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author:("bitis, Panos")
2.  Convergent Findings for Abnormalities of the NF-κB Signaling Pathway in Schizophrenia 
Neuropsychopharmacology  2012;38(3):533-539.
Neurons exhibit a constitutive level of nuclear factor-κB (NF-κB) signaling and this pathway plays a significant role in neurite outgrowth, activity-dependent plasticity, and cognitive function. Transcription factor analysis was performed in a microarray data set profiled in four different brain regions (n=54 comparison group; n=53 schizophrenia (SZ)). An independent postmortem cohort was used for gene expression (n=24 comparison group; n=22 SZ), protein abundance (n=8 comparison group; n=8 SZ), and NF-κB nuclear activity (n=10 comparison group; n=10 SZ) quantification. Expression quantitative trait locus analysis was performed using publicly available data. Prepulse inhibition (PPI) of the acoustic startle reflex was tested in healthy individuals (n=690). Comparison of microarray data showed that NF-κB was among the transcription factors associated with the differential expression of genes in cases vs controls. NF-κB gene and protein levels and nuclear activation were significantly decreased in the superior temporal gyrus of patients with SZ. Upstream NF-κB genes related to translocation were significantly dysregulated in SZ. The gene expression levels of an NF-κB-associated importin (KPNA4: one of the proteins responsible for the translocation of NF-κB to the nucleus) was decreased in SZ and an SNP within the KPNA4 locus was associated with susceptibility to SZ, reduced KPNA4 expression levels and attenuated PPI of the startle reflex in healthy control subjects. These findings implicate abnormalities of the NF-κB signaling pathway in SZ and provide evidence for an additional possible mechanism affecting the translocation of NF-κB signaling to the nucleus.
doi:10.1038/npp.2012.215
PMCID: PMC3547205  PMID: 23132271
biological psychiatry; gene expression; human postmortem; neurogenetics; neurophysiology; prepulse inhibition; schizophrenia / antipsychotics; transcription factor; postmortem; mRNA; superior temporal gyrus; prepulse inhibition; importin; transcription factor
3.  PATTERNS OF MULTI-SITE PAIN AND ASSOCIATIONS WITH RISK FACTORS 
Pain  2013;154(9):1769-1777.
To explore definitions for multi-site pain, and compare associations with risk factors for different patterns of musculoskeletal pain, we analysed cross-sectional data from the Cultural and Psychosocial Influences on Disability (CUPID) study. The study sample comprised 12,410 adults aged 20-59 years from 47 occupational groups in 18 countries. A standardised questionnaire was used to collect information about pain in the past month at each of 10 anatomical sites, and about potential risk factors. Associations with pain outcomes were assessed by Poisson regression, and characterised by prevalence rate ratios (PRRs). Extensive pain, affecting 6-10 anatomical sites, was reported much more frequently than would be expected if the occurrence of pain at each site were independent (674 participants v 41.9 expected). In comparison with pain involving only 1-3 sites, it showed much stronger associations (relative to no pain) with risk factors such as female sex (PRR 1.6 v 1.1), older age (PRR 2.6 v 1.1), somatising tendency (PRR 4.6 v 1.3) and exposure to multiple physically stressing occupational activities (PRR 5.0 v 1.4). After adjustment for number of sites with pain, these risk factors showed no additional association with a distribution of pain that was widespread according to the frequently used American College of Rheumatology (ACR) criteria. Our analysis supports the classification of pain at multiple anatomical sites simply by the number of sites affected, and suggests that extensive pain differs importantly in its associations with risk factors from pain that is limited to only a small number of anatomical sites.
doi:10.1016/j.pain.2013.05.039
PMCID: PMC3747979  PMID: 23727463
4.  Patterns of multisite pain and associations with risk factors 
Pain  2013;154(9):1769-1777.
Summary
In a large cross-sectional survey, pain affecting 6–10 anatomical sites showed substantially different associations with risk factors from pain limited to 1–3 sites.
To explore definitions for multisite pain, and compare associations with risk factors for different patterns of musculoskeletal pain, we analysed cross-sectional data from the Cultural and Psychosocial Influences on Disability (CUPID) study. The study sample comprised 12,410 adults aged 20–59 years from 47 occupational groups in 18 countries. A standardised questionnaire was used to collect information about pain in the past month at each of 10 anatomical sites, and about potential risk factors. Associations with pain outcomes were assessed by Poisson regression, and characterised by prevalence rate ratios (PRRs). Extensive pain, affecting 6–10 anatomical sites, was reported much more frequently than would be expected if the occurrence of pain at each site were independent (674 participants vs 41.9 expected). In comparison with pain involving only 1–3 sites, it showed much stronger associations (relative to no pain) with risk factors such as female sex (PRR 1.6 vs 1.1), older age (PRR 2.6 vs 1.1), somatising tendency (PRR 4.6 vs 1.3), and exposure to multiple physically stressing occupational activities (PRR 5.0 vs 1.4). After adjustment for number of sites with pain, these risk factors showed no additional association with a distribution of pain that was widespread according to the frequently used American College of Rheumatology criteria. Our analysis supports the classification of pain at multiple anatomical sites simply by the number of sites affected, and suggests that extensive pain differs importantly in its associations with risk factors from pain that is limited to only a small number of anatomical sites.
doi:10.1016/j.pain.2013.05.039
PMCID: PMC3747979  PMID: 23727463
Pain; Multisite; Widespread; Definition; Risk factors
5.  RISK FACTORS FOR NEW ONSET AND PERSISTENCE OF MULTI-SITE MUSCULOSKELETAL PAIN IN A LONGITUDINAL STUDY OF WORKERS IN CRETE 
Objectives
To explore occupational and psychological risk factors for the incidence and persistence of multi-site musculoskeletal pain.
Methods
We conducted a longitudinal investigation of three occupational groups in Crete, Greece. Baseline information was obtained at interview about pain in the past year at each of six anatomical sites, and about possible risk factors for subsequent symptoms. Twelve months later, subjects were re-interviewed about pain at the same anatomical sites in the past month. Pain at two or more sites was classed as multi-site. Associations with new development and persistence of multi-site pain at follow-up were assessed by logistic regression.
Results
Analysis was based on 518 subjects (87% of those originally selected for study). At follow-up, multi-site pain persisted in 217 (62%) of those who had experienced it in the year before baseline, and was newly developed in 27 (17%) of those who had not. Persistence of multi-site pain was significantly related to physical loading at work, somatising tendency and beliefs about work as a cause of musculoskeletal pain, with ORs (95%CIs) for the highest relative to the lowest exposure categories of 2.3 (1.0-5.6), 2.6 (1.5-4.6) and 1.9 (1.1-3.3) respectively. Development of new multi-site pain was most strongly associated with working for ≥ 40 hours per week (OR 5.0, 95%CI 1.1-24.0).
Conclusions
Our findings confirm the importance of both physical loading at work and somatising tendency as risk factors for multi-site pain, and suggest that persistence of pain is also influenced by adverse beliefs about work-causation.
doi:10.1136/oemed-2012-100689
PMCID: PMC3526653  PMID: 22864252
6.  Disabling musculoskeletal pain in working populations: Is it the job, the person, or the culture? 
Pain  2013;154(6):856-863.
Summary
Large international variation in the prevalence of disabling forearm and low back pain was only partially explained by established personal and socioeconomic risk factors.
To compare the prevalence of disabling low back pain (DLBP) and disabling wrist/hand pain (DWHP) among groups of workers carrying out similar physical activities in different cultural environments, and to explore explanations for observed differences, we conducted a cross-sectional survey in 18 countries. Standardised questionnaires were used to ascertain pain that interfered with everyday activities and exposure to possible risk factors in 12,426 participants from 47 occupational groups (mostly nurses and office workers). Associations with risk factors were assessed by Poisson regression. The 1-month prevalence of DLBP in nurses varied from 9.6% to 42.6%, and that of DWHP in office workers from 2.2% to 31.6%. Rates of disabling pain at the 2 anatomical sites covaried (r = 0.76), but DLBP tended to be relatively more common in nurses and DWHP in office workers. Established risk factors such as occupational physical activities, psychosocial aspects of work, and tendency to somatise were confirmed, and associations were found also with adverse health beliefs and group awareness of people outside work with musculoskeletal pain. However, after allowance for these risk factors, an up-to 8-fold difference in prevalence remained. Systems of compensation for work-related illness and financial support for health-related incapacity for work appeared to have little influence on the occurrence of symptoms. Our findings indicate large international variation in the prevalence of disabling forearm and back pain among occupational groups carrying out similar tasks, which is only partially explained by the personal and socioeconomic risk factors that were analysed.
doi:10.1016/j.pain.2013.02.008
PMCID: PMC3675684  PMID: 23688828
Low back; Forearm; Pain; International; Socioeconomic; Psychosocial
7.  Assessing the burden of caregivers of patients with mental disorders: translating and validating the involvement evaluation questionnaire into Greek 
Background
The changes in the organization of mental health care services have made the role of the family even more important in caring for patients with mental disorders. Caring may have serious consequences for family caregivers, with a great impact on the quality of family life. This study reports on the translation, cultural adaptation, and validation of the Involvement Evaluation Questionnaire-European Union (IEQ-EU) into the Greek language.
Methods
Caregivers of patients with major mental disorders were interviewed to test a modified version of the IEQ-EU questionnaire. Psychometric measurements included reliability coefficients, exploratory factor analysis and confirmatory analysis by linear structural relations. To measure the concurrent validity we used the Nottingham Health Profile (NHP).
Results
Most caregivers were female (83%), mainly mothers living with the patient (80%), with quite a high level of burden. The Greek version of the IEQ-EU (G-IEQ-EU) demonstrated a good reliability with high internal consistency (α = 0.88), Guttman split-half correlation of 0.71, high test-retest reliability (ICC = 0.82) and good concurrent validity with the NHP. A four-factor structure was confirmed for the G-IEQ-EU, slightly different from the original IEQ. The confirmatory factor analysis demonstrated that the four-factor model offered modest fit to our data.
Conclusions
The G-IEQ-EU is a reasonably valid and reliable tool for use in both clinical and research contexts in order to assess the burden of caregivers of patients with mental disorders.
doi:10.1186/1744-859X-12-3
PMCID: PMC3605393  PMID: 23402385
Caregivers; Mental disorders; Validation
8.  Correction: The CUPID (Cultural and Psychosocial Influences on Disability) Study: Methods of Data Collection and Characteristics of Study Sample 
PLoS ONE  2012;7(10):10.1371/annotation/3faf76e5-f73e-427f-9d60-8f94939b0f7e.
doi:10.1371/annotation/3faf76e5-f73e-427f-9d60-8f94939b0f7e
PMCID: PMC3491867
10.  The CUPID (Cultural and Psychosocial Influences on Disability) Study: Methods of Data Collection and Characteristics of Study Sample 
PLoS ONE  2012;7(7):e39820.
Background
The CUPID (Cultural and Psychosocial Influences on Disability) study was established to explore the hypothesis that common musculoskeletal disorders (MSDs) and associated disability are importantly influenced by culturally determined health beliefs and expectations. This paper describes the methods of data collection and various characteristics of the study sample.
Methods/Principal Findings
A standardised questionnaire covering musculoskeletal symptoms, disability and potential risk factors, was used to collect information from 47 samples of nurses, office workers, and other (mostly manual) workers in 18 countries from six continents. In addition, local investigators provided data on economic aspects of employment for each occupational group. Participation exceeded 80% in 33 of the 47 occupational groups, and after pre-specified exclusions, analysis was based on 12,426 subjects (92 to 1018 per occupational group). As expected, there was high usage of computer keyboards by office workers, while nurses had the highest prevalence of heavy manual lifting in all but one country. There was substantial heterogeneity between occupational groups in economic and psychosocial aspects of work; three- to five-fold variation in awareness of someone outside work with musculoskeletal pain; and more than ten-fold variation in the prevalence of adverse health beliefs about back and arm pain, and in awareness of terms such as “repetitive strain injury” (RSI).
Conclusions/Significance
The large differences in psychosocial risk factors (including knowledge and beliefs about MSDs) between occupational groups should allow the study hypothesis to be addressed effectively.
doi:10.1371/journal.pone.0039820
PMCID: PMC3391206  PMID: 22792189
11.  The Association of Schizophrenia Risk -Amino Acid Oxidase Polymorphisms With Sensorimotor Gating, Working Memory and Personality in Healthy Males 
Neuropsychopharmacology  2011;36(8):1677-1688.
There is evidence supporting a role for the -amino acid oxidase (DAO) locus in schizophrenia. This study aimed to determine the relationship of five single-nucleotide polymorphisms (SNPs) within the DAO gene identified as promising schizophrenia risk genes (rs4623951, rs2111902, rs3918346, rs3741775, and rs3825251) to acoustic startle, prepulse inhibition (PPI), working memory, and personality dimensions. A highly homogeneous study entry cohort (n=530) of healthy, young male army conscripts (n=703) originating from the Greek LOGOS project (Learning On Genetics Of Schizophrenia Spectrum) underwent PPI of the acoustic startle reflex, working memory, and personality assessment. The QTPHASE from the UNPHASED package was used for the association analysis of each SNP or haplotype data, with p-values corrected for multiple testing by running 10 000 permutations of the data. The rs4623951_T-rs3741775_G and rs4623951_T-rs2111902_T diplotypes were associated with reduced PPI and worse performance in working memory tasks and a personality pattern characterized by attenuated anxiety. Median stratification analysis of the risk diplotype group (ie, those individuals homozygous for the T and G alleles (TG+)) showed reduced PPI and working memory performance only in TG+ individuals with high trait anxiety. The rs4623951_T allele, which is the DAO polymorphism most strongly associated with schizophrenia, might tag a haplotype that affects PPI, cognition, and personality traits in general population. Our findings suggest an influence of the gene in the neural substrate mediating sensorimotor gating and working memory, especially when combined with high anxiety and further validate DAO as a candidate gene for schizophrenia and spectrum disorders.
doi:10.1038/npp.2011.49
PMCID: PMC3138651  PMID: 21471957
prepulse inhibition; working memory; personality; -amino acid oxidase; schizophrenia; Glutamate; Psychiatry & Behavioral Sciences; Cognition; Neurogenetics; Sensorimotor Gating
12.  Cannabis-Dependence Risk Relates to Synergism between Neuroticism and Proenkephalin SNPs Associated with Amygdala Gene Expression: Case-Control Study 
PLoS ONE  2012;7(6):e39243.
Background
Many young people experiment with cannabis, yet only a subgroup progress to dependence suggesting individual differences that could relate to factors such as genetics and behavioral traits. Dopamine receptor D2 (DRD2) and proenkephalin (PENK) genes have been implicated in animal studies with cannabis exposure. Whether polymorphisms of these genes are associated with cannabis dependence and related behavioral traits is unknown.
Methodology/Principal Findings
Healthy young adults (18–27 years) with cannabis dependence and without a dependence diagnosis were studied (N = 50/group) in relation to a priori-determined single nucleotide polymorphisms (SNPs) of the DRD2 and PENK genes. Negative affect, Impulsive Risk Taking and Neuroticism-Anxiety temperamental traits, positive and negative reward-learning performance and stop-signal reaction times were examined. The findings replicated the known association between the rs6277 DRD2 SNP and decisions associated with negative reinforcement outcomes. Moreover, PENK variants (rs2576573 and rs2609997) significantly related to Neuroticism and cannabis dependence. Cigarette smoking is common in cannabis users, but it was not associated to PENK SNPs as also validated in another cohort (N = 247 smokers, N = 312 non-smokers). Neuroticism mediated (15.3%–19.5%) the genetic risk to cannabis dependence and interacted with risk SNPs, resulting in a 9-fold increase risk for cannabis dependence. Molecular characterization of the postmortem human brain in a different population revealed an association between PENK SNPs and PENK mRNA expression in the central amygdala nucleus emphasizing the functional relevance of the SNPs in a brain region strongly linked to negative affect.
Conclusions/Significance
Overall, the findings suggest an important role for Neuroticism as an endophenotype linking PENK polymorphisms to cannabis-dependence vulnerability synergistically amplifying the apparent genetic risk.
doi:10.1371/journal.pone.0039243
PMCID: PMC3382183  PMID: 22745721
13.  Work related and psychological determinants of multi-site musculoskeletal pain 
Objectives
Musculoskeletal pain is associated with occupational physical activities and psychosocial risk factors. We evaluated the relative importance of work-related and psychological determinants of the number of anatomical sites affected by musculoskeletal pain in a cross-sectional survey.
Methods
The survey focused on musculoskeletal pain in six body regions (low-back, neck, shoulder, elbow, wrist/hand and knee) among 224 nurses, 200 office workers and 140 postal clerks in Crete (response rate 95%). Information was collected about demographic characteristics, occupational physical load, psychosocial aspects of work, perceptions about causes of pain, mental health, tendency to somatize, and experience of pain in the past 12 months. Poisson regression was used to assess associations of risk factors with the number of painful anatomical sites and interactions were explored using classification and regression trees (CART).
Results
Two-thirds of the study sample reported pain in at least two body sites during the past 12 months, and in 23%, more than three sites were affected. The number of painful anatomical sites was strongly related to both physical load at work and somatizing tendency (with relative risks increased five-fold or more for frequent and disabling multisite pain) , and was also significantly associated with work-related psychosocial factors, and beliefs about work causation. The CART analysis suggested that in the population studied, the leading determinant of the number of painful body sites was somatizing tendency.
Conclusions
In the population studied, pain at multiple anatomical sites is common, and is strongly associated with somatizing tendency, which may have a more important influence on multi-site pain than on pain that is limited to a single anatomical site.
PMCID: PMC3242043  PMID: 20011982
epidemiology; occupational health
14.  The Edinburgh Postnatal Depression Scale: translation and validation for a Greek sample 
BMC Public Health  2009;9:329.
Background
Edinburgh Postnatal Depression Scale (EPDS) is an important screening instrument that is used routinely with mothers during the postpartum period for early identification of postnatal depression. The purpose of this study was to validate the Greek version of EPDS along with sensitivity, specificity and predictive values.
Methods
120 mothers within 12 weeks postpartum were recruited from the perinatal care registers of the Maternity Departments of 4 Hospitals of Heraklion municipality, Greece. EPDS and Beck Depression Inventory-II (BDI-II) surveys were administered in random order to the mothers. Each mother was diagnosed with depression according to the validated Greek version of BDI-II. The psychometric measurements that were performed included: two independent samples t-tests, One-way analysis of variance (ANOVA), reliability coefficients, Explanatory factor analysis using a Varimax rotation and Principal Components Method. Confirmatory analysis -known as structural equation modelling- of principal components was conducted by LISREL (Linear Structural Relations). A receiver operating characteristic (ROC) analysis was carried out to evaluate the global functioning of the scale.
Results
8 (6.7%) of the mothers were diagnosed with major postnatal depression, 14 (11.7%) with moderate and 38 (31.7%) with mild depression on the basis of BDI-II scores. The internal consistency of the EPDS Greek version -using Chronbach's alpha coefficient- was found 0.804 and that of Guttman split-half coefficient 0.742. Our findings confirm the multidimensionality of EPDS, demonstrating a two-factor structure which contained subscales reflecting depressive symptoms and anxiety. The Confirmatory Factor analysis demonstrated that the two factor model offered a very good fit to our data. The area under ROC curve AUC was found 0.7470 and the logistic estimate for the threshold score of 8/9 fitted the model sensitivity at 76.7% and model specificity at 68.3%.
Conclusion
Our data confirm the validity of the Greek version of the EPDS in identifying postnatal depression. The Greek EPDS scale could be used as a useful instrument in both clinical practice and research.
doi:10.1186/1471-2458-9-329
PMCID: PMC2748079  PMID: 19740443
15.  International variation in absence from work attributed to musculoskeletal illness: findings from the CUPID study 
Objectives
To quantify the variation in rates of absence due to musculoskeletal pain across 47 occupational groups (mostly nurses and office workers) from 18 countries, and to explore personal and group-level risk factors that might explain observed differences.
Methods
A standardised questionnaire was used to obtain information about musculoskeletal pain, sickness absence and possible risk factors in a cross-sectional survey of 12 416 workers (92–1017 per occupational group). Additionally, group-level data on socioeconomic variables, such as sick pay and unemployment rates, were assembled by members of the study team in each country. Associations of sickness absence with risk factors were examined by Poisson regression.
Results
Overall, there were more than 30-fold differences between occupational groups in the 12-month prevalence of prolonged musculoskeletal sickness absence, and even among office workers carrying out similar occupational tasks, the variation was more than tenfold. Personal risk factors included older age, lower educational level, tendency to somatise, physical loading at work and prolonged absence for non-musculoskeletal illness. However, these explained little of the variation between occupational groups. After adjustment for individual characteristics, prolonged musculoskeletal sickness absence was more frequent in groups with greater time pressure at work, lower job control and more adverse beliefs about the work-relatedness of musculoskeletal disorders.
Conclusions
Musculoskeletal sickness absence might be reduced by eliminating excessive time pressures in work, maximising employees’ responsibility and control and providing flexibility of duties for those with disabling symptoms. Care should be taken not to overstate work as a cause of musculoskeletal injury.
doi:10.1136/oemed-2012-101316
PMCID: PMC3710073  PMID: 23695413
international; risk factors; time pressure

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