatic niche promotes GSC differentiation using the canonical β-catenin-dependent transcriptional pathway to regulate escort cell survival, adhesion to the germ line and downregulation of self-renewal signaling. Here, we show that in addition to the β-catenin-dependent canonical pathway, dWnt4 also uses downstream components of the Wnt non-canonical pathway to promote escort cell function earlier in development. We find that the downstream non-canonical components, RhoA, Rac1 and cdc42, are expressed at high levels and are active in escort cell precursors of the female larval gonad compared to the adult somatic niche. Consistent with this expression pattern, we find that the non-canonical pathway components function in the larval stages but not in adults to regulate GSC differentiation. In the larval gonad, dWnt4, RhoA, Rac1 and cdc42 are required to promote intermingling of escort cell precursors, a function that then promotes proper escort cell function in the adults. We find that dWnt4 acts by modulating the activity of RhoA, Rac1 and cdc42, but not their protein levels. Together, our results indicate that at different points of development, dWnt4 switches from using the non-canonical pathway components to using a β-catenin-dependent canonical pathway in the escort cells to facilitate the proper differentiation of GSCs. PMID:29370168

External validity of randomized controlled trials in older adults, a systematic review.

PubMed

van Deudekom, Floor J; Postmus, Iris; van der Ham, Danielle J; Pothof, Alexander B; Broekhuizen, Karen; Blauw, Gerard J; Mooijaart, Simon P

2017-01-01

To critically assess the external validity of randomized controlled trials (RCTs) it is important to know what older adults have been enrolled in the trials. The aim of this systematic review is to study what proportion of trials specifically designed for older patients report on somatic status, physical and mental functioning, social environment and frailty in the patient characteristics. PubMed was searched for articles published in 2012 and only RCTs were included. Articles were further excluded if not conducted with humans or only secondary analyses were reported. A random sample of 10% was drawn. The current review analyzed this random sample and further selected trials when the reported mean age was ≥ 60 years. We extracted geriatric assessments from the population descriptives or the in- and exclusion criteria. In total 1396 trials were analyzed and 300 trials included. The median of the reported mean age was 66 (IQR 63-70) and the median percentage of men in the trials was 60 (IQR 45-72). In 34% of the RCTs specifically designed for older patients somatic status, physical and mental functioning, social environment or frailty were reported in the population descriptives or the in- and exclusion criteria. Physical and mental functioning was reported most frequently (22% and 14%). When selecting RCTs on a mean age of 70 or 80 years the report of geriatric assessments in the patient characteristics was 46% and 85% respectively but represent only 5% and 1% of the trials. Somatic status, physical and mental functioning, social environment and frailty are underreported even in RCTs specifically designed for older patients published in 2012. Therefore, it is unclear for clinicians to which older patients the results can be applied. We recommend systematic to transparently report these relevant characteristics of older participants included in RCTs.

The effectiveness of various computer-based interventions for patients with chronic pain or functional somatic syndromes: A systematic review and meta-analysis.

PubMed

Vugts, Miel A P; Joosen, Margot C W; van der Geer, Jessica E; Zedlitz, Aglaia M E E; Vrijhoef, Hubertus J M

2018-01-01

Computer-based interventions target improvement of physical and emotional functioning in patients with chronic pain and functional somatic syndromes. However, it is unclear to what extent which interventions work and for whom. This systematic review and meta-analysis (registered at PROSPERO, 2016: CRD42016050839) assesses efficacy relative to passive and active control conditions, and explores patient and intervention factors. Controlled studies were identified from MEDLINE, EMBASE, PsychInfo, Web of Science, and Cochrane Library. Pooled standardized mean differences by comparison type, and somatic symptom, health-related quality of life, functional interference, catastrophizing, and depression outcomes were calculated at post-treatment and at 6 or more months follow-up. Risk of bias was assessed. Sub-group analyses were performed by patient and intervention characteristics when heterogeneous outcomes were observed. Maximally, 30 out of 46 eligible studies and 3,387 participants were included per meta-analysis. Mostly, internet-based cognitive behavioral therapies were identified. Significantly higher patient reported outcomes were found in comparisons with passive control groups (standardized mean differences ranged between -.41 and -.18), but not in comparisons with active control groups (SMD = -.26 - -.14). For some outcomes, significant heterogeneity related to patient and intervention characteristics. To conclude, there is a minority of good quality evidence for small positive average effects of computer-based (cognitive) behavior change interventions, similar to traditional modes. These effects may be sustainable. Indications were found as of which interventions work better or more consistently across outcomes for which patients. Future process analyses are recommended in the aim of better understanding individual chances of clinically relevant outcomes.

Protein Domain-Level Landscape of Cancer-Type-Specific Somatic Mutations

PubMed Central

Yang, Fan; Petsalaki, Evangelia; Rolland, Thomas; Hill, David E.; Vidal, Marc; Roth, Frederick P.

2015-01-01

Identifying driver mutations and their functional consequences is critical to our understanding of cancer. Towards this goal, and because domains are the functional units of a protein, we explored the protein domain-level landscape of cancer-type-specific somatic mutations. Specifically, we systematically examined tumor genomes from 21 cancer types to identify domains with high mutational density in specific tissues, the positions of mutational hotspots within these domains, and the functional and structural context where possible. While hotspots corresponding to specific gain-of-function mutations are expected for oncoproteins, we found that tumor suppressor proteins also exhibit strong biases toward being mutated in particular domains. Within domains, however, we observed the expected patterns of mutation, with recurrently mutated positions for oncogenes and evenly distributed mutations for tumor suppressors. For example, we identified both known and new endometrial cancer hotspots in the tyrosine kinase domain of the FGFR2 protein, one of which is also a hotspot in breast cancer, and found new two hotspots in the Immunoglobulin I-set domain in colon cancer. Thus, to prioritize cancer mutations for further functional studies aimed at more precise cancer treatments, we have systematically correlated mutations and cancer types at the protein domain level. PMID:25794154

Differential item functioning in the Cambridge Mental Disorders in the Elderly (CAMDEX) Depression Scale across middle age and late life.

PubMed

Estabrook, Ryne; Sadler, Michael E; McGue, Matt

2015-12-01

A long-standing and critical problem in the study of aging and depression is the comparability of measurement across age groups. While psychological measures of depression typically show increased incidence of symptoms with increasing age, rates of depression diagnosis do not show the same age trend. This analysis presents tests of differential item functioning on the depression section of the CAMDEX interview schedule, using factor analysis-derived affective and somatic subscales (McGue & Christensen, 1997). Results for the affective subscale show significant differences in item functioning in the majority of the affective items as a function of age (items "Happy Life," "Lonely," "Nervous" "Worthless," and "Future": χ6(2) = [30.193, 255.971] across items, all p < .0001). Analyses for the somatic subscale show differential item functioning is limited to a single item relating to coping (χ6(2) = 180.754, p < .0001). These results indicate that differences in depression symptoms across age groups are not entirely consistent with a unidimensional depression trait, and that the measurement structure of depression varies over the life span. (c) 2015 APA, all rights reserved).

Review of somatic symptoms in post-traumatic stress disorder.

PubMed

Gupta, Madhulika A

2013-02-01

Post-traumatic stress disorder (PTSD) is associated with both (1) 'ill-defined' or 'medically unexplained' somatic syndromes, e.g. unexplained dizziness, tinnitus and blurry vision, and syndromes that can be classified as somatoform disorders (DSM-IV-TR); and (2) a range of medical conditions, with a preponderance of cardiovascular, respiratory, musculoskeletal, neurological, and gastrointestinal disorders, diabetes, chronic pain, sleep disorders and other immune-mediated disorders in various studies. Frequently reported medical co-morbidities with PTSD across various studies include cardiovascular disease, especially hypertension, and immune-mediated disorders. PTSD is associated with limbic instability and alterations in both the hypothalamic- pituitary-adrenal and sympatho-adrenal medullary axes, which affect neuroendocrine and immune functions, have central nervous system effects resulting in pseudo-neurological symptoms and disorders of sleep-wake regulation, and result in autonomic nervous system dysregulation. Hypervigilance, a central feature of PTSD, can lead to 'local sleep' or regional arousal states, when the patient is partially asleep and partially awake, and manifests as complex motor and/or verbal behaviours in a partially conscious state. The few studies of the effects of standard PTSD treatments (medications, CBT) on PTSD-associated somatic syndromes report a reduction in the severity of ill-defined and autonomically mediated somatic symptoms, self-reported physical health problems, and some chronic pain syndromes.

Mps1 (Monopolar Spindle 1) Protein Inhibition Affects Cellular Growth and Pro-Embryogenic Masses Morphology in Embryogenic Cultures of Araucaria angustifolia (Araucariaceae).

PubMed

Douétts-Peres, Jackellinne C; Cruz, Marco Antônio L; Reis, Ricardo S; Heringer, Angelo S; de Oliveira, Eduardo A G; Elbl, Paula M; Floh, Eny I S; Silveira, Vanildo; Santa-Catarina, Claudete

2016-01-01

Somatic embryogenesis has been shown to be an efficient tool for studying processes based on cell growth and development. The fine regulation of the cell cycle is essential for proper embryo formation during the process of somatic embryogenesis. The aims of the present work were to identify and perform a structural and functional characterization of Mps1 and to analyze the effects of the inhibition of this protein on cellular growth and pro-embryogenic mass (PEM) morphology in embryogenic cultures of A. angustifolia. A single-copy Mps1 gene named AaMps1 was retrieved from the A. angustifolia transcriptome database, and through a mass spectrometry approach, AaMps1 was identified and quantified in embryogenic cultures. The Mps1 inhibitor SP600125 (10 μM) inhibited cellular growth and changed PEMs, and these effects were accompanied by a reduction in AaMps1 protein levels in embryogenic cultures. Our work has identified the Mps1 protein in a gymnosperm species for the first time, and we have shown that inhibiting Mps1 affects cellular growth and PEM differentiation during A. angustifolia somatic embryogenesis. These data will be useful for better understanding cell cycle control during somatic embryogenesis in plants.

Mps1 (Monopolar Spindle 1) Protein Inhibition Affects Cellular Growth and Pro-Embryogenic Masses Morphology in Embryogenic Cultures of Araucaria angustifolia (Araucariaceae)

PubMed Central

Douétts-Peres, Jackellinne C.; Cruz, Marco Antônio L.; Reis, Ricardo S.; Heringer, Angelo S.; de Oliveira, Eduardo A. G.; Elbl, Paula M.; Floh, Eny I. S.; Silveira, Vanildo

2016-01-01

Somatic embryogenesis has been shown to be an efficient tool for studying processes based on cell growth and development. The fine regulation of the cell cycle is essential for proper embryo formation during the process of somatic embryogenesis. The aims of the present work were to identify and perform a structural and functional characterization of Mps1 and to analyze the effects of the inhibition of this protein on cellular growth and pro-embryogenic mass (PEM) morphology in embryogenic cultures of A. angustifolia. A single-copy Mps1 gene named AaMps1 was retrieved from the A. angustifolia transcriptome database, and through a mass spectrometry approach, AaMps1 was identified and quantified in embryogenic cultures. The Mps1 inhibitor SP600125 (10 μM) inhibited cellular growth and changed PEMs, and these effects were accompanied by a reduction in AaMps1 protein levels in embryogenic cultures. Our work has identified the Mps1 protein in a gymnosperm species for the first time, and we have shown that inhibiting Mps1 affects cellular growth and PEM differentiation during A. angustifolia somatic embryogenesis. These data will be useful for better understanding cell cycle control during somatic embryogenesis in plants. PMID:27064899

'I'm more sick than my doctors think': ethical issues in managing somatization in developing countries.

PubMed

Chandra, Prabha S; Satyanarayana, Veena A

2013-02-01

Several ethical issues confront the healthcare professional who is managing somatization in developing countries where cost constraints, low literacy, poverty, poor nutrition and infections and inadequate access to healthcare are common. The paper discusses these in the context of the ethical principles of autonomy, beneficence, non-maleficence and justice. Some of the ethical issues in managing somatization include being influenced by patient distress rather than rational medical decision-making, inadequate attention to the cultural meaning of symptoms, psychologizing versus medicalizing, the ethics of nomenclature and labels, communicating ethically with patients, and managing them adequately given lack of evidence and training. An ethical approach to managing somatization in this context would include using an integrated and simultaneous medical and psychiatric approach. To ensure patient beneficence, the medical, psychological and social assessment should be undertaken side-by-side as much as possible and should be cost effective. Respecting patient autonomy by using adequate communication methods and the patient's cultural model of the illness as part of management is also integral to ethical practice. In the developing world, issues of equity are also an important ethical concern. When more serious illnesses are the health priority, functional syndromes may not get equal importance or resources.

Developmental genes significantly afflicted by aberrant promoter methylation and somatic mutation predict overall survival of late-stage colorectal cancer

PubMed Central

An, Ning; Yang, Xue; Cheng, Shujun; Wang, Guiqi; Zhang, Kaitai

2015-01-01

Carcinogenesis is an exceedingly complicated process, which involves multi-level dysregulations, including genomics (majorly caused by somatic mutation and copy number variation), DNA methylomics, and transcriptomics. Therefore, only looking into one molecular level of cancer is not sufficient to uncover the intricate underlying mechanisms. With the abundant resources of public available data in the Cancer Genome Atlas (TCGA) database, an integrative strategy was conducted to systematically analyze the aberrant patterns of colorectal cancer on the basis of DNA copy number, promoter methylation, somatic mutation and gene expression. In this study, paired samples in each genomic level were retrieved to identify differentially expressed genes with corresponding genetic or epigenetic dysregulations. Notably, the result of gene ontology enrichment analysis indicated that the differentially expressed genes with corresponding aberrant promoter methylation or somatic mutation were both functionally concentrated upon developmental process, suggesting the intimate association between development and carcinogenesis. Thus, by means of random walk with restart, 37 significant development-related genes were retrieved from a priori-knowledge based biological network. In five independent microarray datasets, Kaplan–Meier survival and Cox regression analyses both confirmed that the expression of these genes was significantly associated with overall survival of Stage III/IV colorectal cancer patients. PMID:26691761

Developmental genes significantly afflicted by aberrant promoter methylation and somatic mutation predict overall survival of late-stage colorectal cancer.

PubMed

An, Ning; Yang, Xue; Cheng, Shujun; Wang, Guiqi; Zhang, Kaitai

2015-12-22

Carcinogenesis is an exceedingly complicated process, which involves multi-level dysregulations, including genomics (majorly caused by somatic mutation and copy number variation), DNA methylomics, and transcriptomics. Therefore, only looking into one molecular level of cancer is not sufficient to uncover the intricate underlying mechanisms. With the abundant resources of public available data in the Cancer Genome Atlas (TCGA) database, an integrative strategy was conducted to systematically analyze the aberrant patterns of colorectal cancer on the basis of DNA copy number, promoter methylation, somatic mutation and gene expression. In this study, paired samples in each genomic level were retrieved to identify differentially expressed genes with corresponding genetic or epigenetic dysregulations. Notably, the result of gene ontology enrichment analysis indicated that the differentially expressed genes with corresponding aberrant promoter methylation or somatic mutation were both functionally concentrated upon developmental process, suggesting the intimate association between development and carcinogenesis. Thus, by means of random walk with restart, 37 significant development-related genes were retrieved from a priori-knowledge based biological network. In five independent microarray datasets, Kaplan-Meier survival and Cox regression analyses both confirmed that the expression of these genes was significantly associated with overall survival of Stage III/IV colorectal cancer patients.

Mitochondrial DNA transmission and confounding mitochondrial influences in cloned cattle and pigs.

PubMed

Takeda, Kumiko

2013-04-01

Although somatic cell nuclear transfer (SCNT) is a powerful tool for production of cloned animals, SCNT embryos generally have low developmental competency and many abnormalities. The interaction between the donor nucleus and the enucleated ooplasm plays an important role in early embryonic development, but the underlying mechanisms that negatively impact developmental competency remain unclear. Mitochondria have a broad range of critical functions in cellular energy supply, cell signaling, and programmed cell death; thus, affect embryonic and fetal development. This review focuses on mitochondrial considerations influencing SCNT techniques in farm animals. Donor somatic cell mitochondrial DNA (mtDNA) can be transmitted through what has been considered a "bottleneck" in mitochondrial genetics via the SCNT maternal lineage. This indicates that donor somatic cell mitochondria have a role in the reconstructed cytoplasm. However, foreign somatic cell mitochondria may affect the early development of SCNT embryos. Nuclear-mitochondrial interactions in interspecies/intergeneric SCNT (iSCNT) result in severe problems. A major biological selective pressure exists against survival of exogenous mtDNA in iSCNT. Yet, mtDNA differences in SCNT animals did not reflect transfer of proteomic components following proteomic analysis. Further study of nuclear-cytoplasmic interactions is needed to illuminate key developmental characteristics of SCNT animals associated with mitochondrial biology.

Proteogenomics connects somatic mutations to signalling in breast cancer.

PubMed

Mertins, Philipp; Mani, D R; Ruggles, Kelly V; Gillette, Michael A; Clauser, Karl R; Wang, Pei; Wang, Xianlong; Qiao, Jana W; Cao, Song; Petralia, Francesca; Kawaler, Emily; Mundt, Filip; Krug, Karsten; Tu, Zhidong; Lei, Jonathan T; Gatza, Michael L; Wilkerson, Matthew; Perou, Charles M; Yellapantula, Venkata; Huang, Kuan-lin; Lin, Chenwei; McLellan, Michael D; Yan, Ping; Davies, Sherri R; Townsend, R Reid; Skates, Steven J; Wang, Jing; Zhang, Bing; Kinsinger, Christopher R; Mesri, Mehdi; Rodriguez, Henry; Ding, Li; Paulovich, Amanda G; Fenyö, David; Ellis, Matthew J; Carr, Steven A

2016-06-02

Somatic mutations have been extensively characterized in breast cancer, but the effects of these genetic alterations on the proteomic landscape remain poorly understood. Here we describe quantitative mass-spectrometry-based proteomic and phosphoproteomic analyses of 105 genomically annotated breast cancers, of which 77 provided high-quality data. Integrated analyses provided insights into the somatic cancer genome including the consequences of chromosomal loss, such as the 5q deletion characteristic of basal-like breast cancer. Interrogation of the 5q trans-effects against the Library of Integrated Network-based Cellular Signatures, connected loss of CETN3 and SKP1 to elevated expression of epidermal growth factor receptor (EGFR), and SKP1 loss also to increased SRC tyrosine kinase. Global proteomic data confirmed a stromal-enriched group of proteins in addition to basal and luminal clusters, and pathway analysis of the phosphoproteome identified a G-protein-coupled receptor cluster that was not readily identified at the mRNA level. In addition to ERBB2, other amplicon-associated highly phosphorylated kinases were identified, including CDK12, PAK1, PTK2, RIPK2 and TLK2. We demonstrate that proteogenomic analysis of breast cancer elucidates the functional consequences of somatic mutations, narrows candidate nominations for driver genes within large deletions and amplified regions, and identifies therapeutic targets.

Musculoskeletal overuse injuries and heart rate variability: Is there a link?

PubMed

Gisselman, Angela Spontelli; Baxter, G David; Wright, Alexis; Hegedus, Eric; Tumilty, Steve

2016-02-01

Accurate detection and prevention of overuse musculoskeletal injuries is limited by the nature of somatic tissue injury. In the pathogenesis of overuse injuries, it is well recognized that an abnormal inflammatory response occurs within somatic tissue before pain is perceived which can disrupt the normal remodeling process and lead to subsequent degeneration. Current overuse injury prevention methods focused on biomechanical faults or performance standards lack the sensitivity needed to identify the status of tissue injury or repair. Recent evidence has revealed an apparent increase in the prevalence and impact of overuse musculoskeletal injuries in athletics. When compared to acute injuries, overuse injuries have a potentially greater negative impact on athletes' overall health burden. Further, return to sport rehabilitation following overuse injury is complicated by the fact that the absence of pain does not equate to complete physiological healing of the injured tissue. Together, this highlights the need for exercise monitoring and injury prevention methods which incorporate assessment of somatic tissue response to loading. One system primarily involved in the activation of pathways and neuromediators responsible for somatic tissue repair is the autonomic nervous system (ANS). Although not completely understood, emerging research supports the critical importance of peripheral ANS activity in the health and repair of somatic tissue injury. Due to its significant contributions to cardiac function, ANS activity can be measured indirectly with heart rate monitoring. Heart rate variability (HRV) is one index of ANS activity that has been used to investigate the relationship between athletes' physiological response to accumulating training load. Research findings indicated that HRV may provide a reflection of ANS homeostasis, or the body's stress-recovery status. This noninvasive marker of the body's primary driver of recovery has the potential to incorporate important and as yet unmonitored physiological mechanisms involved in overuse injury development. We hypothesize that abnormal somatic tissue response to accumulating microtrauma may modulate ANS activity at the level of HRV. Exploring the link between HRV modulation and somatic tissue injury has the potential to reveal the putative role of ANS homeostasis on overuse musculoskeletal injury development. Copyright © 2015 Elsevier Ltd. All rights reserved.

A germline mutation of CDKN2A and a novel RPLP1-C19MC fusion detected in a rare melanotic neuroectodermal tumor of infancy: a case report.

PubMed

Barnes, David J; Hookway, Edward; Athanasou, Nick; Kashima, Takeshi; Oppermann, Udo; Hughes, Simon; Swan, Daniel; Lueerssen, Dietrich; Anson, John; Hassan, A Bassim

2016-08-12

Melanotic neuroectodermal tumor of infancy (MNTI) is exceptionally rare and occurs predominantly in the head and neck (92.8 % cases). The patient reported here is only the eighth case of MNTI presenting in an extremity, and the first reported in the fibula. A 2-month-old female presented with a mass arising in the fibula. Exhaustive genomic, transcriptomic, epigenetic and pathological characterization was performed on the excised primary tumor and a derived cell line. Whole-exome analysis of genomic DNA from both the tumor and blood indicated no somatic, non-synonymous coding mutations within the tumor, but a heterozygous, unique germline, loss of function mutation in CDKN2A (p16(INK4A), D74A). SNP-array CGH on DNA samples revealed the tumor to be euploid, with no detectable gene copy number variants. Multiple chromosomal translocations were identified by RNA-Seq, and fusion genes included RPLP1-C19MC, potentially deregulating the C19MC cluster, an imprinted locus containing microRNA genes reactivated by gene fusion in embryonal tumors with multilayered rosettes. Since the presumed cell of origin of MNTI is from the neural crest, we also compared gene expression with a dataset from human neural crest cells and identified 185 genes with significantly different expression. Consistent with the melanotic phenotype of the tumor, elevated expression of tyrosinase was observed. Other highly expressed genes encoded muscle proteins and modulators of the extracellular matrix. A derived MNTI cell line was sensitive to inhibitors of lysine demethylase, but not to compounds targeting other epigenetic regulators. In the absence of somatic copy number variations or mutations, the fully transformed phenotype of the MNTI may have arisen in infancy because of the combined effects of a germline CDKN2A mutation, tumor promoting somatic fusion genes and epigenetic deregulation. Very little is known about the etiology of MNTI and this report advances knowledge of these rare tumors by providing the first comprehensive genomic, transcriptomic and epigenetic characterization of a case.

A Common Variant at the 14q32 Endometrial Cancer Risk Locus Activates AKT1 through YY1 Binding.

PubMed

Painter, Jodie N; Kaufmann, Susanne; O'Mara, Tracy A; Hillman, Kristine M; Sivakumaran, Haran; Darabi, Hatef; Cheng, Timothy H T; Pearson, John; Kazakoff, Stephen; Waddell, Nicola; Hoivik, Erling A; Goode, Ellen L; Scott, Rodney J; Tomlinson, Ian; Dunning, Alison M; Easton, Douglas F; French, Juliet D; Salvesen, Helga B; Pollock, Pamela M; Thompson, Deborah J; Spurdle, Amanda B; Edwards, Stacey L

2016-06-02

A recent meta-analysis of multiple genome-wide association and follow-up endometrial cancer case-control datasets identified a novel genetic risk locus for this disease at chromosome 14q32.33. To prioritize the functional SNP(s) and target gene(s) at this locus, we employed an in silico fine-mapping approach using genotyped and imputed SNP data for 6,608 endometrial cancer cases and 37,925 controls of European ancestry. Association and functional analyses provide evidence that the best candidate causal SNP is rs2494737. Multiple experimental analyses show that SNP rs2494737 maps to a silencer element located within AKT1, a member of the PI3K/AKT/MTOR intracellular signaling pathway activated in endometrial tumors. The rs2494737 risk A allele creates a YY1 transcription factor-binding site and abrogates the silencer activity in luciferase assays, an effect mimicked by transfection of YY1 siRNA. Our findings suggest YY1 is a positive regulator of AKT1, mediating the stimulatory effects of rs2494737 increasing endometrial cancer risk. Identification of an endometrial cancer risk allele within a member of the PI3K/AKT signaling pathway, more commonly activated in tumors by somatic alterations, raises the possibility that well tolerated inhibitors targeting this pathway could be candidates for evaluation as chemopreventive agents in individuals at high risk of developing endometrial cancer. Copyright © 2016 American Society of Human Genetics. Published by Elsevier Inc. All rights reserved.

Millennium Cohort: The 2001-2003 Baseline Prevalence of Mental Disorders in the U.S. Military

DTIC Science & Technology

2007-01-01

close relatives (separa- tion anxiety disorder), gaining weight ( anorexia nervosa ), having multiple physical complaints (somatization disor- der), or...items), other anxiety syndrome (6 items), and bulimia nervosa (4 items), and subthreshold disorders (disorders for which criteria encompass fewer...eating and bu- limia nervosa disorders are combined into eating disorders. The PHQ defines alcohol abuse as an indication of at least one of five

Screening a UK amyotrophic lateral sclerosis cohort provides evidence of multiple origins of the C9orf72 expansion.

PubMed

Fratta, Pietro; Polke, James M; Newcombe, Jia; Mizielinska, Sarah; Lashley, Tammaryn; Poulter, Mark; Beck, Jon; Preza, Elisavet; Devoy, Anny; Sidle, Katie; Howard, Robin; Malaspina, Andrea; Orrell, Richard W; Clarke, Jan; Lu, Ching-Hua; Mok, Kin; Collins, Toby; Shoaii, Maryam; Nanji, Tina; Wray, Selina; Adamson, Gary; Pittman, Alan; Renton, Alan E; Traynor, Bryan J; Sweeney, Mary G; Revesz, Tamas; Houlden, Henry; Mead, Simon; Isaacs, Adrian M; Fisher, Elizabeth M C

2015-01-01

An expanded hexanucleotide repeat in the C9orf72 gene is the most common genetic cause of amyotrophic lateral sclerosis and frontotemporal dementia (C9ALS/FTD). Although 0-30 hexanucleotide repeats are present in the general population, expansions >500 repeats are associated with C9ALS/FTD. Large C9ALS/FTD expansions share a common haplotype and whether these expansions derive from a single founder or occur more frequently on a predisposing haplotype is yet to be determined and is relevant to disease pathomechanisms. Furthermore, although cases carrying 50-200 repeats have been described, their role and the pathogenic threshold of the expansions remain to be identified and carry importance for diagnostics and genetic counseling. We present clinical and genetic data from a UK ALS cohort and report the detailed molecular study of an atypical somatically unstable expansion of 90 repeats. Our results across different tissues provide evidence for the pathogenicity of this repeat number by showing they can somatically expand in the central nervous system to the well characterized pathogenic range. Our results support the occurrence of multiple expansion events for C9ALS/FTD. Copyright © 2015 The Authors. Published by Elsevier Inc. All rights reserved.

Noncoding somatic and inherited single-nucleotide variants converge to promote ESR1 expression in breast cancer.

PubMed

Bailey, Swneke D; Desai, Kinjal; Kron, Ken J; Mazrooei, Parisa; Sinnott-Armstrong, Nicholas A; Treloar, Aislinn E; Dowar, Mark; Thu, Kelsie L; Cescon, David W; Silvester, Jennifer; Yang, S Y Cindy; Wu, Xue; Pezo, Rossanna C; Haibe-Kains, Benjamin; Mak, Tak W; Bedard, Philippe L; Pugh, Trevor J; Sallari, Richard C; Lupien, Mathieu

2016-10-01

Sustained expression of the estrogen receptor-α (ESR1) drives two-thirds of breast cancer and defines the ESR1-positive subtype. ESR1 engages enhancers upon estrogen stimulation to establish an oncogenic expression program. Somatic copy number alterations involving the ESR1 gene occur in approximately 1% of ESR1-positive breast cancers, suggesting that other mechanisms underlie the persistent expression of ESR1. We report significant enrichment of somatic mutations within the set of regulatory elements (SRE) regulating ESR1 in 7% of ESR1-positive breast cancers. These mutations regulate ESR1 expression by modulating transcription factor binding to the DNA. The SRE includes a recurrently mutated enhancer whose activity is also affected by rs9383590, a functional inherited single-nucleotide variant (SNV) that accounts for several breast cancer risk-associated loci. Our work highlights the importance of considering the combinatorial activity of regulatory elements as a single unit to delineate the impact of noncoding genetic alterations on single genes in cancer.

Specialized piRNA Pathways Act in Germline and Somatic Tissues of the Drosophila Ovary

PubMed Central

Malone, Colin D.; Brennecke, Julius; Dus, Monica; Stark, Alexander; McCombie, W. Richard; Sachidanandam, Ravi; Hannon, Gregory J.

2010-01-01

SUMMARY In Drosophila gonads, Piwi proteins and associated piRNAs collaborate with additional factors to form a small RNA-based immune system that silences mobile elements. Here, we analyzed nine Drosophila piRNA pathway mutants for their impacts on both small RNA populations and the subcellular localization patterns of Piwi proteins. We find that distinct piRNA pathways with differing components function in ovarian germ and somatic cells. In the soma, Piwi acts singularly with the conserved flamenco piRNA cluster to enforce silencing of retroviral elements that may propagate by infecting neighboring germ cells. In the germline, silencing programs encoded within piRNA clusters are optimized via a slicer-dependent amplification loop to suppress a broad spectrum of elements. The classes of transposons targeted by germline and somatic piRNA clusters, though not the precise elements, are conserved among Drosophilids, demonstrating that the architecture of piRNA clusters has coevolved with the transposons that they are tasked to control. PMID:19395010

An artificial arm/hand system with a haptic sensory function using electric stimulation of peripheral sensory nerve fibers.

PubMed

Mabuchi, Kunihiko

2013-01-01

We are currently developing an artificial arm/hand system which is capable of sensing stimuli and then transferring these stimuli to users as somatic sensations. Presently, we are evoking the virtual somatic sensations by electrically stimulating a sensory nerve fiber which innervates a single mechanoreceptor unit at the target area; this is done using a tungsten microelectrode that was percutaneously inserted into the use's peripheral nerve (a microstimulation method). The artificial arm/hand system is composed of a robot hand equipped with a pressure sensor system on its fingers. The sensor system detects mechanical stimuli, which are transferred to the user by means of the microstimulation method so that the user experiences the stimuli as the corresponding somatic sensations. In trials, the system worked satisfactorily and there was a good correlation between the pressure applied to the pressure sensors on the robot fingers and the subjective intensities of the evoked pressure sensations.

HPV-negative penile squamous cell carcinoma: disruptive mutations in the TP53 gene are common.

PubMed

Kashofer, Karl; Winter, Elke; Halbwedl, Iris; Thueringer, Andrea; Kreiner, Marisa; Sauer, Stefan; Regauer, Sigrid

2017-07-01

The majority of penile squamous cell carcinomas is caused by transforming human papilloma virus (HPV) infection. The etiology of HPV-negative cancers is unclear, but TP53 mutations have been implicated. Archival tissues of 108 invasive squamous cell carcinoma from a single pathology institution in a low-incidence area were analyzed for HPV-DNA and p16 ink4a overexpression and for TP53 mutations by ion torrent next-generation sequencing. Library preparation failed in 32/108 squamous cell carcinomas. Institutional review board approval was obtained. Thirty of 76 squamous cell carcinomas (43%; average 63 years) were HPV-negative with 8/33 squamous cell carcinomas being TP53 wild-type (24%; average 63 years). Twenty-five of 33 squamous cell carcinomas (76%; average 65 years) showed 32 different somatic TP53 mutations (23 missense mutations in exons 5-8, 6 nonsense, 1 frameshift and 2 splice-site mutations). Several hotspot mutations were detected multiple times (R175H, R248, R282, and R273). Eighteen of 19 squamous cell carcinomas with TP53 expression in immunohistochemistry had TP53 mutations. Fifty percent of TP53-negative squamous cell carcinomas showed mostly truncating loss-of-function TP53 mutations. Patients without mutations had longer survival (5 years: 86% vs 61%; 10 years: 60% vs 22%), but valid clinically relevant conclusions cannot be drawn due to different tumor stages and heterogeneous treatment of the cases presented in this study. Somatic TP53 mutations are a common feature in HPV-negative penile squamous cell carcinomas and offer an explanation for HPV-independent penile carcinogenesis. About half of HPV-negative penile cancers are driven by oncogenic activation of TP53, while a quarter is induced by loss of TP53 tumor suppressor function. Detection of TP53 mutations should be carried out by sequencing, as immunohistochemical TP53 staining could not identify all squamous cell carcinomas with TP53 mutations.

Can agonistic striving lead to unexplained illness? Implicit goals, pain tolerance, and somatic symptoms in adolescents and adults.

PubMed

Ewart, Craig K; Elder, Gavin J; Laird, Kelsey T; Shelby, Grace D; Walker, Lynn S

2014-09-01

We tested the social action theory hypotheses that (a) psychological stress induced by struggling to control others (agonistic striving) is associated with higher levels of subjective somatic symptoms than stress induced by struggling to control the self (transcendence striving); (b) the association between agonistic striving and symptoms is moderated by the ability to tolerate pain; and (c) associations among agonistic goals, pain tolerance, and subjective symptoms are not explained by personality and affective traits or negative emotional responses to personal stressors. Implicit motives and negative emotional reactivity to recurring personal stressors were assessed by Social Competence Interview in 333 adolescents and adults who participated in longitudinal research on functional abdominal pain at a university medical center. Pain tolerance was assessed by graduated thermal pain protocol; subjective somatic symptoms, and personality/affective traits assessed by questionnaires. The primary outcome measure was the self-reported severity of 35 somatic symptoms often experienced in the absence of diagnosable disease. All hypotheses were supported. Nonconscious agonistic strivings may increase the perceived frequency and severity of subjective somatic symptoms; this tendency is greatly magnified by difficulty in self-regulating responses to painful stimuli. Implicit agonistic motives and their associations with symptoms are not explained by individual differences in trait neuroticism, anxiety, depression, anger, or low self-esteem or by negative emotional reactivity to a personal stressor. These findings may afford fruitful insights into mechanisms by which stressful social environments undermine health and suggest promising directions for clinical intervention. (PsycINFO Database Record (c) 2014 APA, all rights reserved).

Control of Anther Cell Differentiation by the Small Protein Ligand TPD1 and Its Receptor EMS1 in Arabidopsis

PubMed Central

Huang, Jian; Zhang, Tianyu; Linstroth, Lisa; Tillman, Zachary; Otegui, Marisa S.; Owen, Heather A.

2016-01-01

A fundamental feature of sexual reproduction in plants and animals is the specification of reproductive cells that conduct meiosis to form gametes, and the associated somatic cells that provide nutrition and developmental cues to ensure successful gamete production. The anther, which is the male reproductive organ in seed plants, produces reproductive microsporocytes (pollen mother cells) and surrounding somatic cells. The microsporocytes yield pollen via meiosis, and the somatic cells, particularly the tapetum, are required for the normal development of pollen. It is not known how the reproductive cells affect the differentiation of these somatic cells, and vice versa. Here, we use molecular genetics, cell biological, and biochemical approaches to demonstrate that TPD1 (TAPETUM DETERMINANT1) is a small secreted cysteine-rich protein ligand that interacts with the LRR (Leucine-Rich Repeat) domain of the EMS1 (EXCESS MICROSPOROCYTES1) receptor kinase at two sites. Analyses of the expressions and localizations of TPD1 and EMS1, ectopic expression of TPD1, experimental missorting of TPD1, and ablation of microsporocytes yielded results suggesting that the precursors of microsporocyte/microsporocyte-derived TPD1 and pre-tapetal-cell-localized EMS1 initially promote the periclinal division of secondary parietal cells and then determine one of the two daughter cells as a functional tapetal cell. Our results also indicate that tapetal cells suppress microsporocyte proliferation. Collectively, our findings show that tapetal cell differentiation requires reproductive-cell-secreted TPD1, illuminating a novel mechanism whereby signals from reproductive cells determine somatic cell fate in plant sexual reproduction. PMID:27537183

Spreading activation in emotional memory networks and the cumulative effects of somatic markers.

PubMed

Foster, Paul S; Hubbard, Tyler; Campbell, Ransom W; Poole, Jonathan; Pridmore, Michael; Bell, Chris; Harrison, David W

2017-06-01

The theory of spreading activation proposes that the activation of a semantic memory node may spread along bidirectional associative links to other related nodes. Although this theory was originally proposed to explain semantic memory networks, a similar process may be said to exist with episodic or emotional memory networks. The Somatic Marker hypothesis proposes that remembering an emotional memory activates the somatic sensations associated with the memory. An integration of these two models suggests that as spreading activation in emotional memory networks increases, a greater number of associated somatic markers would become activated. This process would then result in greater changes in physiological functioning. We sought to investigate this possibility by having subjects recall words associated with sad and happy memories, in addition to a neutral condition. The average ages of the memories and the number of word memories recalled were then correlated with measures of heart rate and skin conductance. The results indicated significant positive correlations between the number of happy word memories and heart rate (r = .384, p = .022) and between the average ages of the sad memories and skin conductance (r = .556, p = .001). Unexpectedly, a significant negative relationship was found between the number of happy word memories and skin conductance (r = -.373, p = .025). The results provide partial support for our hypothesis, indicating that increasing spreading activation in emotional memory networks activates an increasing number of somatic markers and this is then reflected in greater physiological activity at the time of recalling the memories.

New Insights into Somatic Embryogenesis: LEAFY COTYLEDON1, BABY BOOM1 and WUSCHEL-RELATED HOMEOBOX4 Are Epigenetically Regulated in Coffea canephora

PubMed Central

Nic-Can, Geovanny I.; López-Torres, Adolfo; Barredo-Pool, Felipe; Wrobel, Kazimierz; Loyola-Vargas, Víctor M.; Rojas-Herrera, Rafael; De-la-Peña, Clelia

2013-01-01

Plant cells have the capacity to generate a new plant without egg fertilization by a process known as somatic embryogenesis (SE), in which differentiated somatic cells can form somatic embryos able to generate a functional plant. Although there have been advances in understanding the genetic basis of SE, the epigenetic mechanism that regulates this process is still unknown. Here, we show that the embryogenic development of Coffea canephora proceeds through a crosstalk between DNA methylation and histone modifications during the earliest embryogenic stages of SE. We found that low levels of DNA methylation, histone H3 lysine 9 dimethylation (H3K9me2) and H3K27me3 change according to embryo development. Moreover, the expression of LEAFY COTYLEDON1 (LEC1) and BABY BOOM1 (BBM1) are only observed after SE induction, whereas WUSCHEL-RELATED HOMEOBOX4 (WOX4) decreases its expression during embryo maturation. Using a pharmacological approach, it was found that 5-Azacytidine strongly inhibits the embryogenic response by decreasing both DNA methylation and gene expression of LEC1 and BBM1. Therefore, in order to know whether these genes were epigenetically regulated, we used Chromatin Immunoprecipitation (ChIP) assays. It was found that WOX4 is regulated by the repressive mark H3K9me2, while LEC1 and BBM1 are epigenetically regulated by H3K27me3. We conclude that epigenetic regulation plays an important role during somatic embryogenic development, and a molecular mechanism for SE is proposed. PMID:23977240