Effects of aerobic exercise on cognitive performance and individual psychopathology in depressive and schizophrenia patients

Cognitive deficits are core symptoms in patients with schizophrenia (SZ) and major depressive disorder (MDD), but specific and approved treatments for cognitive deterioration are scarce. Experimental and clinical evidence suggests that aerobic exercise may help to reduce psychopathological symptoms and support cognitive performance, but this has not yet been systematically investigated. In the current study, we examined the effects of aerobic training on cognitive performance and symptom severity in psychiatric inpatients. To our knowledge, to date, no studies have been published that directly compare the effects of exercise across disease groups in order to acquire a better understanding of disease-specific versus general or overlapping effects of physical training intervention. Two disease groups (n = 22 MDD patients, n = 29 SZ patients) that were matched for age, gender, duration of disease and years of education received cognitive training combined either with aerobic physical exercise or with mental relaxation training. The interventions included 12 sessions (3 times a week) over a time period of 4 weeks, lasting each for 75 min (30 min of cognitive training + 45 min of cardio training/mental relaxation training). Cognitive parameters and psychopathology scores of all participants were tested in pre- and post-testing sessions and were then compared with a waiting control group. In the total group of patients, the results indicate an increase in cognitive performance in the domains visual learning, working memory and speed of processing, a decrease in state anxiety and an increase in subjective quality of life between pre- and post-testing. The effects in SZ patients compared with MDD patients were stronger for cognitive performance, whereas there were stronger effects in MDD patients compared with SZ patients in individual psychopathology values. MDD patients showed a significant reduction in depressive symptoms and state anxiety values after the intervention period. SZ patients reduced their negative symptoms severity from pre- to post-testing. In sum, the effects for the combined training were superior to the other forms of treatment. Physical exercise may help to reduce psychopathological symptoms and improve cognitive skills. The intervention routines employed in this study promise to add the current psychopathological and medical treatment options and could aid the transition to a multidisciplinary approach. However, a limitation of the current study is the short time interval for interventions (6 weeks including pre- and post-testing).     

Neurotrophic factors in women with crack cocaine dependence during early abstinence: the role of early life stress

Background

Neurotrophic factors have been investigated in the pathophysiology of alcohol and drug dependence and have been related to early life stress driving developmental programming of neuroendocrine systems.

Methods

We conducted a follow-up study that aimed to assess the plasma levels of glial cell line–derived neurotrophic factor (GDNF), brain-derived neurotrophic factor (BDNF), nerve growth factor (NGF), neurotrophin-3 (NT3) and neurotrophin-4/5 (NT4/5) in crack users during 3 weeks of early abstinence in comparison with healthy controls. We performed a comprehensive clinical assessment in female inpatients with crack cocaine dependence (separated into 2 groups: participants with (CSA+) and without (CSA−) a history of childhood sexual abuse) and a group of nonuser control participants.

Results

Our sample included 104 women with crack cocaine dependence and 22 controls; of the women who used crack cocaine, 22 had a history of childhood sexual abuse and 82 did not. The GDNF plasma levels in the CSA+ group increased dramatically during 3 weeks of detoxification. In contrast, those in the CSA− group showed lower and stable levels of GDNF under the same conditions. Compared with the control group, BDNF plasma levels remained elevated and NGF levels were reduced during early abstinence. We found no differences in NT3 and NT4/5 between the patients and controls. However, within-group analyses showed that the CSA+ group exhibited higher levels of NT4/5 than the CSA− group at the end of detoxification.

Limitations

Some of the participants were using neuroleptics, mood stabilizers or antidepressants; our sample included only women; memory bias could not be controlled; and we did not investigate the possible confounding effects of other forms of stress during childhood.

Conclusion

This study supports the association between early life stress and peripheral neurotrophic factor levels in crack cocaine users. During early abstinence, plasmastic GDNF and NT4/5 were the only factors to show changes associated with a history of childhood sexual abuse.     

The association of PTSD with physical and mental health functioning and disability (VA Cooperative Study #569: the course and consequences of posttraumatic stress disorder in Vietnam-era Veteran twins)

Purpose

To assess the relationship of posttraumatic stress disorder (PTSD) with health functioning and disability in Vietnam-era Veterans.

Methods

A cross-sectional study of functioning and disability in male Vietnam-era Veteran twins. PTSD was measured by the Composite International Diagnostic Interview; health functioning and disability were assessed using the Veterans RAND 36-Item Health Survey (VR-36) and the World Health Organization Disability Assessment Schedule 2.0 (WHODAS 2.0). All data collection took place between 2010 and 2012.

Results

Average age of the 5,574 participating Veterans (2,102 Vietnam theater and 3,472 non-theater) was 61.0 years. Veterans with PTSD had poorer health functioning across all domains of VR-36 and increased disability for all subscales of WHODAS 2.0 (all p < .001) compared with Veterans without PTSD. Veterans with PTSD were in poorer overall health on the VR-36 physical composite summary (PCS) (effect size = 0.31 in theater and 0.47 in non-theater Veterans; p < .001 for both) and mental composite summary (MCS) (effect size = 0.99 in theater and 0.78 in non-theater Veterans; p < .001 for both) and had increased disability on the WHODAS 2.0 summary score (effect size = 1.02 in theater and 0.96 in non-theater Veterans; p < .001 for both). Combat exposure, independent of PTSD status, was associated with lower PCS and MCS scores and increased disability (all p < .05, for trend). Within-pair analyses in twins discordant for PTSD produced consistent findings.

Conclusions

Vietnam-era Veterans with PTSD have diminished functioning and increased disability. The poor functional status of aging combat-exposed Veterans is of particular concern.     

HCV very late relapse following an atypical viral kinetics in a HIV patient treated for hepatitis C with direct-acting antivirals

Direct-acting antivirals (DAAs) for the treatment of HCV have dramatically increased the rate of sustained virological response: patients not achieving sustained virological response represent a challenge and rates of late recurrent viremia are very low. We describe here the first case of a very late HCV relapse, following an atypical kinetics (characterized by a spontaneous but transient HCV clearance after an early virological relapse), in a HIV co-infected patient treated with DAAs. Optimal adherence to the therapy was well documented and a phylogenetic analysis ruled out a possible reinfection from a different HCV strain. In conclusion, our case underlines the importance of a long follow-up (>?48 weeks) after DAAs therapies in HCV–HIV co-infected patients who might benefit the most from a very rigorous virological surveillance.     

Chronic liver disease: the detection and characterization of circulating immune complexes.

Circulating immune complexes containing IgG, IgM and hepatitis B surface antigen (HBsAg) in sera from groups of patients with various liver diseases were detected by both the C1q and conglutinin solid phase assays. Elevated levels of antigen non-specific immune complexes were observed in sera from all groups and complexes containing IgG were present to a greater extent than were IgM-containing complexes. Higher levels of complexes were generally obtained using the conglutinin assay than the C1q assay and the two assays were shown to preferentially bind complexes of different size ranges and antigen-antibody ratios. Only sera from HBsAg-positive patients had complexes containing HBsAg, and although serum HBsAg titres and levels of HBsAg-containing complexes were correlated, the correlation coefficient was low. The mean levels of immune complexes and the frequency of positive sera varied between different disease categories, but there was little correlation between levels of the three types of complexes detected by the two tests. Assay of immune complexes in sequential serum samples from an individual patient revealed considerable variation in the levels of the three complex types, demonstrating that the measurement of complexes in single serum samples is of limited value in assessing the potential significance of circulating immune complexes in hepatitis B.     

Decay-Accelerating Factor Suppresses Complement C3 Activation and Retards Atherosclerosis in Low-Density Lipoprotein Receptor-Deficient Mice

Decay-accelerating factor (DAF; CD55) is a membrane protein that regulates complement pathway activity at the level of C3. To test the hypothesis that DAF plays an essential role in limiting complement activation in the arterial wall and protecting from atherosclerosis, we crossed DAF gene targeted mice (daf-1^−/−) with low-density lipoprotein-receptor deficient mice (Ldlr^−/−). Daf-1^−/−Ldlr^−/− mice had more extensive en face Sudan IV staining of the thoracoabdominal aorta than Ldlr^−/− mice, both following a 12-week period of low-fat diet or a high-fat diet. Aortic root lesions in daf-1^−/−Ldlr^−/− mice on a low-fat diet showed increased size and complexity. DAF deficiency increased deposition of C3d and C5b-9, indicating the importance of DAF for downstream complement regulation in the arterial wall. The acceleration of lesion development in the absence of DAF provides confirmation of the proinflammatory and proatherosclerotic potential of complement activation in the Ldlr^−/− mouse model. Because upstream complement activation is potentially protective, this study underlines the importance of DAF in shielding the arterial wall from the atherogenic effects of complement.Complement, a complex cascade of serine proteases, is well characterized as playing a pivotal role in inflammation and in bridging innate and adaptive immunity.¹ Currently, complement is understood to be triggered by three proximal cascades, the classical, alternative, and mannose-binding lectin pathways, which converge on C3 at the central hub of the system. Cleavage of C3 leads to the generation of down-stream proinflammatory mediators, including the anaphylatoxins C3a and C5a and the membrane attack-complex C5b-9. Although the assembly and insertion of C5b-9 into cell membranes may lyse non-nucleated cells, sublytic levels can activate proliferation and/or proinflammatory gene expression.²There is increasing interest in dissecting the possible roles of complement in atherosclerosis in vivo.^3,4 Theoretically, many factors might activate complement in the arterial wall, including Igs, cholesterol crystals, enzymatically-modified low-density lipoprotein (LDL) and apoptotic cells.^{5,6,7,8,9,10,11,12} However, enzymatically-modified LDL is likely to be the most abundant stimulus for complement activation in atherosclerosis, and may act via the alternative pathway and also via direct binding of C1q and C-reactive protein.^8,9,13,14,15 In addition, the classical and alternative pathways are capable of low grade “tick-over” activity.^16,17Previous experimental work has focused on the effects of natural or experimental deficiency of individual complement pathway components. Relevant studies are as follows: (1) rabbits with natural deficiency of C6 have been shown to be protected from diet-induced atherosclerosis^18,19; (2) although C5 deficiency has been found to have no effect on lesion development in high fat diet-fed ApoE^−/− mice,²⁰ a recent study has shown protective effects of an anti-C5 antibody in ApoE^−/− mice deficient in both Cd59a and Cd59b genes²¹; (3) C3 deficient mice crossed with Ldlr^−/− single knock-out mice have been found to have increased aortic lipid deposition with impaired lesion development beyond the foam cell stage²²; (4) crossing Factor B deficient mice with ApoE^−/−Ldlr^−/− double-knock-outs had no effect, arguing against an important role for the alternative pathway in that model²³; and (5) more recently, we have reported that low fat diet-fed Ldlr^−/− mice deficient in classical pathway activity through gene-targeting of C1q (C1qa^−/−) show accelerated atherosclerosis with increased lesion complexity.²⁴ The increased lesion size and complexity in low fat diet-fed C1qa^−/−Ldlr^−/− mice was associated with an increase in lesional apoptotic cells, consistent with previous studies that have demonstrated a direct role for C1q in apoptotic cell clearance, independent of terminal pathway activation.^25,26 Recently, the role of the lectin pathway has also been shown to have atheroprotective functions in mice,²⁷ in line with the involvement of mannose-binding lectin in apoptotic cell clearance and also with the association of mannose-binding lectin deficiency with accelerated atherosclerosis in humans.^28,29Complement activity is tightly regulated by a number of fluid-phase and membrane-bound inhibitors, including the two glycosylphosphatidylinositol-anchored membrane proteins decay-accelerating factor (DAF, CD55) and protectin (CD59). Although CD59 inhibits insertion of C9 into cell membranes and thus the development of C5b-9 membrane attack complexes, DAF binds to C3, thereby accelerating the decay of the two C3 convertases, C3Bb (alternative pathway) and C4b2a (classical and mannose-binding lectin pathways).^30,31,32 Structurally, DAF is a multidomain protein comprising a proximal serine/threonine-rich region and four complement control protein (CCP) domains, of which CCP2 and CCP3 dissociate C3Bb and C4b2a oligomers into constituent proteins. The catalytic mechanism of DAF activity is not fully clear, but the crystal structure and substitution mutants identify Bb (Tyr338), DAF-CCP2 (Arg69, Arg96) and DAF-CCP3 (Phe148 Leu171) as key residues.^33,34The mouse has two DAF genes encoding glycosylphosphatidylinositol-anchored and trans-membrane forms, respectively, with the former being more representative of human DAF.³⁵ Gene-targeting of the glycosylphosphatidylinositol-anchored form has led to the generation of a knock-out strain that is healthy but shows exaggerated inflammation in models of renal, autoimmune, and nervous system diseases.^36,37,38,39 Recently, no protection or exacerbation of atherosclerosis was observed after crossing these mice with the ApoE^−/− strain.⁴⁰Observations that the classical pathway exerts atheroprotective effects without terminal pathway activation suggest the importance of a strong complement regulatory system in the arterial wall.^14,24 Consistent with this, we and others have recently published evidence that CD59 deficiency leads to an acceleration of atherosclerosis in Ldlr^−/− and ApoE^−/− mouse models, establishing the proatherogenic potential of the terminal complement pathway and highlighting the importance of CD59 in its regulation.^21,40,41 In this article, we show that DAF also plays a role in the regulation of atherosclerosis in the Ldlr^−/− model.     

TR-644 a novel potent tubulin binding agent induces impairment of endothelial cells function and inhibits angiogenesis

TR-644 is a novel combretastatin A-4 (CA-4) analogue endowed with potent microtubule depolymerizing activity superior to that of the lead compound and it also has high affinity to colchicines binding site of tubulin. We tested TR-644 anti-angiogenic effects in human umbilical endothelial cells (HUVEC). It showed no significant effects on the growth of HUVEC cells at concentrations below 1,000 nM, but at much lower concentrations (10–100 nM) it induced inhibition of capillary tube formation, inhibition of endothelial cell migration and affected endothelial cell morphology as demonstrated by the disruption of the microtubule network. TR-644 also increased permeability of HUVEC cells in a time dependent manner. The molecular mechanism for the anti-vascular activity of TR-644 was investigated in detail. TR-644 caused G2/M arrest in endothelial cells and this effect correlated with downregulation of the expression of Cdc25C and Cdc2^Tyr15. Moreover TR-644 inhibited VEGF-induced phosphorylation of VE-cadherin but did not prevent the VEGF-induced phosphorylation of FAK. In chick chorioallantoic membrane in vivo assay, TR-644 (0.1–1.0 pmol/egg) efficiently counteracted the strong angiogenic response induced by FGF. Also CA-4, used as reference compound, caused an antagonistic effect, but in contrast, it induced per se, a remarkable angiogenic response probably due to an inflammatory reaction in the site of treatment. In a mice allogenic tumor model, immunohistochemical staining of tumors with anti-CD31 antibody showed that TR-644 significantly reduced the number of vessel, after 24 h from the administration of a single dose (30 mg/Kg).