SuPAR in major depression: Association with 26 weeks antidepressant response and 10-year depression outcomes.

Introduction: Inflammation has been associated with depression and differential antidepressant (AD) treatment response. Soluble urokinase plasminogen activator receptor (suPAR) is a novel measure of chronic inflammation. We investigated whether suPAR is associated with depression severity and AD response. Methods: We included 90 patients with major depressive disorder (MDD) who participated in a part-randomized clinical trial of 26 weeks of treatment with escitalopram or nortriptyline. suPAR levels were measured in serum samples collected at baseline and after 8, 12 and 26 weeks. Mixed effects models for the association between suPAR levels and AD response were performed. By merging with Danish nationwide registers, we included information on psychiatric hospital contacts during ten years after the GENDEP trial. Cox regression analyses calculated the hazard rate ratios between suPAR levels and subsequent hospitalizations. Results: At baseline, higher suPAR levels were not associated with overall depression severity but with greater severity of neurovegetative depressive symptoms, specifically appetite and weight changes. 57 (63.3%) patients responded positively to treatment. Among 57 (63.3%) patients who achieved response, those who responded had significantly higher baseline suPAR levels levels, and response was associated with a significant decrease in suPAR during AD treatment. Remitters decreased from 3.1 ng/ml at baseline to 2.8 ng/ml after 26 weeks (p = 0.003) and responders from 3.0 to 2.8 ng/ml (p = 0.02), whereas non-remitters and non-responders showed unchanged suPAR levels. We found no correlation between a change in suPAR and a change in MADRS, but a lowering of suPAR correlated with a decrease in neurovegetative symptoms. We found no association between suPAR levels and 10-year risk for hospitalizations. Discussion: The present study suggests that an elevated level of chronic inflammation, measured as the suPAR level, is associated with better response to AD treatment.

Hemisphere-dependent endocannabinoid system activity in prefrontal cortex and hippocampus of the Flinders Sensitive Line rodent model of depression.

Altered endocannabinoid (eCB) signalling is suggested as an important contributor to the pathophysiology of depression. To further elucidate this, we conducted a study using a genetic rat model of depression, the Flinders Sensitive Line (FSL), and their controls, the Flinders Resistant Line (FRL) rats. Plasma, right and left prefrontal cortex, and hippocampus were isolated from FSL and FRL rats. We analyzed each region for the eCB anandamide (AEA) and 2-arachidonoylglycerol (2-AG) levels by liquid chromatography/multiple reaction monitoring (LC/MRM), mRNA and protein levels of the cannabinoid type 1 receptor (CB1R), fatty acid amide hydrolase (FAAH) and monoacyl glycerol lipase (MAGL) by real time qPCR and Western blotting. Content of 2-AG was lower in the left side of the hippocampus and prefrontal cortex in FSL rats compared to FRL rats. Inversely, levels of AEA were higher in right hippocampus than in left hippocampus. In plasma, AEA levels were increased and 2-AG decreased. Cannabinoid receptor 1 (Cnr1), Faah and Magl mRNA levels were prominently decreased in right prefrontal cortex of FSL rats as compared to FRL rats. Protein expression of CB1R and FAAH were decreased in left hippocampus. In summary, our data suggest a decreased eCB signalling in the FSL rats, which could contribute to the depressive-like behaviour. Interestingly, the altered eCB system activity appear to be hemisphere-specific in the limbic regions. Our study support the existing literature and showed altered eCB system activity in this particular animal model of depression.

Chronic maternal inflammation or high-fat-feeding programs offspring obesity in a sex-dependent manner.

BACKGROUND/OBJECTIVES: The current world-wide obesity epidemic partially results from a vicious circle whereby maternal obesity during pregnancy predisposes the offspring for accelerated weight gain and development of metabolic syndrome. Here we investigate whether low-grade inflammation, characteristic of the obese state, provides a causal role for this disastrous fetal programming in mice. METHODS: We exposed pregnant and lactating C57BL/6JBom female mice to either high-fat diet (HFD), or continuous infusion of lipopolysaccharide (LPS), a potent trigger of innate immunity, and studied offspring phenotypes. RESULTS: Both maternal LPS or HFD treatments rendered the offspring hyperphagic and inept of coping with a HFD challenge during adulthood, increasing their adiposity and weight gain. The metabolic effects were more pronounced in female offspring, while exposed male offspring mounted a larger inflammatory response to HFD at adulthood. CONCLUSIONS: This supports our hypothesis and highlights the programming potential of inflammation in obese pregnancies.

Airway exposure to multi-walled carbon nanotubes disrupts the female reproductive cycle without affecting pregnancy outcomes in mice.

BACKGROUND: The use of multiwalled carbon nanotubes (MWCNT) is increasing due to a growing use in a variety of products across several industries. Thus, occupational exposure is also of increasing concern, particularly since airway exposure to MWCNTs can induce sustained pulmonary acute phase response and inflammation in experimental animals, which may affect female reproduction. This proof-of-principle study therefore aimed to investigate if lung exposure by intratracheal instillation of the MWCNT NM-400 would affect the estrous cycle and reproductive function in female mice. RESULTS: Estrous cycle regularity was investigated by comparing vaginal smears before and after exposure to 67 µg of NM-400, whereas reproductive function was analyzed by measuring time to delivery of litters after instillation of 2, 18 or 67 µg of NM-400. Compared to normal estrous cycling determined prior to exposure, exposure to MWCNT significantly prolonged the estrous cycle during which exposure took place, but significantly shortened the estrous cycle immediately after the exposed cycle. No consistent effects were seen on time to delivery of litter or other gestational or litter parameters, such as litter size, sex ratio, implantations and implantation loss. CONCLUSION: Lung exposure to MWCNT interfered with estrous cycling. Effects caused by MWCNTs depended on the time of exposure: the estrous stage was particularly sensitive to exposure, as animals exposed during this stage showed a higher incidence of irregular cycling after exposure. Our data indicates that MWCNT exposure may interfere with events leading to ovulation.

Ratings of pain and activity limitation on the visual analogue scale and global impression of change in multimodal rehabilitation of back pain - analyses at group and individual level.

PURPOSE: To evaluate changes in pain intensity and activity limitation, at group and individual levels, and their associations with the global impression of change after multimodal rehabilitation in patients with back pain. METHOD: Patients with long-term back pain (n = 282) participated in a 4-week programme with a follow-up after 6 months. Visual analogue scales (VAS) were used to rate pain intensity and activity limitation. Global impression of change (GIC) was rated on a 7-category scale. The sign test, the Svensson method and the Spearman rank correlation were used for analyses. RESULTS: Significantly lower ratings in pain and activity limitation at follow-up were found at group level. However, a large individual variability was found by the Svensson method. The correlations between GIC and changes in pain and activity limitation were rs = 0.49 and rs = 0.50, respectively. A rated GIC of at least "much better" on group level showed changes of ≥20 mm on the VAS. CONCLUSIONS: At group level, lower VAS ratings were found in patients with back pain. However, a large individual variability in pain and activity limitation was also found resulting in low to moderate associations between GIC and the change in VAS ratings. The large individual variability might be due to the impreciseness in the ratings on the VAS. We have presented a critical discussion of statistical methods in connection with the VAS. Implications for Rehabilitation The use of VAS as a rating instrument may be questioned, especially for perceived pain intensity which is a too complex experience to be rated on a line without any visible categories. Single ratings of pain intensity should preferably be complemented with the ratings of activity limitation in patients with long-term back pain. Global impression of change is a suggested inclusive rating after rehabilitation. The improvement desired by the patient should preferably be determined before rehabilitation.

Effects of a one-year physical activity programme for women with systemic lupus erythematosus - a randomized controlled study.

OBJECTIVES: To study the effects of a one-year physical activity programme on aerobic capacity, physical activity and health-related quality of life (HRQL) in patients with systemic lupus erythematosus (SLE) by a randomized control design. METHODS: Thirty-five women with low or moderate disease activity and organ damage were randomized to intervention (I) or control (C) group. The intervention during months 0-3 consisted of education, supervised aerobic exercise at high intensity and individual coaching, as well as self-managed physical activity at low-to-moderate intensity. During months 4-12, the physical activity was self-managed and the coaching was successively reduced over time. Outcome measures included: maximal oxygen uptake (VO2 max) from a bicycle ergometer test, self-reported physical activity and HRQL (SF-36). RESULTS: VO2 at sub-max. and max. increased, independent of group, during the one-year study period (main effect of time p < 0.0001). VO2 max. increased between baseline and month 3 (p < 0.0001), between months 3 and 6 (p = 0.01) and the increase was sustained at month 12 (ns). Frequency of physical activity at high intensity also increased, independent of group, during the study period. It was increased at months 3, 6 and 12 compared to baseline (p = 0.02, p < 0.001, p = 0.03). Improvement in mental health between baseline and month 6 (p = 0.002) was seen for the I-group, not the C-group (p = 0.03). Disease activity and organ damage did not change. CONCLUSIONS: Physical activity and aerobic capacity increased after supervised exercise and coaching, and the improvement was sustained during the one-year programme. However, no interactions between the group differences were seen, which suggests that repeated measurements could motivate to increased physical activity and thereby to increased aerobic capacity. As sub-max. VO2 increased over time, training-induced changes in VO2 on-kinetics could be another explanation. Little influence on HRQL was seen after the programme. The study indicates that physical activity at high intensity over one year is tolerated by patients with mild to moderate SLE.

Increased serum levels of sortilin are associated with depression and correlated with BDNF and VEGF.

Neurotrophic factors have been investigated in relation to depression. The aim of the present study was to widen this focus to sortilin, a receptor involved in neurotrophic signalling. The serum sortilin level was investigated in 152 individuals with depression and 216 control individuals, and eight genetic markers located within the SORT1 gene were successfully analysed for association with depression. Genotyping was performed using the Sequenom MassARRAY platform. All the individuals returned a questionnaire and participated in a semi-structured diagnostic interview. Sortilin levels were measured by immunoassay, and potential determinants of the serum sortilin level were assessed by generalized linear models. Serum levels of brain-derived neurotrophic factor (BDNF) and vascular endothelial growth factor (VEGF) were measured in previous studies. We identified a significant increase of serum sortilin levels in depressed individuals compared with controls (P=0.0002) and significant positive correlation between serum sortilin levels and the corresponding levels of BDNF and VEGF. None of the genotyped SNPs were associated with depression. Additional analyses showed that the serum sortilin level was influenced by several other factors. Alcohol intake and body mass index, as well as depression, serum BDNF and serum VEGF were identified as predictors of serum sortilin levels in our final multivariate model. In conclusion, the results suggest a role of circulating sortilin in depression which may relate to altered activity of neurotrophic factors.

Plasma brain-derived neurotrophic factor and prefrontal white matter integrity in late-onset depression and normal aging.

OBJECTIVE: To explore the relationship between brain-derived neurotrophic factor (BDNF) and vascular endothelial growth factor (VEGF), cerebral deep white matter lesions (DWMLs), and measures of white matter integrity in patients with late-onset depression, with respect to vascular risk factors. METHOD: We examined 22 patients with late-onset depression and 22 matched controls. Quantification of plasma BDNF and VEGF levels were performed with enzyme-linked immunosorbent assay (ELISA) kits. Measures of white matter integrity comprised apparent diffusion coefficient (ADC) and fractional anisotropy (FA), obtained by diffusion tensor imaging (DTI). Effects of DWMLs, FA, ADC, and vascular risk factors on BDNF and VEGF were assessed using multiple linear regression. RESULTS: The BDNF and VEGF levels did not differ significantly between groups. With pooled data for patients and controls, the BDNF level was positively associated with both number (t = 2.14, P = 0.039) and volume (t = 2.04, P = 0.048) of prefrontal DWMLs and negatively associated with FA in prefrontal normal-appearing white matter (t = -2.40, P = 0.02), adjusted for age and gender. Smoking and hypercholesterolemia was positively associated with the BDNF (t = 2.36, P = 0.023) and VEGF levels (t = 2.28, P = 0.028), respectively. CONCLUSION: Our results suggest a role for BDNF in the complex pathophysiologic mechanisms underlying DWMLs in both normal aging and late-onset depression.

Change in kinesiophobia and its relation to activity limitation after multidisciplinary rehabilitation in patients with chronic back pain.

PURPOSE: To explore the change in kinesiophobia in relation to activity limitation after a multidisciplinary rehabilitation programme in patients with chronic back pain. METHOD: A prospective cohort study was made including 265 patients. Data were collected at baseline, after rehabilitation, and at 6-months follow-up. Outcome measures were the Tampa Scale for kinesiophobia (TSK) and the disability rating index (DRI). The smallest detectable change (SDC) in TSK was set to 8 scores. Relationships between kinesiophobia and activity limitation/physical ability were explored with regard to subgroups with high, medium and low baseline TSK scores, and for those patients who did or did not reach the SDC in TSK. RESULTS: Improvements in TSK showed high effect sizes in the groups with high and medium baseline TSK scores. Improvements in DRI showed medium effect sizes in all three TSK subgroups. One third of the patients reached the SDC in TSK, and this group also improved significantly more in DRI. The correlation between change in TSK and change in DRI was low. Half of the patients with high TSK score at baseline remained having high DRI at follow-up. CONCLUSIONS: Improvement in physical ability was not related to the initial degree of kinesiophobia but to the SDC in TSK. To prevent patients with high kinesiophobia from preserving high activity limitations, it might be useful to include targeted treatment of kinesiophobia.

Effect of multilayer high-compression bandaging on ankle range of motion and oxygen cost of walking.

OBJECTIVE: To evaluate the effects of multilayer high-compression bandaging on ankle range of motion, oxygen consumption and subjective walking ability in healthy subjects. METHOD: A volunteer sample of 22 healthy subjects (10 women and 12 men; aged 67 [63-83] years) were studied. The intervention included treadmill-walking at self-selected speed with and without multilayer high-compression bandaging (Proforeº), randomly selected. The primary outcome variables were ankle range of motion, oxygen consumption and subjective walking ability. RESULTS: Total ankle range of motion decreased 4% with compression. No change in oxygen cost of walking was observed. Less than half the subjects reported that walking-shoe comfort or walking distance was negatively affected. CONCLUSION: Ankle range of motion decreased with compression but could probably be counteracted with a regular exercise programme. There were no indications that walking with compression was more exhausting than walking without. Appropriate walking shoes could seem important to secure gait efficiency when using compression garments.

Wistar rats subjected to chronic restraint stress display increased hippocampal spine density paralleled by increased expression levels of synaptic scaffolding proteins.

The aim of this study was to investigate whether the previously reported effect of chronic restraint stress (CRS) on hippocampal neuron morphology and spine density is paralleled by a similar change in the expression levels of synaptic scaffolding proteins. Adult male Wistar rats were subjected either to CRS (6 h/day) for 21 days or to control conditions. The resulting brains were divided and one hemisphere was impregnated with Golgi-Cox before coronal sectioning and autometallographic development. Neurons from CA1, CA3b, CA3c, and dentate gyrus (DG) area were reconstructed and subjected to Sholl analysis and spine density estimation. The contralateral hippocampus was used for quantitative real-time polymerase chain reaction and protein analysis of genes associated with spine density and morphology (the synaptic scaffolding proteins: Spinophilin, Homer1-3, and Shank1-3). In the CA3c area, CRS decreased the number of apical dendrites and their total length, whereas CA1 and DG spine density were significantly increased. Analysis of the contralateral hippocampal homogenate displayed an increased gene expression of Spinophilin, Homer1, Shank1, and Shank2 and increased protein expression of Spinophilin and Homer1 in the CRS animals. In conclusion, CRS influences hippocampal neuroplasticity by modulation of dendrite branching pattern and spine density paralleled by increased expression levels of synaptic scaffolding proteins.

Assessment of unsupported sitting in patients with spinal cord injury.

STUDY DESIGN: Cross-sectional study using a consecutive sample. OBJECTIVES: To modify the Motor Assessment Scale (MAS) item 3 'balanced sitting' and the Sitting Balance Score (SBS) to ensure suitability for patients with spinal cord injury (SCI), and to assess the inter-rater reliability and validity of these instruments. SETTING: Spinal Care Unit, clinical setting. METHODS: Unsupported sitting was tested by three physiotherapists using MAS and SBS in 48 in-patients with SCI. The validity of the scales was tested using neurological level and extent of injury according to the International Standards for Neurological Classification of Spinal Cord Injury, time since injury and the patients' function, as measured by Functional Independence Measure (FIM) item 9-13 and Five Additional Mobility and Locomotor Items (5AML). RESULTS: The inter-rater reliability was for MAS (k(w)=0.83-0.91) and for SBS (k(w)=0.69-0.96). The correlation between the balance scales were in relation to; neurological injury level (r(s)=0.19-0.51), extent of injury (r(s)=0.57-0.68) and the functional tests as measured by FIM items 9-13 (r(s)=0.13-0.68, highest for going up and down stairs) and 5AML (r(s)=0.10-0.49). The spread of data on the scales was poor. CONCLUSION: The inter-rater reliability of MAS and SBS was very good. The validity was little to moderate, probably because the chosen functional tests measured complex functional tasks and not only unsupported sitting. Both tests appear to be feasible in clinical settings, but will need major revisions. These results can therefore be used as a base for constructing new, better tests of unsupported sitting.

Influence of diurnal phase on startle response in adult rats exposed to dexamethasone in utero.

Depression and pathological anxiety disorders are among the most prevalent neurological diseases in the world and can be precipitated and exacerbated by stress. Prenatal stress alters both behavioral and endocrine responses to stressful stimuli in later life. We have previously observed increased basal acoustic startle response (ASR) in Wistar rats exposed to stress or dexamethasone (DEX) in utero when tested during the light phase of the circadian rhythm, and decreased prepulse inhibition (PPI) in similar animals tested during the dark phase of the cycle. We speculated that this observation of increased basal startle might be influenced by diurnal phase. In the present study, adult female Sprague Dawley rats, stressed prenatally with DEX (200 µg/kg, gestational days 14-21) and postnatally by blood sampling under restraint, were tested for the ASR during both circadian phases (light and dark). Basal startle was increased in animals tested both during the light and the dark phases of the cycle. We hereby replicated our earlier findings in a new strain and laboratory, thus strengthening the validity of our model regarding prenatal stress effects on ASR in female offspring. Our results indicate that observation of increased basal ASR is not solely dependent on diurnal phase. We found no difference in hippocampal glucocorticoid and mineral corticoid receptor expression between groups.

Binding characteristics of selective serotonin reuptake inhibitors with relation to emission tomography studies.

When developing ligands for emission tomography studies, one of the major obstacles lies in the selection of ligand candidates. A previously unattended factor such as the influence of temperature on candidate ligand affinity is likely to play a role. By use of rat brain homogenates, the binding characteristics of [(3)H]-(S)-citalopram and [(3)H]-(+)-McN5652 and the receptor-ligand interaction at the serotonin transporter of 17 selective serotonin reuptake inhibitors were compared at 21 degrees C and 37 degrees C, respectively. Ligand logP values were also calculated. The ratios for K(i) at 37 degrees C vs. 21 degrees C varied between 0.2 and 2.2 for the selective serotonin reuptake inhibitors considered in this study, with most of the ligands displaying an inverse relationship between K(i) and temperature. Ten of the 17 selective serotonin reuptake inhibitors were found to have pK(i) values statistically significantly different at 21 degrees C compared to 37 degrees C (P < 0.05). The logP values ranged between 3.6 and 4.8, except for DASB, 5-iodo-6-nitroquipazine, and paroxetine where logP was 1.9, 2.2, and 5.0, respectively. K(d) was 0.71 nM at 37 degrees C and 0.31 nM at 21 degrees C for [(3)H]-(S)-citalopram. For [(3)H]-(+)-McN5652 K(d) was 0.11 nM at 37 degrees C and 0.08 nM at 21 degrees C. The association and dissociation was much faster for [(3)H]-(S)-citalopram as compared to [(3)H]-(+)-McN5652. It is concluded that temperature may affect K(d) differently and that in vitro dissociation may help to predict whether a given ligand may be useful in PET studies. LogP values do not per se predict the potential of a given ligand as an emission tomography tracer.

Back muscle fatigue in healthy men and women studied by electromyography spectral parameters and subjective ratings.

To obtain reference data for future studies of patients with low back pain, back muscle fatigue was studied by surface electromyography at L1 and L5 lumbar levels in 55 healthy subjects exerting 80% of maximal voluntary contraction of the back extensors in a sitting position. Reference data were the initial value and rate of decrease (slope) of the median frequency during the contraction. The aim was also to study the effects of contraction time, gender differences, electrode locations and correlations with torque, age and subjective ratings. Initial median frequency was 52 Hz +/- 7.5, with no difference between electrode locations; steeper slopes were found at L5 level (-0.44%/s +/- 0.25) than at L1 (-0.36%/s +/- 0.26). No right-left differences and no gender differences were found for these parameters. A correlation was observed between slope and initial median frequency, higher for men (r approximately -0.7) than for women (r approximately -0.5). Intersubject coefficient of variation for the slope was smallest for the longest (45 seconds) recording time (60-70%), but still much higher than for the initial median frequency (14%). The torque and the subjective ratings of fatigue showed no correlation with the electromyography variables. We conclude that the same reference values can be used for men and women. Owing to the large intersubject range of the slope, the clinical use of this variable may, however, be impeded.

Between-days reliability of subjective and objective assessments of back extensor muscle fatigue in subjects without lower-back pain.

BACKGROUND: It is important to evaluate the reliability of common used methods of examining muscle fatigue from the lower back since the methods are used in patient evaluation. METHODS: To establish between-days reliability, ten subjects without lower-back pain performed a Sorensen test, a prone test for back extensor muscles against gravity, on three separate days. EMG was recorded from the L1 and L5 of the back extensor muscles. Fatigue was subjectively rated using a Borg CR-10 scale. Intraclass correlation coefficient, standard error of measurement and coefficient of variation were calculated from a one-way ANOVA. Percent agreement was also calculated. RESULTS: The study revealed good reliability for the slope for the total time (ICC 0.65-0.90), the initial and end median frequency (ICC 0.75-0.89), median frequencies at Borg ratings of three (ICC 0.63-0.88), five (ICC 0.62-0.84) and seven (ICC 0.67-0. 87), endurance time (ICC 0.89). The Borg ratings of the first minute agreed better than those of the second and the third. The Borg ratings at the second and the third test agreed to 40-80%, indicating a need for a practice session. CONCLUSION: The protocol used for assessing fatigue in the back extensor muscles proved to be reliable and is recommended for further use.

Reliability of EMG spectral parameters in repeated measurements of back muscle fatigue.

The change in median frequency of the power spectrum of the electromyographic (EMG) signal may be used as a measure of muscle fatigue. The reliability of the median frequency parameters was investigated for EMG-recording sites at L1 and L5 right and left on the erector spinae. The reliability of subjective fatigue ratings of the back muscles (Borg CR-10 scale) and of maximal trunk extension torque (MVC) was also investigated. Eleven subjects with healthy backs performed a 45-s isometric trunk extension at 80% of MVC twice a day, on three different days. Two-factor analysis of variance was made to obtain the different variances from which the standard error of measurement (SEM) and the intra class correlation coefficient (ICC) were calculated. The SEM within-day was somewhat lower than that between-days. Both were about the same at all four electrode sites. The 95% confidence interval for the studied variables was for the initial median frequency +/- 10 Hz, for the slope +/- 0.4-0.5%/s, for the MVC +/- 36 Nm and for the Borg ratings +/- 1.6. We conclude that, with the presently used method, changes or differences within these limits should be regarded as normal variability. The slope may be of limited value because of its large variability. Whether the low intraclass correlation coefficient for the EMG parameters in the presently studied test group implies a low potential in discriminating subjects with back pain can not be decisively concluded.