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Background: Cerebral Palsy (CP) is a group of permanent, but not unchanging, disorders of movement and/or posture and motor function, which are due to a non-progressive interference, lesion, or abnormality of the developing/immature brain. One clinical presentation is muscle spasticity, which leads to a significant impact on the individual's functionality and quality of life. Spasticity treatment is multidisciplinary and includes pharmacological and physical intervention; intrathecal baclofen shows a positive effect in severe spasticity and suboptimal response to oral drugs, while local injection of Botulinum toxin type A (BTXA) improves muscle tone, motion and pain., Objective: The aim of this study was to evaluate the efficacy of the combined intrathecal baclofen infusion (ITB) - botulinum toxin treatment in the management of spasticity in CP., Methods: 8 patients with spastic tetraparesis were enrolled. All patients were treated with intrathecal Baclofen; in lower limbs, no spastic symptoms appeared, while marked spasticity was noted in upper limbs. We injected the right and left Biceps Brachial (BB) and Flexor Digitorum Superficialis (FDS) muscles with botulinum toxin type A. All patients underwent Myometric measurement, Ashworth Scale, Numerical Rating Scale, and Visual Analogic Scale evaluation before infiltration (T0), 30 days after injection (T1), 60 days after injection (T2), and 90 days after treatment (T3)., Results: All data demonstrated an improvement in spasticity, pain, quality of life, and self-care during the study, with p < 0.05. No side effects appeared., Conclusion: This study demonstrated the efficacy and safety of intrathecal baclofen infusion and botulinum toxin combined treatment in the management of spasticity, pain, quality of life, and selfcare in CP patients., (Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.net.)

Background: Many studies in vitro compared the onset of action, maximum efficacy, and duration of botulinum toxin type A (BoNT/A) preparations., Objective: In this study, we analyzed the onset of action of BoNT/A preparation free of complexing proteins in patients with upper limb spasticity post stroke up to 30 days after treatment., Methods: 75 patients affected by Biceps Brachii spasticity were enrolled. Outcome measures were instrumental muscle tone modification (myometric measurement), improvement of Modified Ashworth Scale (MAS), improvement of elbow's passive extension, and improvement of compound muscle action potential (cMAP) evaluated by electroneurography. We analyzed data at t0 (pre-injection), t1 (1 day after), t2 (7 days after), t3 (14 days after), and t4 (30 days after)., Results: All measurements decreased at t2, t3, and t4 with initial improvement at t2 and maximum improvement at t4; no statistical difference at t1 was found., Conclusion: This study demonstrated the onset of Incobotulinumtoxin A efficacy started after 7 days; this rapid action and efficacy of BoNT/A preparation could improve an intensive rehabilitation program after some days post-injection. Early clinical onset of action could be by the absence of complexing proteins in the preparation., (Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.net.)

IntroductionOxidative stress has been documented in chronic schizophrenia and in the first episode of psychosis, but there are very little data on oxidative stress prior to the disease onset., Objective: This work aimed to compare serum levels of superoxide dismutase (SOD) and glutathione peroxidase (GPx) in young individuals at ultra-high risk (UHR) of developing psychosis with a comparison healthy control group (HC)., Methods: Thirteen UHR subjects and 29 age- and sex-matched healthy controls (HC) were enrolled in this study. Clinical assessment included the Comprehensive Assessment of At-Risk Mental States (CAARMS), the Semi-Structured Clinical Interview for DSM-IV Axis-I (SCID-I) or the Kiddie-SADS-Present and Lifetime Version (K-SADS-PL), and the Global Assessment of Functioning (GAF) scale. Activities of SOD and GPx were measured in serum by the spectrophotometric method using enzyme-linked immunosorbent assay kits., Results: After adjusting for age and years of education, there was a significant lower activity of SOD and lower GPX activity in the UHR group compared to the healthy control group (rate ratio [RR]=0.330, 95% CI 0.187; 0.584, p&lt;0.001 and RR=0.509, 95% CI 0.323; 0.803, p=0.004, respectively). There were also positive correlations between GAF functioning scores and GPx and SOD activities., Conclusion: Our results suggest that oxidative imbalances could be present prior to the onset of full-blown psychosis, including in at-risk stages. Future studies should replicate and expand these results.

Objectives: The study aims to generate an immunological age (IA) trait on the basis of immune cell differentiation parameters, and to test whether the IA is related to age and disease characteristics., Methods: Forty-four euthymic type I bipolar disorder patients were included in this study. Five immunosenescence-related parameters were assessed: proportions of late-differentiated cells (e.g., CD3+CD8+CD28-CD27- and CD3-CD19+IgD-CD27-), and the expression of CD69, CD71, and CD152 after stimulation. Confirmatory factor analysis was applied to generate an IA trait underling the 5 measures., Results: The best-fit model was constituted by 4 parameters that were each related to an underlying IA trait, with 1 cell population positively correlated (CD3+CD8+CD28-CD27- [λ = 0.544, where λ represents the loading of the parameter onto the IA trait] and 3 markers negatively correlated (CD69 [λ = -0.488], CD71 [λ = -0.833], and CD152 [λ = -0.674]). The IA trait was associated with chronological age (β = 0.360, p = .013) and the number of previous mood episodes (β = 0.426, p = .006). In a mediation model, 84% of the effect between manic episodes, and IA was mediated by body mass index., Conclusion: In bipolar disorder type I, premature aging of the immune system could be reliably measured using an index that validated against chronological age, which was related to adverse metabolic effects of the disease course., (Copyright © 2018 John Wiley & Sons, Ltd.)

Preliminary evidence suggests that premature immunosenescence is involved in bipolar disorder (BD) pathophysiology. The cellular marker CD69 is expressed in T lymphocyte surface during their activation and its expression is negatively correlated with age. The objective of this study was to assess the moderating effects of obesity on the reduction of expression of CD69, a marker of immunosenescence. Forty euthymic patients with BD type I, aged 18-65 years, were included in this study. The healthy comparison group consisted of 39 volunteers who had no current or lifetime history of mental disorders, no use of psychotropic medications, and no known family history of mood disorders or psychosis. Peripheral blood mononuclear cells from BD patients and healthy controls were collected and isolated. The cells were allowed to grow in culture and stimulated for 3 days. CD69 was marked and read in flow cytometry. We found that the lower expression of CD69 in BD patients was moderated by body mass index (BMI) in both CD4+ (RR = 0.977, 95% CI 0.960-0.995, p = 0.013) and CD8+ cells (RR = 0.972, 95% CI 0.954-0.990, p = 0.003). Our findings indicate that BMI could potentially influence the process of premature aging in BD.

Recent research has demonstrated that telomere maintenance might be a key integrating point for the cumulative effect of genetic and environmental factors in patients with first-episode psychosis (FEP) and schizophrenia (SCZ). Eighty-one participants with antipsychotic-naïve FEP, 173 with SCZ and 438 HC were enrolled in this study. Psychiatric diagnosis was assessed using the Semi-Structured Clinical Interview for DSM-IV Axis-I (SCID-I). The Positive and Negative Syndrome Scale (PANSS), Young Mania Rating Scale (YMRS) and Calgary Depression Scale for Schizophrenia (CDSS) were used to measure symptoms severity. Telomere length (TL) was determined using a multiplex qPCR assay. After adjustment for age, years of education, and smoking status, we found that patients with SCZ had longer TL (relative ratio (RR) = 1.08) than the HC group (RR = 1.00, Wald χ 2  = 12.48, p = 0.002). Further, non-remitted SCZ patients presented longer TL (RR = 1.00) compared to remitted SCZ (RR = 0.88, Wald χ 2  = 7.20, p = 0.007). TL in patients also correlated to psychopathology assessment in terms of total (p = 0.003) and positive PANSS scores (p = 0.001). No correlation with negative PANSS, YMRS, and CDSS or effects of medication was found on TL. Although the exact pathways underlying longer TL in SCZ patients remain unclear, these findings raise more questions than answers and suggest that TL may be of immense value on SCZ progression. Further studies are required to investigate the association of TL in FEP and SCZ., (Copyright © 2017 Elsevier Ltd. All rights reserved.)

The present study aimed at investigating possible alterations in the serum lipid profile of euthymic patients with bipolar disorder type I (BD) compared to healthy controls (HC). Thirty-five individuals from both genders were recruited, with 14 diagnosed and treated as BD patients (BD group) and 21 healthy subjects (HC group). Clinical assessment was based on the Structured Clinical Interview for DSM-IV Axis I Disorders (SCID-I), Young Mania Rating Scale (YMRS), and 17-items of Hamilton Depression Rating Scale (HDRS-17) data, which were used to confirm diagnosis, to verify psychiatric comorbidities, and to estimate the severity of manic and depressive symptoms. Ultra-high performance liquid chromatography (UHPLC) coupled to high resolution mass spectrometry (HRMS) was applied to analyze the lipids extracted from all serum samples from both studied groups. In this pioneer and exploratory study, we observed different serum lipid profiles for BD and HC groups, especially regarding glycerophospholipid, glycerolipid, and sphingolipid distribution. Multivariate statistical analyses indicated that 121 lipids were significantly different between BD and HC. Phosphatidylinositols were identified as the most altered lipids in BD patient sera. The results of this preliminary study reinforce the role of lipid abnormalities in BD and offer additional methodological possibilities for investigation in the field., (Copyright © 2017 Elsevier B.V. All rights reserved.)

Background: The objective of this study was to identify molecular alterations in the human blood serum related to bipolar disorder, using nuclear magnetic resonance (NMR) spectroscopy and chemometrics., Methods: Metabolomic profiling, employing 1 H-NMR, 1 H-NMR T 2 -edited, and 2D-NMR spectroscopy and chemometrics of human blood serum samples from patients with bipolar disorder (n = 26) compared with healthy volunteers (n = 50) was performed., Results: The investigated groups presented distinct metabolic profiles, in which the main differential metabolites found in the serum sample of bipolar disorder patients compared with those from controls were lipids, lipid metabolism-related molecules (choline, myo-inositol), and some amino acids (N-acetyl-L-phenyl alanine, N-acetyl-L-aspartyl-L-glutamic acid, L-glutamine). In addition, amygdalin, α-ketoglutaric acid, and lipoamide, among other compounds, were also present or were significantly altered in the serum of bipolar disorder patients. The data presented herein suggest that some of these metabolites differentially distributed between the groups studied may be directly related to the bipolar disorder pathophysiology., Conclusions: The strategy employed here showed significant potential for exploring pathophysiological features and molecular pathways involved in bipolar disorder. Thus, our findings may contribute to pave the way for future studies aiming at identifying important potential biomarkers for bipolar disorder diagnosis or progression follow-up.

Aim: This study aimed to compare plasma copeptin levels, the c-terminal of provasopressin, between individuals with bipolar disorder (BD) and healthy controls and to assess the relation between copeptin and metabolic parameters., Methods: We measured plasma levels of copeptin in individuals with BD (n = 55) and healthy controls (n = 21). Information related to psychiatric/medical history, as well as to metabolic comorbidities and laboratorial parameters was also captured. Insulin resistance and β-cell function in basal state were calculated from fasting plasma glucose and C-peptide using the HOMA2 calculator. Impaired glucose metabolism was defined as pre-diabetes or type 2 diabetes mellitus. Copeptin, adiponectin, and leptin plasma levels were determined by enzyme-linked immunosorbent assay., Results: Plasma copeptin levels were lower in individuals with BD, relative to healthy controls (P < 0.001). There were significant interactions between BD and plasma copeptin on β-cell function (rate ratio [RR] = 1.048; P = 0.030) and on leptin levels (RR = 1.087; P = 0.012), indicating that there was a positive correlation between these markers in the BD group, but a negative one in healthy controls. Finally, in individuals with BD only, the association between β-cell function, body mass index (RR = 1.007; P < 0.001), and insulin resistance (RR = 1.001; P = 0.037) was moderated by copeptin levels., Conclusion: Copeptin levels were lower in individuals with BD than in healthy controls. There were differential associations between copeptin and metabolic parameters within the BD and healthy control subgroups, suggesting an association between abnormal copeptin and metabolic dysregulation only in the BD population., (© 2017 The Authors. Psychiatry and Clinical Neurosciences © 2017 Japanese Society of Psychiatry and Neurology.)

Using 1 H NMR-based metabolomics in association to chemometrics analysis, we analyzed here the metabolic differences between schizophrenia patients (SCZ) compared to healthy controls (HCs). HCs and SCZ patients underwent clinical interview using the Structured Clinical Interview for DSM Disorders (SCID). SCZ patients were further assessed by Positive and Negative Syndrome Scale (PANSS), Calgary Depression Scale, Global Assessment of Functioning Scale (GAF), and Clinical Global Impressions Scale (CGI). Using the principal component analysis (PCA) and supervised partial least-squares discriminate analysis (PLS-DA) in obtained NMR data, a clear group separation between HCs and SCZ patients was achieved. Interestingly, all metabolite compounds identified as exclusively present in the SCZ group, except for the gamma-aminobutyric acid (GABA), were never previously associated with mental disorders. Although the initial perception of an absence of obvious biological link among the different key molecules exclusively observed in each group, and no identification of any specific pathway yet, the present work represents an important contribution for the identification of potential biomarkers to inform diagnosis, as it was possible to completely separate the affected SCZ patients from HCs, with no outliers or exceptions. In addition, the data presented here reinforced the role of the modulation of glycolysis pathway and the loss of GABA interneuron/hyperglutamate hypothesis in SCZ., (Copyright © 2016 Elsevier B.V. All rights reserved.)

Telomere length attrition has been demonstrated in schizophrenia but not in individuals in ultra high risk (UHR) for psychosis. The present study aimed to compare the leukocyte telomere length (TL) between patients at UHR for psychosis and healthy controls (HC). Twenty-two participants with UHR and 88 HC were enrolled in this study. Telomere lengths were determined using a multiplex qPCR assay. After adjustment for age, sex, ethnicity, and education, patients in UHR, compared with HC groups, had shorter telomere length (RR: 0.929, p=0.031). Shorter leukocyte telomere length in UHR could represent early signs of accelerated aging in this population., (Copyright © 2017 Elsevier B.V. and ECNP. All rights reserved.)

According to the "selfish brain" theory, the brain regulates its own energy supply influencing the peripheral metabolism and food intake according to its needs. The immune system has been likewise "selfish" due to independent energy consumption; and it may compete with the brain (another high energy-consumer) for glucose. In mood disorders, stress in mood episodes or physiological stress activate homeostasis mechanisms from the brain and the immune system to solve the imbalance. The interaction between the selfish brain and the selfish immune system may explain various conditions of medical impairment in mood disorders, such as Metabolic Syndrome (MetS), obesity, type 2 diabetes mellitus (T2DM) and immune dysregulation. The objective of this study is to comprehensively review the literature regarding the competition between the brain and the immune system for energy substrate. Targeting the energetic regulation of the brain and the immune system and their cross-talk open alternative treatments and a different approach in the study of general medical comorbidities in mood disorders, although more investigation is needed., (Copyright © 2016 Elsevier Ltd. All rights reserved.)

Background: Early life stress (ELS) and addiction are related to age-related diseases and telomere shortening. However, the role of telomere length (TL) in crack cocaine addiction remains unknown. The purpose of this study was to investigate the TL in a sample of crack cocaine dependent-women who reported an ELS history and in a community-based sample of elderly women as a reference group for senescence., Methods: This study included treatment seeking crack cocaine dependents women (n=127) and elderly women without a psychiatric diagnosis (ELD, n=49). The crack cocaine sample was divided in two groups according to their Childhood Trauma Questionnaire (CTQ) scores: presence of history of childhood abuse and neglect (CRACK-ELS) and absence of ELS history (CRACK). TL was assessed by T/S ratio obtained from peripheral blood DNA using quantitative PCR assay., Results: CRACK and CRACK-ELS subjects exhibited shortened TL in comparison to the ELD group, despite their younger age. Among crack cocaine sample, CRACK-ELS group had significantly shorter telomeres than the CRACK group. Correlation analysis within crack cocaine group indicated that TL was negatively correlated with emotional abuse scores., Conclusions: These results support previous findings associating telomere shortening with both ELS and drug addiction. This study suggests new evidence of a distinct biological phenotype for drug-dependent women with ELS. The results support the biological senescence hypothesis underpinning ELS experience., (Copyright © 2016 Elsevier Inc. All rights reserved.)

Aging is associated with an increase in the prevalence of obstructive sleep apnea syndrome (OSAS) as well as the shortening of telomeres. It is known that OSAS-related factors are stimuli that can contribute to the acceleration of cellular senescence. Thus, the present study aimed to compare the leukocyte telomere length (LTL) between OSAS patients and controls, as well as to verify the correlation between LTL and sleep parameters. We used DNA extracted of 928 individuals from EPISONO to measure the LTL by the quantitative real-time polymerase chain reaction. All individuals were subjected to one full-night polysomnography. LTL was significantly shorter in OSAS patients compared to controls. The results showed negative correlations between LTL and the following variables: apnea-hypopnea index, respiratory disturbance index, desaturation index and wake after sleep onset. LTL was positively correlated with sleep efficiency, total sleep time, basal, minimum and maximum oxygen saturation. Lastly, it was observed that OSAS severity was associated with shorter LTL even after adjusting for sex, age, years of schooling, body mass index, diabetes, stroke and heart attack. In conclusion, our study indicates the presence of an association between LTL and OSAS and a significant impact of severity of OSAS in telomeres shortening.

Background: Immuno-inflammatory imbalances have been documented in schizophrenia, but very little is known about the immunological changes prior to the onset of disease., Objective: This work aimed to compare serum levels of pro- and anti-inflammatory cytokines in young subjects at ultra-high risk (UHR) of developing psychosis with age- and sex-matched healthy controls., Methods: A total of 12 UHR and 16 age- and sex-matched healthy controls (HC) subjects were enrolled in this study. Clinical profile was assessed using the Comprehensive Assessment of At-Risk Mental States (CAARMS), Semi-Structured Clinical Interview for DSM-IV Axis-I (SCID-I) or Kiddie-SADS-Present and Lifetime Version (K-SADS-PL), and Global Assessment of Functioning (GAF) scale. Serum interleukin (IL)-2, IL-4, IL-6, IL-10, tumor necrosis factor (TNF)-α, IFN-γ, and IL-17 were measured by flow cytometry using the Th1/Th2/Th17 cytometric bead array., Results: Compared with the healthy control group, patients in UHR showed increased IL-6 levels (Z=-2.370, p=0.018) and decreased IL-17 levels in serum (Z=-1.959, p=0.050). Levels of IL-17 positively correlated to the values in GAF symptoms (rho=0.632, p=0.028)., Conclusion: Our results suggest that immunological imbalances could be present in the early stages of psychosis, including in at-risk stages. Future studies should replicate and expand these results., (Copyright © 2016 Elsevier B.V. All rights reserved.)

Aim: Childhood maltreatment (CM) has been related to a persistent reprograming of stress-response. Copeptin is a marker of hypothalamic-pituitary-adrenal axis activation; however, few studies have examined copeptin levels in children exposed to CM. The aim of this study was to compare serum copeptin levels in children reporting child abuse and/or neglect and children with no history of CM., Methods: This study included 65 children with a positive history of moderate to severe CM, as reported by themselves and their parent(s) during a clinical interview, and 71 children with no history of CM as a comparison group. CM was considered moderate to severe based on the child-reported frequency of being exposed to events related to sexual abuse, physical abuse, emotional abuse, emotional neglect, and/or physical neglect. Child psychopathology symptoms were assessed using the Child Behavior Checklist (CBCL). We measured serum copeptin concentration using enzyme-linked immunosorbent assay., Results: Children exposed to CM exhibited higher levels of serum copeptin compared to children without CM when controlling for sex, age, and psychiatric morbidity. The CBCL total score, including internalizing and externalizing symptoms, was higher in children with CM. We found no correlation between copeptin and CBCL scores for internalizing symptoms and externalizing symptoms., Conclusion: CM is associated with copeptin serum levels independently of age, sex, and symptom severity. Copeptin is a promising new biomarker for children with a history of abuse and/or neglect., (© 2016 The Authors. Psychiatry and Clinical Neurosciences © 2016 Japanese Society of Psychiatry and Neurology.)

This study aimed to examine the role of oxidative stress in bipolar disorder (BD) by evaluating the relationship among antioxidant enzymes activities, impaired glucose metabolism (IGM) and illness course. We measured the activities of plasma superoxide dismutase (SOD) and glutathione peroxidase (GPx) in individuals with BD (N = 55) and healthy controls (N = 28). Information related to current and past psychiatric/medical history, as well as prescription of any pharmacological treatments was captured. Impaired glucose metabolism was operationalized as pre-diabetes or type 2 diabetes mellitus. Our results showed that, after adjustment for age, gender, alcohol use, smoking and current medication, both BD (p < 0.001) and IGM (p = 0.019) were associated with increased GPx activity, whereas only BD was associated with decreased SOD activity (p = 0.008). We also observed an interaction between BD and IGM on SOD activity (p = 0.017), whereas the difference between BD and controls was only significant in individuals with IGM (p = 0.009). IGM, GPx and SOD activity were independently associated with variables of illness course. Moreover, IGM moderated the association between SOD activity and number of mood episodes (p < 0.001), as a positive correlation between SOD activity and mood episodes was observed only in participants with IGM. In conclusion, BD and IGM are associated with independent and synergistic effects on markers of oxidative stress. The foregoing observations suggest that the heterogeneity observed in previous studies evaluating antioxidant enzymes in BD may be a function of concurrent IGM; and that imbalances in the oxidative system may subserve the association between BD and IGM, as well as its relationship with illness course., (Copyright © 2016 Elsevier Ltd. All rights reserved.)

There is consistent evidence that inflammation is involved in mental disorders pathogenesis. Herein, using data from the High Risk Cohort Study for Psychiatric Disorders, we investigated the relationship between parental mood disorders (PMD), environmental factors, serum interleukin-6 (IL6) and mental health problems in children aged 6-12. We measured the serum levels of IL6 in 567 children. Information related to socio-demographic characteristics, mental health problems and multiple risk factors, as well as parent's psychiatric diagnosis, was captured. We evaluated two groups of environmental risk factors (i.e. perinatal complications and social disadvantage) using a cumulative risk model. Results showed that higher serum levels of IL6 were associated with PMD (RR=1.072, p=0.001), perinatal complications (RR=1.022, p=0.013) and social disadvantage (RR=1.024, p=0.021). There was an interaction between PMD and social disadvantage (RR=1.141, p=0.021), as the effect of PMD on IL6 was significantly higher in children exposed to higher levels of social disadvantage. Moreover, there was a positive correlation between IL6 and mental health problems (RR=1.099, p=0.026), which was moderated by exposure to perinatal complications or social disadvantage (RR=1.273, p=0.015 and RR=1.179, p=0.048, respectively). In conclusions, there is evidence of a differential inflammatory activation in children with PMD and exposure to environmental risk factors, when compared to matched peers. Systemic inflammation may be involved in the pathway linking familial risk and mental health problems., (Copyright © 2016 Elsevier Ltd. All rights reserved.)

Objectives: Accumulating evidence indicates that oxidative stress and neurotrophins have a bidirectional relationship. In this post hoc, exploratory analysis, we investigated the association between plasma brain-derived neurotrophic factor (BDNF) levels and activities of the antioxidant enzymes glutathione peroxidase (GPx) and superoxide dismutase (SOD) in individuals with bipolar disorder (BD) and healthy controls., Methods: We measured plasma levels of BDNF and activities of GPx and SOD in individuals with BD (n=59) and healthy controls (n=26). Information related to current and past psychiatric/medical history, as well as to metabolic comorbidities, was also reported., Results: There were negative correlations between BDNF, GPx (r=-.449, P≤.001) and GPx/SOD ratio (r=-.503, P<.001), and a positive correlation between BDNF and SOD (r=.254, P=.020). There was a moderating effect of body mass index (BMI) on the association between BDNF and GPx/SOD rate ratio [(RR)=1.002, P=.034]; interactions between impaired glucose metabolism (IGM), GPx (RR=1.016, P=.033), and GPx/SOD ratio (RR=1.026, P=.002) were also observed. These results were significant in models that included age, gender, alcohol, tobacco and medication use., Conclusions: There was a robust and independent correlation between peripheral BDNF and antioxidant enzyme activities in individuals with BD, which was moderated by metabolic comorbidities. These results reinforce the concept that these systems are associated and further extend knowledge of the putative effect of metabolic comorbidities in the pathophysiological substrates of BD., (© 2016 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Objectives: The neurotrophin brain-derived neurotrophic factor (BDNF) has been proposed as a potential biomarker in bipolar disorder (BD). However, current evidence is limited and results have been highly heterogeneous. This study aimed to assess the moderating effect of impaired glucose metabolism (IGM) on plasma levels of BDNF in individuals with BD, and on the relationship between BDNF and variables of illness course., Methods: We measured and compared the plasma levels of BDNF in individuals with BD (n=57) and healthy controls (n=26). IGM was operationalized as pre-diabetes or type 2 diabetes mellitus. Information related to current and past psychiatric/medical history, as well as prescription of pharmacological treatments was also captured., Results: Individuals with BD had lower levels of BDNF, relative to healthy controls, after adjustment for age, gender, current medications, smoking, alcohol use, and IGM (P=.046). There was no effect of IGM (P=.860) and no interaction between BD diagnosis and IGM (P=.893). Peripheral BDNF levels were positively correlated with lifetime depressive episodes (P<.001), psychiatric hospitalizations (P=.001) and suicide attempts (P=.021). IGM moderated the association between BDNF and the number of previous mood episodes (P<.001), wherein there was a positive correlation in euglycemic participants and a negative correlation in individuals with IGM., Conclusions: BD is independently associated with lower levels of BDNF; IGM may modify the relationship between BDNF and BD course, suggesting an interactive effect of BDNF with metabolic status on illness progression., (© 2016 John Wiley & Sons A/S Published by John Wiley & Sons Ltd.)

Background: The longitudinal course of bipolar disorder (BD) is highly heterogeneous, and is moderated by the presence of general medical comorbidities. This study aimed to investigate the moderating effects of impaired glucose metabolism (IGM) on variables of illness course and severity in a BD population., Methods: Fifty-five patients with BD were evaluated. All subjects were evaluated with respect to current and past psychiatric and medical disorders, as well as lifetime use of any medication. Body mass index (BMI) and metabolic parameters were obtained. IGM was operationalized as pre-diabetes or type 2 diabetes mellitus., Results: Thirty (54.5%) individuals had IGM. After adjustment for age, gender, ethnicity, alcohol use, smoking, BMI and past and current exposure to psychotropic medications, individuals with IGM, when compared to euglycemic participants, had an earlier age of onset (RR: 0.835, p=0.024), longer illness duration (RR: 1.754, p=0.007), a higher number of previous manic/hypomanic episodes (RR: 1.483, p=0.002) and a higher ratio of manic/hypomanic to depressive episodes (RR: 1.753, p=0.028). Moreover, we observed a moderating effect of IGM on the association between number of mood episodes and other variables of illness course, with the correlation between lifetime mood episodes and frequency of episodes being significantly greater in the IGM subgroup (RR: 1.027, p=0.029). All associations observed herein remained significant after adjusting for relevant confounding factors (e.g. age, alcohol and tobacco use, exposure to psychotropic agents, BMI)., Limitations: Cross-sectional design, small sample size., Conclusions: Comorbid IGM may be a key moderator of illness progression in BD., (Copyright © 2016 Elsevier B.V. All rights reserved.)

Objectives: To compare hair cortisol concentrations (HCC) in drug-naïve first-episode psychosis (FEP) patients and healthy controls and to investigate the correlations between HCC and psychopathology., Methods: Twenty-four drug-naïve FEP patients and 27 gender- and age-matched healthy control subjects were recruited. The Structured Clinical Interview for DSM-IV (SCID-1) was used to confirm/rule out diagnoses, and the Positive and Negative Symptoms Scale (PANSS) was used to assess symptom severity. Hair samples (2-3 cm long) obtained from the posterior vertex region of the scalp were processed in 1-cm segments considering a hair growth rate of 1 cm per month. The 1-cm segments were classified according to their proximity to the scalp: segment A was the closest to the scalp and referred to the month prior to inclusion in the study. Segments B and C referred to the 2nd and 3rd months prior to the time of evaluation respectively. Hair steroid extraction was performed using a known protocol., Results: Two-way analysis of covariance (ANCOVA) with gender and age as covariates revealed a group effect (F1.106 = 4.899, p = 0.029) on HCC. Between-segment differences correlated with total PANSS score and with PANSS General Psychopathology subscale and total score., Conclusions: Our findings suggest that hypothalamic-pituitary-adrenal (HPA) axis, as assessed by long-term (3-month) cortisol concentration, is abnormal in the early stages of psychosis. The magnitude of changes in HCC over time prior to the FEP correlates to psychopathology. HPA axis abnormalities might begin prior to full-blown clinical presentation requiring hospital admission.

Replicated evidence indicates that individuals with BD are differentially affected by metabolic comorbidities and that its occurrence is a critical mediator and/or moderator of BD outcomes. This study aimed to explore the role of adipokines on bipolar disorder (BD) course and its relationship with metabolic comorbidities (i.e. type 2 diabetes mellitus, obesity). We measured plasma levels of adiponectin and leptin, as well as anthropometric and metabolic parameters of 59 patients with BD and 28 healthy volunteers. Our results showed that, in female participants, adiponectin was lower in individuals with BD, relative to healthy controls (p = 0.017). In the BD population, adiponectin levels were correlated with fasting glucose (r = -0.291, p = 0.047), fasting insulin (r = -0.332, p = 0.023), C-peptide (r = 0.040, p = 0.040), homeostatic model assessment-insulin resistance (r = -0.411, p = 0.004), HDL (r = 0.508, p < 0.001), VLDL (r = -0.395, p = 0.005) and triglycerides (r = -0.310, p = 0.030). After adjustment for age, gender and BMI, individuals with BD and low adiponectin levels (i.e. < 7.5 μg/ml), had a higher number of mood episodes (p < 0.001), lower number of psychiatric hospitalizations (p = 0.007), higher depressive symptoms (p < 0.001) and lower levels of functioning (p = 0.020). In conclusion, adiponectin levels, either directly or as a proxy of metabolic dysfunction, is independently associated with an unfavorable course of illness in BD., (Copyright © 2015 Elsevier Ltd. All rights reserved.)

Major depressive disorder (MDD) affects millions of individuals and is highly comorbid with many age associated diseases such as diabetes mellitus, immune-inflammatory dysregulation and cardiovascular diseases. Oxidative/nitrosative stress plays a fundamental role in aging, as well as in the pathogenesis of neurodegenerative/neuropsychiatric disorders including MDD. In this review, we critically review the evidence for an involvement of oxidative/nitrosative stress in acceleration of aging process in MDD. There are evidence of the association between MDD and changes in molecular mechanisms involved in aging. There is a significant association between telomere length, enzymatic antioxidant activities (SOD, CAT, GPx), glutathione (GSH), lipid peroxidation (MDA), nuclear factor κB, inflammatory cytokines with MDD. Major depression also is characterized by significantly lower concentration of antioxidants (zinc, coenzyme Q10, PON1). Since, aging and MDD share a common biological base in their pathophysiology, the potential therapeutic use of antioxidants and anti-aging molecules in MDD could be promising.

Objective: To investigate the association between peripheral biomarkers and child psychopathology in a large community sample., Method: A total of 625 aged 6- to 13-year old subjects were recruited from a community school-based study. Psychopathology was assessed using the Child Behaviour Checklist (CBCL). Psychiatric diagnosis was evaluated using the Development and Well-Being Assessment. The following biomarkers were examined in peripheral blood: brain-derived neurotrophic factor, cytokines (IL-2, IL-4, IL-6, IL-10, IL-17, IFN-g, and TNF-α), chemokines (eotaxin/CCL11, IP-10, MCP-1), cytokine receptors (sTNFR1 and sTNFR2), and the oxidative stress marker TBARS., Results: We found significant associations between sTNFR2, eotaxin/CCL11 and CBCL total score, as well as with specific dimensions of psychopathology. There were different patterns of association between these biomarkers and psychological and behavioural symptoms in children with and without a mental disorder. TBARS, IL-6 and MCP-1 were more specific to some clusters of symptoms in children with a psychiatric diagnosis., Conclusion: Our data support the potential use of biomarkers, especially those involved in immune-inflammatory pathways, in investigating neurodevelopmental psychopathology. Their association with different dimensions of symptoms might be of useful when analyzing illness severity and clusters of symptoms within specific disorders., (© 2015 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Previous studies of our group showed increased plasmatic Angiotensin-I Converting Enzyme (ACE) activity in schizophrenia (SCZ) patients compared to healthy controls, which was also associated to poor cognitive functioning. The ACE main product angiotensin II (Ang-II) has pro-inflammatory properties. Activated immune-inflammatory responses in SCZ and their association with disease progression and cognitive impairments are also well-described. Therefore, we examined here the association of plasma ACE activity and inflammatory mediators in 33 SCZ patients and 92 healthy controls. Non-parametric correlations were used to investigate the association of the enzyme activity and the peripheral levels of immune inflammatory markers as interleukins, tumor necrosis factor (TNF-α), and interferon (IFN-γ). Although no significant correlations could be observed for ACE activity and measured cytokines levels in healthy controls, a significant positive correlation for ACE enzymatic activity and IL-17a levels was observed in SCZ patients. Correcting for gender did not change these results. Moreover, a significant association for ACE activity and IFN-γ levels was also observed. To our knowledge, this is the first study to show a significant association between higher ACE activity and the levels of cytokines, namely IL-17a and IFN-γ, in patients with SCZ., (Copyright © 2015 Elsevier Ireland Ltd. All rights reserved.)

Objective: To characterize the early stages of bipolar disorder (BD), defined as the clinical prodrome/subsyndromal stage and first-episode phase, and strategies for their respective treatment., Methods: A selective literature search of the PubMed, Embase, PsycINFO, and ISI databases from inception until March 2014 was performed. Included in this review were articles that a) characterized prodromal and first-episode stages of BD or b) detailed efficacy and safety/tolerability of interventions in patients considered prodromal for BD or those with only one episode of mania/hypomania., Results: As research has only recently focused on characterization of the early phase of BD, there is little evidence for the effectiveness of any treatment option in the early phase of BD. Case management; individual, group, and family therapy; supportive therapy; and group psychoeducation programs have been proposed. Most evidence-based treatment guidelines for BD do not address treatment specifically in the context of the early stages of illness. Evidence for pharmacotherapy is usually presented in relation to illness polarity (i.e., manic/mixed or depressed) or treatment phase., Conclusions: Although early recognition and treatment are critical to preventing unfavorable outcomes, there is currently little evidence for interventions in these stages of BD.

Schizophrenia is accompanied by alterations in immuno-inflammatory pathways, including abnormalities in cytokine profile. The immune assessment of patients in a first episode of psychosis (FEP) and particularly in drug naïve patients is very important to further elucidate this association. The objectives of this study are to delineate the cytokine profile (IL-2, IL-10, IL-4, IL-6, IFNγ, TNFα and IL-17) in FEP patients (n=55) versus healthy controls (n=57) and to examine whether the presence of depressive symptoms in FEP is accompanied by a specific cytokine profile. We found increased levels of IL-6, IL-10 and TNFα in FEP patients when compared to healthy controls. FEP patients with depression showed higher IL-4 and TNFα levels versus those without depression. Cytokine levels were not correlated to the total PANSS and the positive or negative subscale scores. Our results suggest that FEP is accompanied by a cytokine profile indicative of monocytic and T regulatory cell (Treg) activation. Depression in FEP is accompanied by monocytic and Th-2 activation, whereas FEP without depression is characterized by Treg activation only. In conclusion, depression emerged as a key component explaining the cytokines imbalance in FEP that is responsible for a large part of the immune-inflammatory abnormalities described., (Copyright © 2015 Elsevier B.V. All rights reserved.)

Background: There is robust evidence that schizophrenia is characterized by immune-inflammatory abnormalities, including variations on cytokine levels. The results of previous studies, however, are heterogeneous due to several confounding factors, such as the effects of antipsychotic drugs. Therefore, research on drug-naïve first-episode psychosis (FEP) patients is essential to elucidate the role of immune processes in that disorder., Methods: The aim of this study is to compare cytokine levels (IL-2, IL-10, IL-4, IL-6, IFN-γ, TNF-α, and IL-17) in drug-naïve FEP patients both before and after treatment with risperidone for 10 weeks, and to investigate possible associations between cytokine levels and clinical responses to treatment and presence of depressive symptoms. It this study, we included 55 drug-naïve FEP patients who had repeated measurements of cytokine levels and 57 healthy controls., Results: We found that FEP patients had significantly higher IL-6, IL-10 and TNF-α levels than healthy controls. After risperidone treatment, these three cytokines and additionally IL-4 decreased significantly. No significant difference was found between the post-treatment cytokine levels in FEP patients and in healthy controls, suggesting that these alterations in cytokine profiles are a state marker of FEP. No significant association was found between risperidone-induced changes in cytokines and the clinical response to treatment or the presence of depression. There was a significant inverse association between the risperidone-induced changes in IL-10 and the negative symptoms., Conclusions: In conclusion, our results show a specific cytokine profile in FEP patients (monocytic and regulatory T-cell activation) and suggest immunoregulatory effects of risperidone treatment, characterized by suppressant effects on monocytic, Th2, and T-regulatory functions., (© The Author 2015. Published by Oxford University Press on behalf of CINP.)

Mounting evidence suggests a chronic pro-inflammatory state in individuals with bipolar disorder (BD). Stress exposure is known to exacerbate several inflammatory conditions as well as psychiatric disorders. Here, we analyzed plasma levels of pro-inflammatory cytokines and their soluble receptors to realistic acute psychosocial stress challenge in BD. Thirteen euthymic type 1 BD patients and 15 matched controls underwent the Trier Social Stress Test protocol (TSST). Blood samples were collected before and after TSST and plasma cytokines interleukin IL-2, IL-6, IL-33, and tumor necrosis factor alpha (TNF-α) were measured. In addition TNF-α soluble receptors TNFR1 and TNFR2, and IL-33 soluble receptor sST2 were assessed. Increased IL-33 and reduced sST2 levels were observed in BD subjects as compared to controls, independently of stress exposure. Following TSST, there were higher levels of IL-2 and reduced levels of sTNFR1 in both groups. However, the magnitude change for both cytokines was found higher in controls than BD subjects. Our data suggest that BD patients have differential stress reactivity as compared to controls, possibly related to an immunologic imbalance and failure of regulatory mechanisms., (Copyright © 2014 Elsevier Ireland Ltd. All rights reserved.)

Bipolar Disorder (BD) has been conceptualized as both a cyclic and a progressive disorder. Mechanisms involved in neuroprogression in BD remain largely unknown although several non-mutually exclusive models have been proposed as explanatory frameworks. In the present paper, we propose that the pathophysiological changes observed in BD (e.g. brain structural alterations, cognitive deficits, oxidative stress imbalance, amyloid metabolism, immunological deregulation, immunosenescence, neurotrophic deficiencies and telomere shortening) converge on a model of accelerated aging (AA). Aging can be understood as a multidimensional process involving physical, neuropsychological, and social changes, which can be highly variable between individuals. Determinants of successful aging (e.g environmental and genetic factors), may also confer differential vulnerability to components of BD pathophysiology and contribute to the clinical presentation of BD. Herein we discuss how the understanding of aging and senescence can contribute to the search for new and promising molecular targets to explain and ameliorate neuroprogression in BD. We also present the strengths and limitations of this concept., (Copyright © 2014 Elsevier Ltd. All rights reserved.)

Although several studies have pointed to a possible role of interleukin 2 (IL-2) in schizophrenia (SZ), association between IL-2 and the different groups of symptoms has not been explored. The objective of this study was to investigate a possible correlation of peripheral IL-2 levels with symptoms and cognitive performance in patients with SZ. In addition, we compared the plasma levels of IL-2 between patients with SZ and healthy controls. Twenty-nine chronically medicated outpatients with SZ according to DSM-IV were compared with twenty-six healthy controls. The patients were evaluated with the Positive and Negative Syndrome Scale (PANSS), the Calgary Depression Scale for Schizophrenia (CDSS), the Clinical Global Impression (CGI) and the Global Assessment of Functioning (GAF). All the participants had blood collected into EDTA tubes by venipuncture between 9:00 and 10:00AM. Plasma concentrations of IL-2 were determined by cytometric bead array. A computerized neuropsychological battery assessed verbal learning, verbal fluency, working memory, set shifting, executive function, inhibition and intelligence. Patients with SZ had lower levels of IL-2 than healthy controls (p<0.001). In the SZ group, IL-2 levels were positively correlated with scores in the digit span test (rho=0.416, P=0.025) and intelligence (rho=0.464, P=0.011). We also found a negative correlation between IL-2 and total score in the negative subscale of PANSS (rho=-0.447, p=0.015). Our findings suggest that IL-2 may be involved in the mechanisms related to cognitive deterioration and negative symptomatology in schizophrenia., (Copyright © 2014. Published by Elsevier Inc.)

In the last decades convergent findings from several lines of evidence has revealed a robust association between major depressive disorder (MDD) and inflammatory pathways. Despite this, the translation of these findings into new and better treatments for MDD has not occurred. The objective of this study is to comprehensively review what is already known with reasonable certainty on inflammatory pathways in MDD, to clarify some points that have been insufficiently studied and to discuss the implications of these findings for future studies targeting inflammatory pathways as a therapeutic tool for individuals with MDD., (© 2014 S. Karger AG, Basel.)

Objective: Bipolar disorder (BD) has been associated with persistent low-grade inflammation and premature cell senescence, as shown by reduced telomere length (TL). The human cytomegalovirus (CMV) has increasingly been implicated in accelerated immunosenescence in aging studies. Here, we compared CMV serology and its relationships with cell senescence markers, including TL and lymphocyte subsets, in patients with type I BD and healthy controls., Methods: Twenty-two euthymic female patients with BD type I and 17 age-matched healthy controls were selected for the study. A sample of blood was collected and mononuclear cells and DNA were isolated and TL measured. CMV immunoglobulin M (IgM) and IgG titers were measured using chemiluminescent assays. Lymphocyte subsets [T, natural killer (NK) and NKT] were phenotyped by flow cytometry., Results: Individuals with BD had shorter TLs but higher CMV IgG levels than controls (both p < 0.01). CMV IgG level was inversely correlated with TL. None of the subjects showed IgM reactivity for CMV, excluding acute viral infection. CMV IgG level was associated with expansion of senescent CD8+CD28- T cells and NK cells, which are involved in viral control., Conclusions: These data support the hypothesis of accelerated aging in BD, as shown by shortened telomeres, higher seropositivity for CMV, and expansion of senescent T cells., (© 2013 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Bipolar disorder (BD) has been associated with immune imbalance, including lymphocyte activation and increased pro-inflammatory cytokines. Immune activation is part of stress response, and psychosocial stress has been implicated in the pathogenesis of psychiatric disorders. Here, we investigated the neuroendocrine and immune responses to acute psychosocial stress challenge in BD. Thirteen euthymic participants with type 1 BD and 15 healthy controls underwent the Trier Social Stress Test protocol (TSST). Blood samples were collected before and after TSST. Lymphocytes were isolated and stimulated in vitro to assess lymphocyte activation profile, lymphocyte sensitivity to dexamethasone, mitogen-activated protein kinase (MAPK) and nuclear factor kappa B (NF-κB) signaling by flow cytometry. Heart rate and salivary cortisol levels were monitored across the task. BD participants exhibited blunted stress responses as shown by reduced heart rate and salivary cortisol levels in comparison to healthy controls. BD was also associated with reduction in the percentage of regulatory T cells, but with expansion of activated T cells. When compared to controls, patients showed increased lymphocyte MAPK p-ERK and p-NF-κB signaling after the stress challenge, but exhibited a relative lymphocyte resistance to dexamethasone. In conclusion, stress-related neuroendocrine responses are blunted, associated with increased immune activation and lower sensitivity to glucocorticoids in BD. An inability in reducing NF-κB and MAPK signaling following TSST could be underlying the immune imbalance observed in BD., (Copyright © 2013 Elsevier Inc. All rights reserved.)

Bipolar disorder (BD) has been associated with an immunologic imbalance shown by increased peripheral inflammatory markers. The underlying mechanisms of this phenomenon may include changes in circulating cells and differential activation of mitogen-activated protein kinases (MAPKs). Twenty-seven euthymic female subjects with BD type I (all medicated) and 24 age- and sex-matched controls were recruited in this study. Lymphocytes were isolated and stimulated in vitro to assess Th1/Th17/Th2 cytokines (IL-2, IL-4, IL-6, IL-10, IL-17, IFN-γ and TNF-α) and MAPK phosphorylation. The expression of phospho-MAPKs, a large panel of lymphocyte subsets and cytokines were assessed by multi-color flow cytometry. BD patients had reduced proportions of natural T regulatory cells (CD4+ CD25+ FoxP3+) (p<0.01) in parallel to higher cytokine production (all p<0.01) than healthy controls. In particular, BD was associated with a strong bias to Th1 rather than Th2 profile. There was an expansion of senescence-associated cells (CD8+ CD28-) in BD (p<0.0001). T cells of BD patients had an increased p-ERK signaling (p<0.0001), indicating lymphocyte activation. Our data suggest that multiple molecular and cellular mechanisms may contribute to the immunologic imbalance observed in BD. In addition, our data concur to an early senescence process in these patients., (Copyright © 2012 Elsevier Ltd. All rights reserved.)

Introduction: Bipolar disorder is diagnosed on the basis of patient and/or family reports and behavioral observation. Traditionally regarded as an affective disorder involving behavioral changes, bipolar disorder has been reconceptualized as a multisystem disease associated with mood, cognitive, metabolic, autonomic and sleep/wake dysfunctions. Accordingly, recent studies have focused on the identification of biomarkers related to the pathophysiological mechanisms underlying the development, clinical presentation and course of bipolar disorder., Areas Covered: This article provides an overview of the available literature regarding circulating peripheral and neuroimaging biomarkers in bipolar disorder. Neurotrophic factors, immune parameters, oxidative stress parameters, hormones and neuroimaging findings were taken into consideration., Expert Opinion: Biomarkers research in bipolar disorder is a new field with an expanding knowledge. Current evidence suggests that a single biomarker will not be able to cover the biological and clinical complexity of bipolar disorder. Alternatively, a composite of biomarkers, including neurotrophic factors, cytokines and oxidative stress molecules, may be promising to identify altered mood states and neuroprogression in bipolar disorder.

Neutrophil migration to inflamed sites is crucial for both the initiation of inflammation and resolution of infection, yet these cells are involved in perpetuation of different chronic inflammatory diseases. Gastrin-releasing peptide (GRP) is a neuropeptide that acts through G protein coupled receptors (GPCRs) involved in signal transmission in both central and peripheral nervous systems. Its receptor, gastrin-releasing peptide receptor (GRPR), is expressed by various cell types, and it is overexpressed in cancer cells. RC-3095 is a selective GRPR antagonist, recently found to have antiinflammatory properties in arthritis and sepsis models. Here we demonstrate that i.p. injection of GRP attracts neutrophils in 4 h, and attraction is blocked by RC-3095. Macrophage depletion or neutralization of TNF abrogates GRP-induced neutrophil recruitment to the peritoneum. In vitro, GRP-induced neutrophil migration was dependent on PLC-β2, PI3K, ERK, p38 and independent of Gαi protein, and neutrophil migration toward synovial fluid of arthritis patients was inhibited by treatment with RC-3095. We propose that GRPR is an alternative chemotactic receptor that may play a role in the pathogenesis of inflammatory disorders.

Objective: To compare histologic artifacts caused by carbon dioxide (CO2) or 810-nm diode surgical lasers used to obtain small biopsy specimens of skin from healthy dogs., Design: Prospective study., Animals: 4 dogs., Procedure: 21 skin biopsy specimens were collected from each dog. Three biopsy specimens were obtained with a CO2 or an 810-nm diode laser at 3 operating settings each, and 3 biopsy specimens were obtained with a 6-mm biopsy punch instrument (controls). After processing, biopsy specimens were examined for artifacts related to laser-tissue interactions. Microscopically visible char was measured from the lateral edge of each specimen obtained with a laser., Results: There were no significant differences among mean char distances in biopsy specimens obtained with the CO2 laser at various settings. Mean char distance was significantly greater in all skin biopsy specimens obtained with the diode laser, compared with those obtained with the CO2 laser. Mean char distance was significantly greater in biopsy specimens obtained with the 810-nm diode laser at high power, compared with biopsy specimens obtained with the 810-nm diode laser at low power., Conclusions and Clinical Relevance: Results indicated that the CO2 laser caused less thermal injury at margins of skin biopsy specimens; therefore, if a surgical laser is used for removal of cutaneous masses or to obtain skin biopsy specimens, use of the CO2 laser is recommended. Veterinarians performing a biopsy by using a surgical laser should be aware that laser-induced artifacts may render small biopsy specimens useless for providing accurate histologic diagnosis.