Bulk RNA sequencing for analysis of post COVID-19 condition in adolescents and young adults.

BACKGROUND: Post COVID-19 condition (PCC) is a complication of SARS-COV-2 infection and can lead to long-term disability. METHODS: The present study was designed to analyse the gene expression patterns of PCC through bulk RNA sequencing of whole blood and to explore the potential molecular mechanisms of PCC. Whole blood was collected from 80 participants enrolled in a prospective cohort study following SARS-CoV-2 infected and non-infected individuals for 6 months after recruitment and was used for bulk RNA sequencing. Identification of differentially expressed genes (DEG), pathway enrichment and immune cell deconvolution was performed to explore potential biological pathways involved in PCC. RESULTS: We have found 13 differentially expressed genes associated with PCC. Enriched pathways were related to interferon-signalling and anti-viral immune processes. CONCLUSION: The PCC transcriptome is characterized by a modest overexpression of interferon-stimulated genes, pointing to a subtle ongoing inflammatory response.

Spinal pain in employees exposed to abusive supervision: Evidence of a sex and CRHR1 CTC haplotype interaction.

Previous findings suggest that exposure to social stress in the form of abusive supervision may increase the risk of musculoskeletal disorders. In the present study, we examined the link between abusive supervision, the CRHR1 genotype and spinal pain. The data were collected through a national survey drawn from the National Central Employee Register by Statistics Norway. A total of 1226 individuals returned both the questionnaire and the saliva kit. Abusive supervision was measured by a 5-item version of the Tepper's 2000 scale. Spinal pain was measured by 3 items (neck-, upper and low back pain). Genotyping with regard to CRHR1 rs242941, rs242939 and rs1876828 was carried out using Taqman assay, and Phase v.2.1.1 was used to define the CRHR1 allele combinations. The analyses revealed that abusive supervision was associated with spinal pain. In particular, we observed a strong effect of abusive supervision on spinal pain in female +CTC/+CTC carriers (p = 0.002). Moreover, using +CTC/+CTC as a reference, +CTC/-CTC and -CTC/-CTC both showed protective effects (p = 0.024, p = 0.002, respectively). Also, our data demonstrated a clear sex and CRHR1 CTC haplotype interaction (p = 0.013). No such gene-environment interaction was seen in men. Our data demonstrated that the CRHR1 CTC haplotype may exacerbate the effect of abusive supervision on spinal pain in female employees. Hence, the present study supports the theory that both gender and the CRHR1 genotype, may moderate the pain responses to social stressors.

Workplace bullying increases the risk of anxiety through a stress-induced ß2-adrenergic receptor mechanism: a multisource study employing an animal model, cell culture experiments and human data.

OBJECTIVES: Several studies show that severe social stressors, e.g., in the form of exposure to workplace bullying in humans, is associated with negative mental health effects such as depression and anxiety among those targeted. However, the understanding of the underlying biological mechanisms that may explain the relationship between exposure to bullying and such negative health outcomes is scarce. The analyses presented here focus on understanding the role of the ß2-adrenergic receptors (ADRB2) on this association. METHODS: First, a resident-intruder paradigm was used to investigate changes in circulating norepinephrine (NE) in rat serum induced by repeated social defeat and its relationship with subsequent social behavior. Second, the direct effects of the stress-hormones NE and cortisol, i.e., synthetic dexamethasone (DEX), on the ADRB2 expression (qPCR) and monocyte chemoattractant protein-1 (MCP-1) release (immunoassay) was examined in cultured EL-1 cells. Third, in a probability sample of 1052 Norwegian employees, the 9-item short version of the Negative Acts Questionnaire-Revised (S-NAQ) inventory, Hopkins Symptom Checklist and genotyping (SNP TaqMan assay) were used to examine the association between social stress in the form of workplace bullying and anxiety moderated by the ADRB2 genotype (rs1042714) in humans. RESULTS: The present study showed a clear association between reduced social interaction and increased level of circulating NE in rats previously exposed to repeated social defeat. Parallel cell culture work, which was performed to examine the direct effects of NE and DEX on ADRB2, demonstrated ADRB2 downregulation and MCP-1 upregulation in cultured EL-1 cells. Genotyping with regard to the ADRB2 genotype; rs1042714 CC vs CG/GG, on human saliva samples, showed that individuals with CC reported more anxiety following exposure to bullying behaviors as compared to the G carriers. CONCLUSION: We conclude that workplace bullying promotes anxiety and threaten well-being through an ADRB2 associated mechanism.

Associations between exposure to workplace bullying and insomnia: a cross-lagged prospective study of causal directions.

OBJECTIVE: Workplace bullying has been established as a significant correlate of sleep problems. However, little is known regarding the causal direction between bullying and sleep. The aim of this study was to examine temporal relationships between bullying and symptoms of insomnia. METHODS: Reciprocal and prospective associations between exposure to workplace bullying and symptoms of insomnia were investigated in a national probability sample comprising 1149 Norwegian employees. Data stemmed from a two-wave full panel survey study with a 6-month time interval between the baseline and follow-up assessments. Models with stabilities, forward-, reverse-, and reciprocal associations were tested and compared using Structural Equation Modelling. Analyses were adjusted for age, gender, and the stability in the outcome variables over time. Workplace bullying was assessed with the nine-item Short Negative Acts Questionnaire. Insomnia was assessed with a previously validated three item scale reflecting problems with sleep onset, sleep maintenance, and early morning awakening. RESULTS: The forward association model, which showed that exposure to workplace bullying prospectively increased levels of insomnia (b = 0.08; p < 0.001), had best fit with the data [CFI = 0.94; TLI = 0.93; RMSEA = 0.049 (0.046-0.052)]. The reverse association model where insomnia influences risk of being subjected to bullying was not supported. CONCLUSION: Workplace bullying is a risk factor for later insomnia. There is a need for further studies on moderating and mediating variables that can explain how and when bullying influence sleep.

Repeated social defeat promotes persistent inflammatory changes in splenic myeloid cells; decreased expression of ß-arrestin-2 (ARRB2) and increased expression of interleukin-6 (IL-6).

BACKGROUND: Previous studies suggest that persistent exposure to social stress in mammals may be associated with multiple physiological effects. Here, we examine the effects of social stress in rats, i.e. repeated social defeat, on behavior, hypothalamic-pituitary-adrenal (HPA)-axis and immune system. METHODS: A resident-intruder paradigm, where an intruder rat was exposed to social stress by a dominant resident rat for 1 hour each day for 7 consecutive days was used. The day after the last stress exposure in the paradigm the data were analyzed. Variation in social interaction was observed manually, whereas locomotion was analyzed off-line by a purpose-made software. Gene expression in the pituitary gland, adrenal gland and myeloid cells isolated from the spleen was measured by qPCR. RESULTS: The exposure to social stress induced decreased weight gain and increased locomotion. An increased nuclear receptor subfamily group C number 1 (NR3C1) expression in the pituitary gland was also shown. In myeloid cells harvested from the spleen, we observed decreased expression of the ß2-adrenergic receptor (ADRB2) and ß-arrestin-2 (ARRB2), but increased expression of interleukin-6 (IL-6). Subsequent analyses in the same cells showed that ARRB2 was negatively correlated with IL-6 following the stress exposure. CONCLUSION: Our results show that that the experience of social stress in the form of repeated social defeat in rats is a potent stressor that in myeloid cells in the spleen promotes persistent inflammatory changes. Future research is needed to examine whether similar inflammatory changes also can explain the impact of social stress, such as bullying and harassment, among humans.

Exposure to workplace bullying, microRNAs and pain; evidence of a moderating effect of miR-30c rs928508 and miR-223 rs3848900.

Prolonged exposure to bullying behaviors may give rise to symptoms such as anxiety, depression and chronic pain. Earlier data suggest that these symptoms often are associated with stress-induced low-grade systemic inflammation. Here, using data from both animals and humans, we examined the moderating role of microRNAs (miRNAs, miRs) in this process. In the present study, a resident-intruder paradigm, blood samples, tissue harvesting and subsequent qPCR analyses were used to screen for stress-induced changes in circulating miRNAs in rats. The negative acts questionnaire (NAQ), TaqMan assays and a numeric rating scale (NRS) for pain intensity were then used to examine the associations among bullying behaviors, relevant miRNA polymorphisms and pain in a probability sample of 996 Norwegian employees. In rats, inhibited weight gain, reduced pituitary POMC expression, adrenal Nr3c1 mRNA downregulation, as well as increased miR-146a, miR-30c and miR-223 in plasma were observed following 1 week of repeated exposure to social stress. When following up the miRNA findings from the animal study in the human working population, a stronger relationship between NAQ and NRS scores was observed in subjects with the miR-30c GG genotype (rs928508) compared to other subjects. A stronger relationship between NAQ and NRS scores was also seen in men with the miR-223 G genotype (rs3848900) as compared to other men. Our findings show that social stress may induce many physiological changes including changed expression of miRNAs. We conclude that the miR-30c GG genotype in men and women, and the miR-223 G genotype in men, amplify the association between exposure to bullying behaviors and pain.Lay summaryUsing an animal model of social stress, we identified miR-146a, miR-30c and miR-223 as potentially important gene regulatory molecules that may be involved in the stress response. Interestingly, human genotypes affecting the expression of mature miR-30c and miR-223 had a moderating effect on the association between exposure to bullying and pain. Subjects with the miR-30c rs928508 GG genotype had a significantly stronger association between exposure to bullying behaviors and pain than other subjects. The same was observed in men with the miR-223 rs3848900 G genotype, as compared to other men.

Associations between clinical symptoms, plasma norepinephrine and deregulated immune gene networks in subgroups of adolescent with Chronic Fatigue Syndrome.

BACKGROUND: Chronic Fatigue Syndrome (CFS) is one of the most important causes of disability among adolescents while limited knowledge exists on genetic determinants underlying disease pathophysiology. METHODS: We analyzed deregulated immune-gene modules using Pathifier software on whole blood gene expression data (29 CFS patients, 18 controls). Deconvolution of immune cell subtypes based on gene expression profile was performed using CIBERSORT. Supervised consensus clustering on pathway deregulation score (PDS) was used to define CFS subgroups. Associations between PDS and immune, neuroendocrine/autonomic and clinical markers were examined. The impact of plasma norepinephrine level on clinical markers over time was assessed in a larger cohort (91 patients). RESULTS: A group of 29 immune-gene sets was shown to differ patients from controls and detect subgroups within CFS. Group 1P (high PDS, low norepinephrine, low naïve CD4+ composition) had strong association with levels of serum C-reactive protein and Transforming Growth Factor-beta. Group 2P (low PDS, high norepinephrine, high naïve CD4+ composition) had strong associations with neuroendocrine/autonomic markers. The corresponding plasma norepinephrine level delineated 91 patients into two subgroups with significant differences in fatigue score. CONCLUSION: We identified 29 immune-gene sets linked to plasma norepinephrine level that could delineate CFS subgroups. Plasma norepinephrine stratification revealed that lower levels of norepinephrine were associated with higher fatigue. Our data suggests potential involvement of neuro-immune dysregulation and genetic stratification in CFS.

Five-year development of lumbar disc degeneration-a prospective study.

OBJECTIVE: To examine the impact of demographic, clinical, and genetic factors as well as herniated discs on 5-year development of disc degeneration in the lumbar spine, and to investigate associations between changes in lumbar degenerative findings and pain. MATERIALS AND METHODS: In 144 patients with lumbar radicular pain or low back pain, we scored disc degeneration, herniated discs, and high-intensity zones in the posterior annulus fibrosus on lumbar magnetic resonance imaging (MRI) at baseline and 5-year follow-up. Genotyping (TaqMan assay) was performed for genes encoding vitamin D receptor (VDR), collagen XIα (COL11A), matrix metalloproteinase 1/9 (MMP1/MMP9), and interleukin 1α/1RN (IL-1α/IL-1RN). Associations were analyzed using multivariate linear regression adjusted for age, sex, smoking, body mass index, and baseline scores for degenerated discs and herniated discs (when analyzing impact of baseline factors) or for pain (when analyzing associations with pain). RESULTS: Progression of disc degeneration over 5 years was significantly (p < 0.001) related to higher age and less disc degeneration at baseline, but not to sex, smoking, body mass index, herniated discs, or variants in the studied genes. No associations were identified between changes in disc degeneration or high-intensity zones and pain at 5-year follow-up. However, increased number of herniated discs over 5 years was associated with pain at rest (p = 0.019). CONCLUSIONS: Age and disc degeneration at baseline, rather than genetic factors, influenced the 5-year development of disc degeneration in patients with lumbar radicular pain or low back pain. Development of herniated discs was related to pain at rest.

Alcohol Use and Psychosocial Stressors in the Norwegian Workforce.

BACKGROUND: Although alcohol use can have detrimental effects for employees, little is known about the prevalence, distribution, and correlates in the Norwegian workforce. AIMS: To determine the overall and the work-related prevalence of weekly alcohol use, and to establish associations between psychosocial work stressors and alcohol use among Norwegian employees. METHODS: Data were from a 2015 national probability sample of 1,608 Norwegian employees (response rate 32%). Job demands, lack of job control, role expectations, workplace bullying, and leadership were examined as correlates of several dimensions of alcohol use. RESULTS: Average weekly alcohol consumption was 4.28 units (SD = 7.91). Male workers reported significantly higher consumption than female workers. Also, 2.6% of male and 2.0% of female workers reported problematic alcohol use. Only 0.1% of workers reported weekly alcohol use before the workday, 0.4% reported weekly use during the workday, 20.1% reported weekly use after ending the work day, and 80% reported use during weekends/days off. Alcohol intake increased with age, but was not related to marital status, educational level, work schedule, or leadership position. Problematic alcohol use was related to job demands and workplace bullying. Alcohol use after work was positively related to lack of job control and role ambiguity and negatively related to bullying. Conclusions/importance: Weekly alcohol use before and during the workday is not prevalent among Norwegian workers. Interventions to reduce job demands and workplace bullying may reduce problematic alcohol intake, whereas increasing job control and reducing role ambiguity may reduce after work use.

MicroRNA-223 demonstrated experimentally in exosome-like vesicles is associated with decreased risk of persistent pain after lumbar disc herniation.

BACKGROUND: Previous findings have demonstrated that lumbar radicular pain after disc herniation may be associated with up-regulation of inflammatory mediators. In the present study we examined the possible role of extracellular microRNAs (miRs) in this process. METHODS: Single unit recordings, isolation of exosome-like vesicles, electron microscopy, nanoparticle tracking analysis, western blot analysis and qPCR were used in rats to demonstrate the effect of nucleus pulposus (NP) applied onto the dorsal nerve roots. ELISA and qPCR were used to measure the level of circulating IL-6 and miRs in a 1-year observational study in patients after disc herniation. RESULTS: In the rats, enhanced spinal cord nociceptive responses were displayed after NP applied onto the dorsal nerve roots. An increased release of small non-coding RNAs, including miR-223, miR-760 and miR-145, from NP in exosome-like vesicles was demonstrated. In particular, the NP expression of miR-223, which inhibited the nociceptive spinal signalling, was increased. In the patients, increased extracellular miR-223 was also verified in the acute phase after disc herniation. The increased miR-223 expression was, however, only observed in those who recovered (sex, age and smoking were included as covariates). CONCLUSIONS: Our findings suggest that miR-223, which can be released from the NP after disc herniation, attenuates the neuronal activity in the pain pathways. Dysregulation of miR-223 may predict chronic lumbar radicular pain. Trial registration/ethics REK 2014/1725.

Local up-regulation of interferon-γ (IFN-γ) following disc herniation is involved in the inflammatory response underlying acute lumbar radicular pain.

Lumbar radicular pain after disc herniation may be associated with release of pro-inflammatory cytokines from nucleus pulposus (NP) tissue. In the present study we examined the role of interferon-γ (IFN-γ) and cluster of differentiation 68 (CD68) in the acute phase of this process. First, in an animal model mimicking the clinical situation after disc herniation, the role of IFN-γ close to the dorsal nerve roots was studied. Next, in patients with lumbar radicular pain due to disc herniation, we examined how two single nucleotide polymorphisms (SNPs; rs2069705 and rs2069718) are important for the IFN-γ expression influenced the pain behavior. The animal data demonstrated a significant increase in the nociceptive activity at the spinal level after local application of NP and IFN-γ onto the dorsal nerve roots. A positive correlation between IFN-γ and CD68 in the NP tissue was also demonstrated. In the patients, a significant increase in Oswestry Disability Index (ODI) score was observed in carriers of the IFN-γ SNPs; rs2069705 A and rs2069718 G alleles. The present data suggest that IFN-γ close to the dorsal nerve roots may contribute to the pathogenesis, the nociceptive activity and the pain behavior following lumbar disc herniation.

Genes associated with persistent lumbar radicular pain; a systematic review.

BACKGROUND: The aim of the present study was to provide an overview of the literature addressing the role of genetic factors and biomarkers predicting pain recovery in newly diagnosed lumbar radicular pain (LRP) patients. METHODS: The search was performed in Medline OVID, Embase, PsycInfo and Web of Science (2004 to 2015). Only prospective studies of patients with LRP addressing the role of genetic factors (genetic susceptibility) and pain biomarkers (proteins in serum) were included. Two independent reviewers extracted the data and assessed methodological quality. RESULTS: The search identified 880 citations of which 15 fulfilled the inclusion criteria. Five genetic variants; i.e., OPRM1 rs1799971 G allele, COMT rs4680 G allele, MMP1 rs1799750 2G allele, IL1α rs1800587 T allele, IL1RN rs2234677 A allele, were associated with reduced recovery of LRP. Three biomarkers; i.e., TNFα, IL6 and IFNα, were associated with persistent LRP. CONCLUSION: The present results indicate that several genetic factors and biomarkers may predict slow recovery in LRP. Still, there is a need for replication of the findings. A stricter use of nomenclature is also highly necessary. TRIAL REGISTRATION: The review is registered PROSPERO 20th of November 2015. Registration number is CRD42015029125 .

Serum levels of the pro-inflammatory interleukins 6 (IL-6) and -8 (IL-8) in patients with lumbar radicular pain due to disc herniation: A 12-month prospective study.

Earlier studies indicate that lumbar radicular pain after disc herniation may be associated with a local inflammation induced by leakage of nucleus pulposus (NP) into the spinal canal and neuroforamen. In the present study we addressed the role of two interleukins, IL-6 and IL-8 in such long-lasting lumbar radicular pain. All 127 patients were recruited from Oslo University Hospital, Ullevål, Norway. At inclusion, 6weeks and 12months, serum concentrations of IL-6 and IL-8 were analyzed by enzyme-linked immunosorbent assay (ELISA) and pain intensity was reported on a 0-10cm visual analog scale (VAS). Significantly higher levels of IL-6 and IL-8 in serum were found in patients with VAS ⩾3 at 12months, than in patient with VAS <3 at 12months (p⩽0.01, test of between-subjects effect, repeated measures ANOVA, covariates for IL-6: age, smoking; covariates for IL-8: smoking, treatment). For the first time we show that chronic lumbar radicular pain may be associated with a persistent increase of the pro-inflammatory substances IL-6 and IL-8 in serum after disc herniation.

Effects of low-dose clonidine on cardiovascular and autonomic variables in adolescents with chronic fatigue: a randomized controlled trial.

BACKGROUND: Chronic Fatigue Syndrome (CFS) is a common and disabling condition in adolescence with few treatment options. A central feature of CFS is orthostatic intolerance and abnormal autonomic cardiovascular control characterized by sympathetic predominance. We hypothesized that symptoms as well as the underlying pathophysiology might improve by treatment with the alpha2A-adrenoceptor agonist clonidine. METHODS: A total of 176 adolescent CFS patients (12-18 years) were assessed for eligibility at a single referral center recruiting nation-wide. Patients were randomized 1:1 by a computer system and started treatment with clonidine capsules (25 µg or 50 µg twice daily, respectively, for body weight below/above 35 kg) or placebo capsules for 9 weeks. Double-blinding was provided. Data were collected from March 2010 until October 2012 as part of The Norwegian Study of Chronic Fatigue Syndrome in Adolescents: Pathophysiology and Intervention Trial (NorCAPITAL). Effect of clonidine intervention was assessed by general linear models in intention-to-treat analyses, including baseline values as covariates in the model. RESULTS: A total of 120 patients (clonidine group n = 60, placebo group n = 60) were enrolled and started treatment. There were 14 drop-outs (5 in the clonidine group, 9 in the placebo group) during the intervention period. At 8 weeks, the clonidine group had lower plasma norepinephrine (difference = 205 pmol/L, p = 0.05) and urine norepinephrine/creatinine ratio (difference = 3.9 nmol/mmol, p = 0.002). During supine rest, the clonidine group had higher heart rate variability in the low-frequency range (LF-HRV, absolute units) (ratio = 1.4, p = 0.007) as well as higher standard deviation of all RR-intervals (SDNN) (difference = 12.0 ms, p = 0.05); during 20° head-up tilt there were no statistical differences in any cardiovascular variable. Symptoms of orthostatic intolerance did not change during the intervention period. CONCLUSIONS: Low-dose clonidine reduces catecholamine levels in adolescent CFS, but the effects on autonomic cardiovascular control are sparse. Clonidine does not improve symptoms of orthostatic intolerance. TRIAL REGISTRATION: Clinical Trials ID: NCT01040429, date of registration 12/28/2009.

Subjective health complaints in patients with lumbar radicular pain and disc herniation are associated with a sex - OPRM1 A118G polymorphism interaction: a prospective 1-year observational study.

BACKGROUND: Earlier observations show that development of persistent pain may be associated with the genetic variability in the gene encoding for the µ-opioid receptor 1, the OPRM1 A118G (rs1799971). The aim of this study was to investigate the association between OPRM1 genotype and subjective health complaints in patients with radicular pain and disc herniation. METHODS: A prospective, 1-year observational study was conducted at a hospital back clinic, including 118 Caucasian patients with lumbar radicular pain and MRI confirmed disc herniation. Single nucleotide polymorphism genotyping regarding the OPRM1 A118G was performed. The data of individuals with AA versus AG or GG were analysed separately by linear mixed models. The Subjective Health Complaints Inventory (0-81) including 27 common complaints experienced the previous month on a scale from not at all (0) to severe (3) was used as outcome. Pain, prior duration of leg pain, age, smoking status, and lumbar disc surgery were considered as covariates. RESULTS: In total 23 of 118 patients were carriers of the OPRM1 G-allele. All patients except female carriers of the G-allele reported a decrease in pain from baseline to 1 year. Female carriers of the G-allele reported significantly higher subjective health complaints score during the study time span than male carriers of the G-allele when controlling for pain and pain duration. CONCLUSION: The present data indicate that, when controlling for pain intensity and duration, subjective health complaints are associated with a sex - OPRM1 A118G polymorphism interaction in patients with radicular pain.

The association between Modic changes and pain during 1-year follow-up in patients with lumbar radicular pain.

OBJECTIVE: To examine whether Modic changes influence pain during a 1-year follow-up in patients with lumbar radicular pain. MATERIALS AND METHODS: A total of 243 patients with lumbar radicular pain due to disc herniation were recruited from two hospitals in Norway and followed up at 6 weeks, 6 months, and 12 months. On baseline lumbar magnetic resonance images, two observers independently evaluated Modic changes (types I-III; craniocaudal size 0-3). Outcomes were sensory pain (McGill Pain Questionnaire), back and leg pain (visual analogue scale, VAS). Association between Modic type and outcomes was explored with a mixed model and then by two-way analysis of variance (ANOVA) at each time point with Modic and treatment groups (surgical, n = 126; nonsurgical, n = 117) as fixed factors, adjusted for disc degeneration, age, sex, smoking, and duration of radicular pain. Modic size was also analyzed using ANOVA. RESULTS: Pain scores had decreased significantly at 1-year follow-up. Modic type was significantly related to McGill sensory scores (mixed model: p = 0.014-0.026; ANOVA: p = 0.007 at 6 weeks), but not to VAS back pain or VAS leg pain scores. At 6 weeks, the mean McGill sensory score was higher in Modic I than in Modic II-III patients (p = 0.003) and in patients without Modic changes (p = 0.018). Modic size L1-S1 was not associated with pain outcomes. CONCLUSION: Patients with lumbar radicular pain have a substantial pain reduction during 1-year follow-up, but Modic type I changes may imply a slower initial decrease in sensory pain.

Workplace bullying and subsequent health problems.

BACKGROUND: Cross-sectional studies demonstrate that exposure to bullying in the workplace is positively correlated with self-reported health problems. However, these studies do not provide a basis to draw conclusions on the extent to which bullying leads to increased health problems or whether health problems increase the risk of being bullied. To provide better indications of a causal relationship, knowledge from prospective studies on the association between bullying in the workplace and health outcomes is therefore summarised. MATERIAL AND METHOD: We conducted a systematic literature review of original articles from central literature databases on longitudinal associations between bullying in the workplace and health. Average associations between bullying and health outcomes are calculated using meta-analysis. RESULTS: A consistent finding across the studies is that exposure to bullying is significantly positively related to mental health problems (OR =1.68; 95% KI 1.35-2.09) and somatic symptoms (OR = 1.77; 95% KI 1.41-2.22) over time. Mental health problems are also associated with subsequent exposure to bullying (OR = 1.74; 95% KI 1.44-2.12). INTERPRETATION: Bullying is positively related to mental health problems and somatic symptoms. The association between mental health problems and subsequent bullying indicates a self-reinforcing process between mental health and bullying. The methodological quality of the studies that were conducted is relatively sound. However, based on the existing knowledge base there are no grounds for conclusions regarding an unambiguous causal relationship between bullying and health.

Pain intensity the first year after lumbar disc herniation is associated with the A118G polymorphism in the opioid receptor mu 1 gene: evidence of a sex and genotype interaction.

Earlier studies have shown that the single nucleotide polymorphism (SNP) A118G (rs1799971) in the opioid receptor mu 1 (OPRM1) gene may affect pain sensitivity. In the present study we investigated whether the A118G SNP could predict clinical outcome regarding progression of pain intensity and disability in patients with low back pain and sciatica after lumbar disc herniation. Patients (n = 258) with lumbar disc herniation and sciatic pain, all European-Caucasian, were recruited from two hospitals in Norway. Pain and disability were rated on a visual analog scale (VAS), by McGill Sensory Questionnaire and by Oswestry Disability Index (ODI) over a 12 months period. The data revealed a significant interaction between sex and A118G genotype regarding the pain intensity during the 12 months (VAS, p = 0.002; McGill, p = 0.021; ODI, p = 0.205, repeated-measures ANOVA). We found that */G women had a slower recovery rate than the */G men. Actually, the */G women had 2.3 times as much pain as the */G men 12 months after the disc herniation (VAS, p = 0.043, one-way ANOVA; p = 0.035, Tukey HSD). In contrast, the A/A women and A/A men seemed to have almost exactly the same recovery rate. The present data suggest that OPRM1 G allele increases the pain intensity in women, but has a protective effect in men the first year after disc herniation.

Stress-induced headache in the general working population is moderated by the NRCAM rs2300043 genotype.

OBJECTIVES: Earlier findings suggest that social stress such as abusive supervision may promote pain. In the present study we examine the possible moderating role of genetic variability in the NRCAM gene in this process. METHODS: The data were collected through a national survey drawn from the National Central Employee Register by Statistics Norway. A total of 1,205 individuals returned both the questionnaire and the saliva kit. Abusive supervision was scored by a 5-item version of the Tepper's 2,000 scale. Headache was measured on a four-category scale; 'not bothered,' 'a little bothered,' 'considerably bothered', 'seriously bothered'. Genotyping with regards to NRCAM rs2300043 was carried out using Taqman assay. Ordinal logistic regression was used to analyse the data. RESULTS: For males exposed to abusive supervision, those carrying the rs2300043 CC genotype reported the highest levels of headache. Women showed a trend towards the opposite pattern. Women with the rs2300043 CC genotype seem to have a weaker effect of abusive supervision regarding reported headache than their male counterparts with the CC genotype when exposed to abusive supervision. CONCLUSIONS: The present results indicated that the association between abusive supervision and headache in men with the NRCAM rs2300043 C allele was stronger than in other men. This suggests that the NRCAM genotype in men is important for the tolerance of social stress e.g., repeated negative acts from a superior. In contrast, a trend, though non-significant, towards the opposite pattern was observed in women. Our result suggests that the NRCAM genotype in men manifestly affects stress-induced pain such as headache.

Expression of ANK3 moderates the association between childhood trauma and affective traits in severe mental disorders.

Exposure to early life trauma increases the risk of psychopathology later in life. Here we investigated if ANK3 mRNA levels influence the relationship between childhood trauma experiences and clinical characteristics in mental disorders. A sample of 174 patients with bipolar disorder and 291 patients with schizophrenia spectrum disorder were included. Patients were diagnosed using the Structured Clinical Interview for DSM-IV, and childhood trauma was assessed using the childhood trauma questionnaire. Age at illness onset and number of psychotic and affective episodes were assessed from interview and medical records. Current depressive symptoms were measured using the calgary depression scale for schizophrenia and the inventory for depressive symptomatology. ANK3 expression was analyzed in whole blood using the Illumina HumanHT-12 v4 Expression BeadChip. Analyses were carried out with the Process adjusted for confounders. Within the total sample, patients with both high ANK3 expression and with the most severe childhood sexual abuse had more manic/hypomanic episodes and an earlier age at onset of the first episode. ANK3 mRNA levels also moderated the relationship between emotional neglect and manic/hypomanic episodes. Our results suggest that ANK3 expression levels moderate the association between specific types of childhood trauma and affective traits in mental disorders.