Somatic Screening Research Articles

Is Somatic Health Screening in Patients With Severe Mental Illness of Added Value?

To evaluate the added value of somatic screening for patients with severe mental illness over regular care. We compared the information on somatic health problems collected by screening with the general practitioner (GP) files (n = 118). The mean number of somatic health problems detected with somatic health screening was significantly higher than those noted in GP records (p < .01). Somatic health screening is an addition to the care provided by the GP. Advanced mental health nurses can play a key role in somatic health screening and initiating further cooperation and communication of GP and mental health care.

1678 – Do vitamin d levels in bipolar and schizophenia outpatients differ? outcome of a dutch cross-sectional study

Itzhaky (2012) found significantly lower vitamin D level in patients with schizophrenia than in healthy controls. Measurement of vitamine-D in bipolar and schizophrenia/schizoaffective outpatients. Determining the prevalence of vitamin D deficiency in outpatients with bipolar disorder, schizophrenia or schizoaffective disorder in the Netherlands. Outpatients in the Alkmaar region aged 18w65 years with a bipolar disorder, Schizophrenia/schizoaffective disorder were asked to add vitamin D levels determination to the annual standard blood sample taking. 111 patients, 54 with schizophrenia/schizoaffective disorder and 57 with bipolar disorder, participated. 58 (53%) was male, mean age 47 (SD 9.9) years. 64 (58%) showed vitamin-D insufficiency (< 50 nmol/L), 32 (29%) vitamin-D deficiency (< 30 nmol/L). 7 (6.3%) female patients aged >50 had a serum level between 30–50 nmol/l. No significant differences were found between bipolar disorder and schizophrenia/schizoaffective disorder. To prevent osteoporosis, vitamin D supplementation is advised with vitamin D-levels below 30nmol/l or below 50 in women >50 years and men >70 years, (Dutch Health Council). Using to this criterion 39 patients (35%) of the study-population needed vitamine-D supplement. If confirmed, addition of vitamine-D levels to the annual somatic screening of patients with bipolar disorder, schizophrenia/schizoaffective disorder is indicated. Limitation: the impact of the season on vitamine-D levels was not corrected for in either population.

Abstract LB-404: Genomic analysis reveals roles for chromatin modification and axon guidance in pancreatic cancer

Abstract Pancreatic cancer (PC) is the fourth leading cause of cancer death with an overall 5-year survival rate of &amp;lt; 5%, a statistic that has not changed in almost 50 years. A deeper understanding of the underlying molecular pathophysiology is expected to advance the urgent need to develop effective therapeutic and early detection strategies for this disease. Genomic characterisation of Pancreatic Ductal Adenocarcinoma (PDAC), which accounts for over 90% of PC has to date relied on targeted PCR based exome sequencing of primary and metastatic lesions propagated as xenografts or cell lines. Here we use exome sequencing and copy number analysis to define genomic aberrations in a prospectively accrued clinical cohort (n = 142) of early (Stage I and II) PDAC. Detailed analysis of 99 informative tumours identified 1984 non-silent mutations and 1628 significant CNV events, and defined 439 significantly mutated genes based on stringent Significant Mutated Gene and GISTIC analysis. Integration with functional data from in vitro shRNA and in vivo Sleeping Beauty-mediated somatic mutagenesis screens provided supportive evidence for 182 of these as candidate driver mutations. Pathway based analysis recapitulated clustering of mutations in core signalling pathways in PDAC, and identified multiple new components in each, particularly in DNA damage repair mechanisms (ATM, TOP2A, RPA1, BRCC3). We also identified frequent and diverse somatic aberrations in genes involved in chromatin modification (SWI/SNF complex members, SETD2, EPC1), and novel mechanisms such as axon guidance (Semaphorin, Slit, Netrin and Ephrin signalling), extending the number of core perturbed pathways in PDAC. Aberrant expression of axon guidance genes co-segregated with poor patient survival, and in animal models was associated with disease development and progression, further implicating perturbation of the axon guidance pathway as a novel mechanism important in PDAC. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr LB-404. doi:1538-7445.AM2012-LB-404

Abstract 1835: Phosphodiesterase 4D (PDE4D) selective inhibitors as candidate drugs for prostate cancer

Abstract Our laboratory used an insertional somatic mutagenesis screen in mice to identify novel genes that may drive prostate cancer initiation and progression. Using this screen, we have identified candidate prostate cancer genes including the candidate oncogene phosphodiesterase 4D (PDE4D). Investigation of PDE4D showed that it was over-expressed in human prostate cancer cell lines and in human prostate cancers. Stable knockdown of PDE4D by shRNA reduced the growth and migration of prostate cancer cells in vitro and in vivo. Several small molecule PDE4D-selective inhibitors have been developed, including cilomilast and NVP-ABE171, and we have used them as potential anti-prostate cancer drugs in vitro and in vivo. The inhibitors were able to reduce the growth of prostate cancer cells in the context of epithelial mono-cultures or co-cultures that modeled stromal-epithelial interactions. Daily oral administration of PDE4D inhibitors for 6 weeks also reduced the growth of several prostate cancer xenograft lines in vivo through a dramatic induction of apoptosis. Interestingly, NVP-ABE171 and cilomilast also reduced the size of the prostates of treated mice without impacting overall animal health or the sizes of other organs. Under in vitro conditions in which prostate cancer cell growth was inhibited by either NVP-ABE171 or cilomilast, we also observed changes in the activation of potential downstream molecular targets of PDE4D inhibition including the sonic hedgehog and mitogen-activated protein kinase pathways. We are continuing studies with these inhibitors to further support the use of NVP-ABE171 and cilomilast as anti-prostate cancer drugs and to understand their mechanism(s) of action in the prostate. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 1835. doi:1538-7445.AM2012-1835

P-249 - Somatic screening in psychiatric out-patients: additional value of the physical examination

It is a well-known fact that psychiatric in-patients often suffer from severe somatic problems, like diabetes mellitus or cardiovascular disease. Risk factors for somatic problems are frequently found, like obesity and smoking. In the Netherlands there are no clear recommendations for a standard somatic screening of psychiatric out-patients. In 2008 a pilot study was performed by GGZ Breburg, to investigate whether performing a somatic screening discloses any unknown physical information. This study showed that at least one ‘aspect of somatic concern’ (ASC) was found in 79% of all included patients. 63% of these somatic problems were previously unknown. Somatic screening showed to be useful, but until now there are no clear guidelines or supportive instruments available. Objectives and aims: The objective of this study was to investigate the additional value of physical examination in the process of the construction of a screener for somatic problems in new psychiatric out-patients. Newly referred out-patients (n = 70) were somatically screened by a screening questionnaire and additional medical interview, laboratory examination and physical examination. When a somatic problem found, was previously unknown, the patient was referred to the general practitioner or a medical specialist. At least one ASC was found in 81,4% of all patients. In 45,7% of all patients this somatic problem was newly found. 12% of all newly found somatic problems were solely found by physical examination. Physical examination creates substantial additive information in the somatic screening of psychiatric out-patients.

A Comprehensive Guide to Sleeping Beauty-Based Somatic Transposon Mutagenesis in the Mouse.

Recent advances in whole genome analyses made possible by next-generation DNA sequencing, high-density array comparative genome hybridization (aCGH), and other technologies have made it apparent that cancers harbor numerous genomic changes. However, without functional correlation or validation, it has proven difficult to determine which genetic changes are necessary or sufficient to produce cancer. Thus, it is still necessary to perform unbiased functional studies using model organisms to help interpret the results of whole genome analyses of human tumors. To this end, a Sleeping Beauty (SB) transposon-based mutagenesis technology was developed to identify genes that, when mutated, can cause cancer. Herein a detailed methodology to initiate and carry out an SB transposon mutagenesis screen is described. Although this system might be used to identify genes involved with many cellular phenotypes, it has been primarily implemented for cancer. Thus, SB transposon somatic cell screens for cancer development are highlighted. Curr. Protoc. Mouse Biol. 1:347-368 © 2011 by John Wiley & Sons, Inc.

Abstract 3046: Phosphodiesterase 4D (PDE4D) as a new drug target for prostate cancer

Abstract Our laboratory used an insertional somatic mutagenesis screen in mice to identify novel genes that may drive prostate cancer initiation and progression. Using this screen, we have identified candidate prostate cancer genes including the candidate oncogene phosphodiesterase 4D (PDE4D). Investigation of PDE4D showed that it was over-expressed in human prostate cancer cell lines and in human prostate cancers. Stable knockdown of PDE4D by shRNA reduced the growth and migration of prostate cancer cells in vitro and in vivo. PDE4D has been implicated in the pathogenesis of chronic obstructive pulmonary disease (COPD). Several small molecule PDE4D selective inhibitors have been developed and tested in clinical trials for COPD. Although these studies showed that the inhibitors had modest efficacy as a therapy for COPD, they confirmed that the inhibitors were safe for use in humans at doses that inhibited PDE4D in vivo. Based on our previous studies with PDE4D, we postulated that PDE4D small molecule inhibitors would be candidate anti-prostate cancer drugs. Daily oral administration of PDE4D inhibitors, NVP-ABE171 or cilomilast, for 6 weeks significantly reduced the growth of LNCaP-C4 prostate cancer xenografts in immune-compromised mice. Under in vitro conditions in which prostate cancer cell growth was inhibited by either NVP-ABE171 or cilomilast, we also observed changes in the activation of potential downstream molecular targets of PDE4D inhibition. Affected pathways included the sonic hedgehog and mitogen-activated protein kinase pathways. We also tested the potential role of the PDE4D pathway in prostate cancer stromal-epithelial interactions by modeling these interactions using novel microchannel co-culture devices. In this context, PDE4D inhibitors reduced the activation of Shh pathway target genes in mesenchymal cells and reduced the proliferation of epithelial cancer cell lines, supporting the potential importance of the PDE4D pathway for prostate cancer stromal-epithelial interactions. We are continuing in vitro and in vivo studies with these candidate drugs to further support the use of NVP-ABE171 and cilomilast as anti-prostate cancer drugs and to understand their mechanism of action. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 3046. doi:10.1158/1538-7445.AM2011-3046

HADStress: A Somatic Symptom Screen for Posttraumatic Stress Among Somali Refugees

This study assessed whether a simple, readily implemented four-symptom somatic screen would be able to effectively identify current posttraumatic stress symptoms in victimized populations. The sample consisted of 622 Somali community-dwelling refugees who fled widespread violence and trauma occurring in East Africa during 1990-1992. Data were collected during 2000-2003 and included demographic characteristics, number of types of torture and nontorture trauma experienced earlier in Africa, and current self-rated posttraumatic stress symptoms, as measured by the Posttraumatic Stress Disorder Checklist (PCL). The sample was also assessed with the HADStress screen, which was developed for this study, to determine whether the screen was effective in detecting current posttraumatic stress symptoms. The HADStress screen assessed for the presence of four somatic symptoms: Headaches, Appetite change, Dizziness, and Sleep problems. All items were given equal weight. Possible scores on the screen range from 0 to 4, with higher scores indicating more somatic symptoms. Univariate analysis showed that persons who experienced more types of trauma (both torture and nontorture trauma) and persons who had higher PCL scores (indicating more current posttraumatic stress symptoms) had significantly higher HADStress scores. Negative binomial regression analysis showed that PCL scores were the most effective variable in predicting HADStress scores. On the Tukey-B post hoc analysis, a HADStress score of 0 or 1 was associated with a mean PCL score of less than 30, a score of 2 was associated with a mean PCL score of 40.28, and a score of 4 was associated with a mean PCL score of 51.07 (suggesting that over 50% of this group would have active posttraumatic stress disorder). A score of 2 or higher on the HADStress scale among refugees warrants additional evaluation for posttraumatic stress symptoms in clinical settings. For communitywide efforts at early recognition and treatment, a cutoff score of 4 may be more practical and cost-effective.

HADStress: A Somatic Symptom Screen for Posttraumatic Stress Among Somali Refugees

This study assessed whether a simple, readily implemented four-symptom somatic screen would be able to effectively identify current posttraumatic stress symptoms in victimized populations.The sample consisted of 622 Somali community-dwelling refugees who fled widespread violence and trauma occurring in East Africa during 1990-1992. Data were collected during 2000-2003 and included demographic characteristics, number of types of torture and nontorture trauma experienced earlier in Africa, and current self-rated posttraumatic stress symptoms, as measured by the Posttraumatic Stress Disorder Checklist (PCL). The sample was also assessed with the HADStress screen, which was developed for this study, to determine whether the screen was effective in detecting current posttraumatic stress symptoms. The HADStress screen assessed for the presence of four somatic symptoms: Headaches, Appetite change, Dizziness, and Sleep problems. All items were given equal weight. Possible scores on the screen range from 0 to 4, with higher scores indicating more somatic symptoms.Univariate analysis showed that persons who experienced more types of trauma (both torture and nontorture trauma) and persons who had higher PCL scores (indicating more current posttraumatic stress symptoms) had significantly higher HADStress scores. Negative binomial regression analysis showed that PCL scores were the most effective variable in predicting HADStress scores. On the Tukey-B post hoc analysis, a HADStress score of 0 or 1 was associated with a mean PCL score of less than 30, a score of 2 was associated with a mean PCL score of 40.28, and a score of 4 was associated with a mean PCL score of 51.07 (suggesting that over 50% of this group would have active posttraumatic stress disorder).A score of 2 or higher on the HADStress scale among refugees warrants additional evaluation for posttraumatic stress symptoms in clinical settings. For communitywide efforts at early recognition and treatment, a cutoff score of 4 may be more practical and cost-effective.

HADStress screen for posttraumatic stress: replication in ethiopian refugees.

Purpose was to assess whether a 4-symptom somatic screen, shown to correlate with current post-traumatic stress symptoms in 1 refugee group, could function as a screening instrument in another group of refugees. Sample consisted of 512 community-dwelling refugees from Ethiopia. Data collection included demography, types of torture and nontorture trauma experienced a decade earlier in Africa, and current posttraumatic stress symptoms. Somatic symptoms included headaches (H), appetite change (A), dizziness and faintness (D), and sleep problems (S), added with equal weighting into the HADStress Screen, ranging from 0 to 4. Results showed that age, gender, torture, and other trauma experiences from a decade ago, and current posttraumatic stress symptoms predicted current somatic symptoms on univariate analyses. On a negative binomial regression model, current posttraumatic stress symptoms, male gender, and number of torture types predicted a high HADStress score. Post hoc tests supported cut-off levels at 3 and at 4 symptoms. Conclusion is that the HADStress Screen can serve as an efficient, nonthreatening screen for posttraumatic stress symptoms among refugees.

P.3.c.001 Association between HTR2C polymorphisms and the metabolic syndrome in patients using antipsychotics: a replication study

Background: In two previous studies we investigated the possible association between the rs1414334 C/G and 759 C/T polymorphisms in the gene that encodes the 5HT2c receptor (HTR2c) and prevalence of the metabolic syndrome in a schizophrenic population [1,2]. In both studies we found an association between the variant rs1414334 C-allele and an increased prevalence of the metabolic syndrome. The objective of the current study was to try to replicate our previous findings in a different patient sample. Methods: Patients were included from an ongoing 'Pharmacotherapy Monitoring and Outcome survey': PHAMOUS (http:// www.phamous.eu/). PHAMOUS combines a yearly somatic screening with routine outcome assessment in patients using antipsychotics. A cross-sectional design was used to investigate the association between HTR2C variants and the metabolic syndrome in patients diagnosed with schizophrenia or related disorders. Patients, ≥18 years, were eligible for inclusion if they used antipsychotic drugs and gave informed consent. Primary endpoint was prevalence of the metabolic syndrome, as defined by the definition by the National Cholesterol Education Program's Adult Treatment panel III (NCEP:ATP IIIa). HbA1c was used when fasting glucose values were unavailable. Secondary endpoints were associations between HTR2c polymorphisms and individual parameters contributing to the metabolic syndrome, as well as effects of individual antipsychotics. Primary determinants were the 759 C/T and rs1414334:C>G polymorphisms in the X-linked HTR2c gene. The association between HTR2C genotypes (carriership of the variant HTR2C allele) and prevalence of the metabolic syndrome was investigated with logistic regression. Results were expressed as Odds Ratio's with a 95% confidence interval (95% CI). Data were investigated for potential confounding effects of age, ethnicity, DSM-IV diagnosis, gender, use of SSRI's and antipsychotic drugs. Results: In total, 186 patients, mainly male (68%) and Caucasian (93%) were included. Olanzapine (23%), risperidone (22%) and clozapine (17%) where the most frequently prescribed antipsychotic drugs. The variant rs1414334 C-allele was significantly associated with the metabolic syndrome (OR 3.99; 95% CI 1.40-11.33) (table 1). There was a trend for an association between the variant rs1414334 C-allele and the metabolic syndrome in patients using risperidone (OR 16.50; 95% CI 0.73-375.43, p 0.08). There was also a trend for an association between the variant rs1414334 C-allele and an increased risk for reaching the cutoff points for lowered HDL (OR 2.47; 95% CI 0.95-6.42) and elevated triglyceride levels (OR 2.21; 95% CI 0. 94-5.18) respectively).(Table presented) Conclusions: This study confirms our previous findings that the variant C-allele of the rs1414334 polymorphism is associated with the metabolic syndrome.

Efficient Genetic Reprogramming of Unmodified Somatic Neural Progenitors Uncovers the Essential Requirement of Oct4 and Klf4

Significant breakthroughs have been recently achieved in reprogramming somatic cells to a pluripotent embryonic state by the ectopic expression of specific transcription factors. One of the major drawbacks of reprogramming strategies lays in the low efficiency of the process. It is likely that the required complex epigenetic-remodeling events could be cell-type specific and more rational approaches to cell source selection might help to improve the outcome of the procedure. Because the use of somatic stem cells, and specifically neural stem cells (NSCs), as nuclear donors significantly increased the efficiency of somatic cell nuclear transfer, we aimed to determine whether genetically unmodified somatic NSCs could be more easily reprogrammed to pluripotency than unmodified mouse embryonic fibroblasts. Retroviral transduction of the factors Oct4, Sox2, Klf4, and c-Myc successfully reverted NSCs to a pluripotent embryonic stem cell-like state with a 2-fold efficiency increase, faster kinetic, and with a lower number of viral integrations. Quantification analysis of reprogramming-associated genes revealed that NSCs endogenously expressed high levels of Sox2 and c-Myc. Accordingly, NSCs could be successfully induced to pluripotency through the ectopic viral expression of the other two factors (Oct4 and Klf4). These findings suggest that endogenous expression of reprogramming genes could help the reprogramming process and somatic stem cells might be more prone to reprogramming due to their specific genetic background. Genetic-based somatic cell screening might provide essential information for the selection of alternative cell sources more suitable to direct reprogramming.

From germline towards somatic mutations in the pathophysiology of vascular anomalies

The localized structural abnormalities that arise during vasculogenesis, angiogenesis and lymphangiogenesis, the developmental processes which give rise to the adult vasculature, are collectively termed vascular anomalies. The last 2 years have seen an explosion of studies that underscore paradominant inheritance, the combination of inherited changes with somatic second-hits to the same genes, as underlying rare familial forms. Moreover, local, somatic genetic defects that cause some of the common sporadic forms of these malformations have been unraveled. This highlights the importance of assessing for tissue-based genetic changes, especially acquired genetic changes, as possible pathophysiological causes, which have been largely overlooked except in the area of cancer research. Large-scale somatic screens will therefore be essential in uncovering the nature and prevalence of such changes, and their downstream effects. The identification of disease genes combined with exhaustive, precise clinical delineations of the entire spectra of associated phenotypes guides better management and genetic counseling. Such a synthesis of information on functional and phenotypic effects will enable us to make and use animal models to test less invasive, targeted, perhaps locally administered, biological therapies.

Another Adaptor in the T Cell Receptor Orchestra: CARMA1

Two groups report the importance of a membrane-associated guanylate like kinase (MAGUK) domain-containing protein (CARMA1) in the activation of the transcription factor NF-κB in response to T cell receptor (TCR) ligation. Wang et al. isolated CARMA1 in a somatic mutagenesis screen of T cell lines with a selective defect in NF-κB signaling. Expression of activated protein kinase c θ (PKC θ), the adaptor Bcl10, or the MALTI protein did not restore NF-κB signaling. Expression of CARMA1, which is an adaptor protein and has a caspase recruitment domain (CARD), a PDZ domain, an SH3 domain, and the guanlyate kinase-like domain, restored NF-κB signaling. Coexpression experiments in human embryonic kidney (HEK 293) cells with various combinations of CARMA1, PKC θ, and BCL10 suggested that CARMA1 may serve to promote the PCK θ -induced phosphorylation of Bcl10. Gaide et al. determined that, in T cells, a population of CARMA1 was constitutively associated with detergent-insoluble domains, called lipid rafts, and that the interaction between CARMA1 and the TCR and CARMA1 and Bcl10 was stimulated upon TCR ligation. A mutant version of CARMA1 that could not interact with Bcl10 selectively inhibited TCR-stimulated NF-κB signaling in T cells. The results from these two groups suggest that CARMA1 may serve as a selective adaptor to specifically direct the activated TCR signal to NF-κB. The potential therapeutic importance of these results for the development of immunosuppressive drugs is discussed by Wallach. D. Wang, Y. You, S. M. Case, L. M. McAllister-Lucas, L. Wang, P. S. DiStefano, G. Nuñez, J. Bertin, X. Lin, A requirement for CARMA1 in TCR-induced NF-κB activation. Nature Immunol. 3 , 830-835 (2002). [Online Journal] O. Gaide, B. Favier, D. F. Legler, D. Bonnet, B. Brissoni, S. Valitutti, C. Bron, J. Tschopp, M. Thome, CARMA1 is a critical lipid raft-associated regulator of TCR-induced NF-κB activation. Nature Immunol. 3 , 836-843 (2002). [Online Journal] D. Wallach, Up the down staircase. Nature Immunol. 3 , 802-803 (2002). [Online Journal]

A Study of Somatic Cell Count Variation and Screening Tests Reactions in a Lactation

A Study of Somatic Cell Count Variation and Screening Tests Reactions in a Lactation

Multiphasic screening programme for somatic diseases among elderly long-term psychiatric patients.

Older people in institutions are often disabled by physical disease (Wilsonet al., 1962). Psychiatric patients, in general, have more somatic disorders than mentally healthy people (Westrin, 1961; Shepherdet al., 1964; Maguire and Granville-Grossman, 1968). In fact, most elderly long-term psychiatric patients in hospital suffer from one or more somatic disorders (Ask, 1962). Even a small improvement in the general health of these patients may be of importance for their daily life activities, and also reduce the requirements for assistance. An established regular somatic screening of these patients will help to detect disease which otherwise may be over-looked.