Prognostic potential of serum mesencephalic astrocyte-derived neurotrophic factor in acute intracerebral hemorrhage: a prospective observational study.

OBJECTIVE: Mesencephalic astrocyte-derived neurotrophic factor (MANF) expressions are dramatically up-regulated in injured brain tissues, thereby conferring neurological protective effects. We intended to determine significance of serum MANF as a prognostic biomarker of intracerebral hemorrhage (ICH). METHODS: In this prospective, observational study done from February 2018 to July 2021, 124 patients with new-onset primary supratentorial ICH were consecutively enrolled. Also, a group of 124 healthy individuals constituted controls. Their serum MANF levels were detected using the Enzyme-Linked Immunosorbent Assay. National Institutes of Health Stroke Scale (NIHSS) and hematoma volume were designated as the two severity indicators. Early neurologic deterioration (END) was referred to as an increase of 4 or greater points in NIHSS scores or death at post-stroke 24 h. Post-stroke 90-day modified Rankin scale (mRS) scores of 3-6 was considered as a poor prognosis. Serum MANF levels were analyzed using multivariate analysis with respect to its association with stroke severity and prognosis. RESULTS: Patients, in comparison to controls, displayed markedly elevated serum MANF levels (median, 24.7 versus 2.7 ng/ml; P < 0.001), and serum MANF levels were independently correlated with NIHSS scores (beta, 3.912; 95% confidence interval (CI), 1.623-6.200; VIF = 2.394; t = 3.385; P = 0.002), hematoma volumes (beta, 1.688; 95% CI, 0.764-2.612; VIF = 2.661; t = 3.617; P = 0.001) and mRS scores (beta, 0.018; 95% CI, 0.013-0.023; VIF = 1.984; t = 2.047; P = 0.043). Serum MANF levels significantly predicted END and poor 90-day prognosis with areas under receiver operating characteristic curve at 0.752 and 0.787 respectively. END and prognostic predictive abilities were similar between serum MANF levels and NIHSS scores plus hematoma volumes (all P > 0.05). Combination of serum MANF levels with NIHSS scores and hematoma volumes had significantly higher prognostic capability than each of them (both P < 0.05). Serum MANF levels above 52.5 ng/ml and 62.0 ng/ml distinguished development of END and poor prognosis respectively with median-high sensitivity and specificity values. Using multivariate analysis, serum MANF levels > 52.5 ng/ml predicted END with odds ratio (OR) value of 2.713 (95% CI, 1.004-7.330; P = 0.042) and > 62.0 ng/ml predicted a poor prognosis with OR value of 3.848 (95% CI, 1.193-12.417; P = 0.024). Using restricted cubic spline, there was a linear correlation between serum MANF levels and poor prognosis or END risk (both P > 0.05). Nomograms were well established to predict END and a poor 90-day prognosis. Under calibration curve, such combination models were comparatively stable (using Hosmer & Lemeshow test, both P > 0.05). CONCLUSION: Increased serum MANF levels after ICH, in independent correlation with disease severity, independently distinguished risks of END and 90-day poor prognosis. Therefore, serum MANF may be a potential prognostic biomarker of ICH.

PEDF, a pleiotropic WTC-LI biomarker: Machine learning biomarker identification and validation.

Biomarkers predict World Trade Center-Lung Injury (WTC-LI); however, there remains unaddressed multicollinearity in our serum cytokines, chemokines, and high-throughput platform datasets used to phenotype WTC-disease. To address this concern, we used automated, machine-learning, high-dimensional data pruning, and validated identified biomarkers. The parent cohort consisted of male, never-smoking firefighters with WTC-LI (FEV1, %Pred< lower limit of normal (LLN); n = 100) and controls (n = 127) and had their biomarkers assessed. Cases and controls (n = 15/group) underwent untargeted metabolomics, then feature selection performed on metabolites, cytokines, chemokines, and clinical data. Cytokines, chemokines, and clinical biomarkers were validated in the non-overlapping parent-cohort via binary logistic regression with 5-fold cross validation. Random forests of metabolites (n = 580), clinical biomarkers (n = 5), and previously assayed cytokines, chemokines (n = 106) identified that the top 5% of biomarkers important to class separation included pigment epithelium-derived factor (PEDF), macrophage derived chemokine (MDC), systolic blood pressure, macrophage inflammatory protein-4 (MIP-4), growth-regulated oncogene protein (GRO), monocyte chemoattractant protein-1 (MCP-1), apolipoprotein-AII (Apo-AII), cell membrane metabolites (sphingolipids, phospholipids), and branched-chain amino acids. Validated models via confounder-adjusted (age on 9/11, BMI, exposure, and pre-9/11 FEV1, %Pred) binary logistic regression had AUCROC [0.90(0.84-0.96)]. Decreased PEDF and MIP-4, and increased Apo-AII were associated with increased odds of WTC-LI. Increased GRO, MCP-1, and simultaneously decreased MDC were associated with decreased odds of WTC-LI. In conclusion, automated data pruning identified novel WTC-LI biomarkers; performance was validated in an independent cohort. One biomarker-PEDF, an antiangiogenic agent-is a novel, predictive biomarker of particulate-matter-related lung disease. Other biomarkers-GRO, MCP-1, MDC, MIP-4-reveal immune cell involvement in WTC-LI pathogenesis. Findings of our automated biomarker identification warrant further investigation into these potential pharmacotherapy targets.

Elevated plasma Ninjurin-1 levels in atrial fibrillation is associated with atrial remodeling and thromboembolic risk.

BACKGROUND: Nerve injury-induced protein 1 (Ninj1) is elevated in various inflammatory diseases. The soluble form of Ninj1 yield by matrix metalloproteinase cleavage is a secreted protein and inhibits cell adhesion and inflammation. However, the role of plasma Ninj1 in atrial fibrillation (AF) has not been reported. The present study aimed to investigate the correlation between plasma Ninj1 levels and AF. METHODS: A total of 96 AF patients [age 66.00 (60.00, 72.00) years, male 56 (58.33%)] and 51 controls without AF [age 65.00 (55.00, 68.00) years, male 21 (41.18%)] were enrolled in this study. Plasma Ninj1 concentrations were detected using enzyme-linked immunosorbent assay. Also, the clinical characteristics, left atrial volume index (LAVI), CHA2DS2-VASc score, and HAS-BLED score were evaluated. RESULTS: Plasma Ninj1 levels were significantly higher in patients with AF than in controls (P < 0.001). Plasma Ninj1 levels were positively correlated with LAVI (P = 0.019) and CHA2DS2-VASc score (P = 0.024). Logistic regression analysis confirmed that the Ninj1 plasma levels were associated with AF (P = 0.009). The receiver operating characteristic analysis showed that plasma Ninj1 had a predictive value for AF (P < 0.001). CONCLUSIONS: Plasma Ninj1 levels were elevated in patients with AF, associated with left atrial enlargement and thromboembolic risk in AF.

The prevalence of anti-neurofascin-155 antibodies in patients with neuromyelitis optica spectrum disorders.

Anti-neurofascin-155 (NF155) antibodies have been observed in two cases with neuromyelitis optica spectrum disorders (NMOSD). This study investigated the prevalence of anti-NF155 antibodies in patients with NMOSD and the clinical features of anti-NF155 antibody-positive patients. Sera from 129 patients with NMOSD were screened with anti-NF155 antibodies by cell-based assay (CBA) and re-examined using immunostaining of teased mouse sciatic nerve fibres. Fifty-six patients with multiple sclerosis (MS) and 50 healthy controls (HC) were also enrolled for detecting anti-NF155 antibodies. A total of 12.40% (16 of 129) of patients with NMOSD were positive for anti-NF155 antibodies confirmed by both CBA and immunostaining. Immunoglobulin (Ig) G1 was the predominant subclass. However, none of 56 MS patients or 50 HC were positive for anti-NF155 antibodies. Anti-NF155 antibody-positive NMOSD patients had a higher proportion of co-existing with autoimmune diseases (p < 0.001) and higher positive rates of serum non-organ-specific autoantibodies, including anti-SSA antibodies (p < 0.001), anti-SSB antibodies (p = 0.008), anti-Ro-52 antibodies (p < 0.001) and rheumatoid factor (p < 0.001). Five anti-NF155 antibody-positive NMOSD patients who took part in the nerve conduction study showed mildly abnormal results. Differences in some nerve conduction study parameters were observed between anti-NF155 antibody-positive and negative patients. Anti-NF155 antibodies occurred in a small proportion of NMOSD patients. Anti-NF155 antibody-positive NMOSD patients tended to co-exist with autoimmune diseases.

Long-term high-intensity interval training increases serum neurotrophic factors in elderly overweight and obese Chinese adults.

PURPOSE: To compare the effects of 12-week high-intensity interval training (HIIT) and vigorous-intensity continuous training (VICT) on cognitive function, physical fitness, VO2max, serum neurotransmitters and neurotrophic factors in overweight and obese elderly individuals. METHODS: Twenty-nine physically inactive older adults (18 males and 11 females) with a mean age of 64.8 ± 3.9 years were randomly divided into a control group (CON, n = 9), an HIIT group (4 × 3 min at 90% VO2max interspersed with 3 min at 60% VO2max, n = 10) and a VICT group (25 min at 70% VO2max, n = 10) and submitted to 12 weeks of training. Cognitive function questionnaires, physical fitness, VO2max, serum neurotransmitters and neurotrophic factors were determined at baseline and post training. RESULTS: Twelve weeks of HIIT and VICT improved the VO2max (4.19 ± 2.21 and 1.84 ± 1.63 mL/kg/min, respectively, p = 0.005), sit-and-reach distance (8.7 ± 3.0 and 7.8 ± 3.8 cm, p = 0.033), choice reaction time (- 0.115 ± 0.15 and - 0.09 ± 0.15 s, p = 0.004) and one-leg stand time (4.4 ± 3.4 and 4.2 ± 4.0 s, p < 0.001) of the elderly participants. The serum concentrations of brain-derived neurotrophic factor (375.5 ± 247.9 and 227.0 ± 137.1 pg/ml, p = 0.006), nerve growth factor (33.9 ± 16.7 and 23.3 ± 14.5 pg/ml, p = 0.037), neurotrophin-3 (24.2 ± 9.33 and 16.3 ± 5.91 pg/ml, p = 0.006) and neurotrophin-4 (10.4 ± 3.8 and 7.8 ± 5.0 pg/ml, p = 0.029) increased significantly in the HIIT and VICT groups after training. In addition, compared to VICT, HIIT significantly increased VO2max and the serum neurotrophin-3 concentration. Serum concentrations of the neurotransmitters acetylcholine, dopamine and serotonin trended upward with training. No significant change was observed in the cognitive function questionnaire scores (p > 0.05). CONCLUSION: HIIT is suitable for elderly adults and is more effective than VICT for improving VO2max and serum neurotrophin-3 concentrations. CHINESE CLINICAL TRIAL REGISTRY NUMBER: No. ChiCTR1900022315, date of registration: 4 April 2019.

The Impact of Physical Exercise on the Circulating Levels of BDNF and NT 4/5: A Review.

(1) Background: One mechanism through which physical activity (PA) provides benefits is by triggering activity at a molecular level, where neurotrophins (NTs) are known to play an important role. However, the expression of the circulating levels of neurotrophic factors, brain-derived neurotrophic factor (BDNF) and neurotrophin-4 (NT-4/5), in response to exercise, is not fully understood. Therefore, the aim was to provide an updated overview on the neurotrophin (NT) variation levels of BDNF and NT-4/5 as a consequence of a long-term aerobic exercise intervention, and to understand and describe whether the upregulation of circulating NT levels is a result of neurotrophic factors produced and released from the brain, and/or from neurotrophic secreting peripheral organs. (2) Methods: The articles were collected from PubMed, SPORTDiscus, Web of Science, MEDLINE, and Embase. Data were analyzed through a narrative synthesis. (3) Results: 30 articles studied humans who performed training protocols that ranged from 4 to 48 weeks; 22 articles studied rodents with an intervention period that ranged from 4 to 64 weeks. (4) Conclusions: There is no unanimity between the upregulation of BDNF in humans; conversely, concerning both BDNF and NT-4/5 in animal models, the results are heterogeneous. Whilst BDNF upregulation appears to be in relative agreement, NT-4/5 seems to display contradictory and inconsistent conclusions.

Neurosteroids and Neurotrophic Factors: What Is Their Promise as Biomarkers for Major Depression and PTSD?

Even though major depressive disorder (MDD) and post-traumatic stress disorder (PTSD) are among the most prevalent and incapacitating mental illnesses in the world, their diagnosis still relies solely on the characterization of subjective symptoms (many of which are shared by multiple disorders) self-reported by patients. Thus, the need for objective measures that aid in the detection of and differentiation between psychiatric disorders becomes urgent. In this paper, we explore the potential of neurosteroids and neurotrophic proteins as biomarkers for MDD and PTSD. Circulating levels of the GABAergic neuroactive steroid, allopregnanolone, are diminished in MDD and PTSD patients, which corroborates the finding of depleted neurosteroid levels observed in animal models of these disorders. The neurotrophic protein, brain-derived neurotropic factor (BDNF), is also reduced in the periphery and in the brain of MDD patients and depressed-like animals that express lower neurosteroid levels. Although the role of BDNF in PTSD psychopathology seems less clear and merits more research, we propose a causal link between allopregnanolone levels and BDNF expression that could function as a biomarker axis for the diagnosis of both MDD and PTSD.

Neurotrophins as a reliable biomarker for brain function, structure and cognition: A systematic review and meta-analysis.

Neurotrophins are signalling molecules involved in the formation and maintenance of synapses in the brain. They can cross the blood-brain barrier and be detected in peripheral blood, suggesting they may be a potential biomarker for brain health and function. In this review, the available literature was systematically searched for studies comparing peripheral neurotrophins levels with MRI and cognitive measures in healthy adults. Twenty-four studies were identified, six of which included a neuroimaging outcome. Fifteen studies measuring cognition were eligible for meta-analysis. The majority of studies measured levels of brain-derived neurotrophic factor (BDNF), with few assessing other neurotrophins. Results revealed BDNF is related to some neuroimaging outcomes, with some studies suggesting older age may be an important factor. A higher proportion of studies who had older samples observed significant effects between cognition and neurotrophin levels. When cognitive studies were pooled together in a meta-analysis, there was a weak non-significant effect between BDNF and cognitive outcomes. There was also a high level of heterogeneity between cognitive studies. Results indicated that gender was a notable source of the heterogeneity, but additional studies employing relevant covariates are necessary to better characterise the inter-relationship between circulating neurotrophins and cognition.

Deficient neurotrophic factors of CSPG4-type neural cell exosomes in Alzheimer disease.

Exosomes derived from chondroitin sulfate proteoglycan (CSPG) 4 type neural precursor cells (CSPG4Es) were purified from human plasma by sequential immunoabsorption with anti-CSPG4 and anti-platelet growth factor receptor α mAb to characterize the potential in vivo roles of CSPG4 cells in neuronal repair. Hepatocyte growth factor, fibroblast growth factors (FGFs)-2 and -13, and type 1 insulin-like growth factor (IGF-1), which enhance neuronal survival and functions, were quantified in CSPG4E extracts. For CSPG4Es of 24 healthy control subjects, mean levels of hepatocyte growth factor, FGF-13, and IGF-1, but not FGF-2, were significantly higher by up to 7-fold than in their neuronal-derived exosomes, and mean levels of all 4 growth factors were significantly higher by up to 8-fold than in their astrocyte-derived exosomes. Mean CSPG4E levels of all growth factors were significantly lower in patients with mild Alzheimer disease (AD) ( n = 24) than in age- and sex-matched cognitively normal control subjects ( n = 24). Mean CSPG4E levels of all growth factors were also significantly lower in 15 patients at the stage of moderate dementia from AD (AD2) and at their preclinical stage 3 to 8 yr earlier (AD1), with no differences between values at stages AD1 and AD2. Current findings suggest that CSPG4 cells export in exosomes higher levels of neurotrophic factors than neurons or astrocytes and that CSPG4E neurotrophic factors are diminished early in AD, with no significant progression of decreases later in the course.-Goetzl, E. J., Nogueras-Ortiz, C., Mustapic, M., Mullins, R. J., Abner, E. L., Schwartz, J. B., Kapogiannis, D. Deficient neurotrophic factors of CSPG4-type neural cell exosomes in Alzheimer disease.

Decreased Circulating MANF in Women with PCOS is Elevated by Metformin Therapy and is Inversely Correlated with Insulin Resistance and Hyperandrogenism.

Mesencephalic astrocyte-derived neurotrophic factor (MANF) is a novel neurotrophic factor. Although recent studies have suggested that MANF appeared to be associated with insulin resistance, the results have been inconsistent. The aim of our study was to determine the serum MANF levels in women with PCOS and controls, to investigate their relationship to insulin resistance, and to evaluate circulating MANF changes with metformin intervention in PCOS women. We conducted a series of cross-sectional and interventional studies in 90 newly diagnosed patients with PCOS and 60 age- and gender-matched controls. Oral glucose tolerance test and euglycemic-hyperinsulinemic clamps were performed to assess the glucose tolerance and insulin sensitivity. Forty-three women with PCOS were randomly assigned to six months of oral metformin therapy. Serum MANF levels were significantly lower in women with PCOS than in controls. Serum MANF levels were positively correlated with M-value and negatively correlated with body mass index (BMI), body fat percentage (FAT), homeostatic model assessment of insulin resistance (HOMA-IR), and free androgen index (FAI). Multivariate stepwise regression demonstrated that serum MANF levels were independently associated with M-value and FAI. After six months of metformin treatment, there was a significant increase in serum MANF levels in PCOS women. Serum MANF levels are decreased in women with PCOS, and are reversely related to insulin resistance and hyperandrogenism. Metformin treatment elevates serum MANF levels and alleviates insulin resistance and hyperandrogenism in PCOS women.

Circulating Mesencephalic Astrocyte-Derived Neurotrophic Factor Negatively Correlates With Atrial Apoptosis in Human Chronic Atrial Fibrillation.

Atrial apoptosis has been found to be majorly involved in the pathogenesis of human atrial fibrillation (AF). Mesencephalic astrocyte-derived neurotrophic factor exerts an antiapoptotic effect for multiple cell types. However, the correlation between MANF and atrial apoptosis in AF is still undefined. In this study, 59 patients with valvular or congenital heart disease were divided into 2 groups: AF group and sinus rhythm (SR) group. We found that the apoptotic atrial myocytes in the right atrial appendage tissues of the AF group were significantly more than those of the SR group, whereas mRNA and protein levels of MANF in the AF group were significantly down-regulated compared with those in the SR group. The serum MANF in patients with AF was markedly lower than that in patients with SR, which was inversely correlated with atrial apoptosis in patients with AF. In addition, the AF group had the greater inflammation and endoplasmic reticulum stress compared with the SR group. These findings suggest that MANF downregulation may lead to more atrial apoptosis in human chronic AF, indicating MANF as a potential therapeutic agent in AF treatment.

Plasma angiogenesis and oxidative stress markers in patients with diabetic retinopathy.

Background: Neovascularization in the retina and hyperglycaemia-induced oxidative stress are implicated in the pathogenesis of diabetic retinopathy (DR). In this study, we hypothesized that the plasma angiogenic and oxidative stress markers associated with these derangements could aid in the screening of diabetic patients who are at an increased risk of developing retinopathy.Methods: This study included normal (n = 148), type2 diabetes without retinopathy (DNR; n = 148), proliferative DR (PDR; n = 74) and non-PDR (NPDR; n = 148) subjects. Plasma concentrations of vascular endothelial growth factor-A (VEGF-A), hypoxia-inducible factor-1α (HIF-1α), matrix metalloproteinase-9 (MMP-9), pigment epithelium-derived factor (PEDF), nitric oxide (NO), soluble receptors for advanced glycation end products (sRAGE), malondialdehyde (MDA) and protein thiols were estimated.Results: A statistically significant increase was observed in the plasma concentrations of pro-angiogenic factors and markers of oxidative stress in both retinopathy groups. By contrast, the concentrations of anti-angiogenic factors and antioxidants were decreased significantly in these groups. Receiver operating characteristic analysis indicated that the plasma thresholds of HIF-1α and PEDF can be suitable markers in case of NPDR. However, in PDR, HIF-1α, NO, MMP-9 and PEDF showed high sensitivity and specificity.Conclusions: The factors associated with hypoxia, matrix degradation and angiogenic inhibition play a crucial role in predicting DR.

Two-hour postload plasma glucose and pigment epithelium-derived factor levels are markers of coronary artery inflammation in type 2 diabetic patients.

BACKGROUND: We have previously found that pioglitazone attenuates inflammation in the left main trunk of coronary artery (LMT), evaluated as target-to-background ratio (TBR) by 18F-fluorodeoxyglucose-positron emission tomography/computed tomography (FDG-PET/CT) in patients with impaired glucose tolerance or type 2 diabetes. OBJECTIVES: We assessed which clinical variables could predict the change in TBR in the LMT after 4-month add-on therapy with oral hypoglycemic agents (OHAs). METHODS: A total of 38 type 2 diabetic patients with carotid atherosclerosis who had already received OHAs except for pioglitazone was enrolled. At baseline and 4 months after add-on therapy with pioglitazone or glimepiride, all patients underwent 75 g oral glucose tolerance test, blood chemistry analysis, and FDG-PET/CT. RESULTS: Fasting plasma glucose, 30-, 60-, 90-, 120-minutes postload plasma glucose, HbA1c, and LMT-TBR values were significantly decreased by add-on therapy, whereas high-density lipoprotein-cholesterol and adiponectin levels were increased. Increased serum levels of pigment epithelium-derived factor (PEDF), a marker of insulin resistance and non-use of aspirin at baseline could predict the favorable response of LMT-TBR to add-on therapy. Moreover, Δ120-minutes postload plasma glucose and ΔPEDF were independent correlates of ΔLMT-TBR. CONCLUSIONS: Our present study suggests that 120-minutes postload plasma glucose and PEDF values may be markers and potential therapeutic targets of coronary artery inflammation in type 2 diabetic patients. CLINICAL TRIAL REGISTRATION: URL: http://clinicaltrials.gov . Unique identifier: NCT00722631. New markers for diabetes and CAD is on the horizon! Two-hour postload plasma glucose and pigment epithelium derived factor are markers of coronary artery inflammation in type 2 diabetic patients.

Decreased Expression of Cerebral Dopamine Neurotrophic Factor in Platelets of Stroke Patients.

BACKGROUND: Cerebral dopamine neurotrophic factor plays a critical role in repairing and maintaining healthy neurons in pathological conditions such as stroke. However, the association between cerebral dopamine neurotrophic factor expression and stroke has only recently been investigated in preclinical models and is rarely described in human studies. OBJECTIVES: The aims of this were to examine neurological alterations mirrored in human blood platelet cerebral dopamine neurotrophic factor gene expression. Cerebral dopamine neurotrophic factor is expressed in both the central nervous system and peripheral blood. Blood platelets are often used to model neuronal behavior because they exhibit biochemical impairments similar to brain tissues of patients with neurological disorders. METHODS: RNA was isolated from platelets and cDNA was synthesized to quantify cerebral dopamine neurotrophic factor gene expression of 36 stroke patients compared to 72 healthy aged-matched controls through real-time PCR. Further grouping analyses of data with regard to age, sex, and medication history were performed. RESULTS: Cerebral dopamine neurotrophic factor gene expression was significantly reduced in stroke patients relative to control subjects (P = .013). Subsequent analysis revealed a significant difference in expression between males and females within the control group (P = .026). Decreased cerebral dopamine neurotrophic factor expression was only observed in male stroke patients compared to their sex-matched controls (P = .008). Grouping stroke patients based on their medication history did not significantly alter cerebral dopamine neurotrophic factor gene expression. CONCLUSIONS: Further studies investigating cerebral dopamine neurotrophic factor expression could be directed towards the interplay of the central nervous system, hematopoietic derivatives, and utilizing cerebral dopamine neurotrophic factor as a therapeutic tool.

Neurotrophic factors in bipolar disorders patients with manic episode

Background/aim: Neurotrophins are one of the most important molecule groups affecting cerebral neuroplasticity. The amount of evidence about the role of changes in neuroplasticity in the pathophysiology of bipolar disease is growing. Materials and methods: We measured serum levels of brain-derived neurotrophic factor (BDNF), nerve growth factor (NGF), neurotrophin-3 (NT-3), glial cell-line derived neurotrophic factor (GDNF), vascular endothelial growth factor (VEGF), insulin-like growth factor-1 (IGF-1), fibroblast growth factor (FGF)-2, neuritin 1 (Nrn 1) in bipolar 1 manic episode patients (n = 45) and healthy control group. Results: When controlled for age, BMI and cortisol, it was found that the serum levels of BDNF, NGF, NT-3, VEGF and FGF-2 of bipolar manic episode patients were not statistically different compared to those of the control group. GDNF level and Nrn 1 levels were significantly lower (P = 0.003 and P = 0.025 respectively) while IGF-1 levels were significantly higher than the control group (P = 0.0001). ROC analysis was performed and the area under the the curve was calculated as 0.737, 0.766 for GDNF, IGF-1 respectively. Conclusion: The changes in the levels of GDNF, IGF-1 and Nrn 1 might be involved in pathopysiology of bipolar disorder, and GDNF, IGF-1 may be considered as state markers in bipolar manic episode.

Higher serum VGF protein levels discriminate bipolar depression from major depressive disorder.

Misdiagnosis between major depressive disorder (MDD) and bipolar depression (BD) is quite common. Our previous study found significantly lower serum VGF (non-acronymic) in MDD patients. However, it is unclear whether same changes occur in BD patients. Therefore, we aimed to investigate the relationship between serum VGF levels in BD and MDD patients. General information, scores of 17-item Hamilton Depression Rating Scale (HDRS), and fasting blood samples of all participants including 30 MDD patients, 20 BD patients, and 30 healthy controls (HC) were collected. Serum VGF levels were measured by Enzyme-linked immunosorbent assay kits. Pearson correlation analysis was used to analyze correlations between serum VGF levels and clinical information. Receiver operating characteristic (ROC) curve and likelihood ratios (LRs) were used to analyze the differential potential of serum VGF. Serum VGF levels were significantly lower in MDD patients but higher in BD patients compared with HC (both PTukey < 0.01). No correlation was found between serum VGF levels and any data of subjects. The optimal cutoff for serum VGF in discriminating BD patients from MDD patients was ≥1093.85 pg/ml (AUC = 0.990, sensitivity of 95%, specificity of 100% and accuracy of 95%). LRs further confirmed the differential efficiency of serum VGF in distinguishing BD and MDD patients with +LR of infinity and -LR of 0. The results suggest that serum VGF level changed significantly in MDD and BD patients and serum VGF may be an indicator for differentiating BD patients from MDD patients.

Association of Circulating Proinflammatory and Anti-inflammatory Protein Biomarkers in Extremely Preterm Born Children with Subsequent Brain Magnetic Resonance Imaging Volumes and Cognitive Function at Age 10 Years.

OBJECTIVES: To examine elevated neonatal inflammatory and neurotrophic proteins from children born extremely preterm in relation to later childhood brain Magnetic Resonance Imaging volumes and cognition. STUDY DESIGN: We measured circulating inflammation-related proteins and neurotrophic proteins on postnatal days 1, 7, and 14 in 166 children at 10 years of age (73 males; 93 females). Top quartile levels on ≥2 days for ≥3 inflammation-related proteins and for ≥4 neurotrophic proteins defined exposure. We examined associations among protein levels, brain Magnetic Resonance Imaging volumes, and cognition with multiple linear and logistic regressions. RESULTS: Analyses were adjusted for gestational age at birth and sex. Children with ≥3 elevated inflammation-related proteins had smaller grey matter, brain stem/cerebellar, and total brain volumes than those without elevated inflammation-related proteins, adjusted for neurotrophic proteins. When adjusted for inflammation-related proteins, children with ≥4 neurotrophic proteins, compared with children with no neurotrophic proteins, had larger grey matter and total brain volumes. Higher grey matter, white matter, and cerebellum and brainstem volumes were significantly correlated with higher IQ. Grey and white matter volumes were correlated with each other (r = -0.18; P = .021), and cerebellum and brainstem was highly correlated with grey matter (r = 0.55; P < .001) and white matter (r = 0.29; P < .001). Adjusting for other brain compartments, cerebellum and brainstem was associated with IQ (P = .016), but the association with white matter was marginally significant (P = .051). Grey matter was not associated with IQ. After adjusting for brain volumes, elevated inflammation-related proteins remained significantly associated with a lower IQ, and elevated neurotrophic proteins remained associated with a higher IQ. CONCLUSIONS: Newborn inflammatory and neurotrophin protein levels are associated with later brain volumes and cognition, but their effects on cognition are not entirely explained by altered brain volumes.

Effect of Sertraline, Dosulepin, and Venlafaxine on Non-BDNF Neurotrophins in Patients With Depression: A Cohort Study.

BACKGROUND: The neurotrophic hypothesis of depression has been mostly studied with a focus on brain-derived neurotrophic factor (BDNF) leading to lack of data on non-BDNF neurotrophins (NTs). The aim of this study was to evaluate the effect of antidepressant drugs on changes in serum nerve growth factor (NGF), neurotrophin 3 (NT-3), and neurotrophin 4 (NT-4). METHODS: A prospective cohort study was conducted on 105 patients with depression who were subgrouped to the group 1 (mild and moderate depression without somatic syndrome treated with sertraline), group 2 (mild and moderate depression with somatic syndrome treated with dosulepin), and group 3 (severe depression without psychotic symptoms treated with venlafaxine). At baseline, the severity of depression (Montgomery-Asberg Depression Rating Scale [MADRS]), serum NGF, NT-3, and NT-4 were estimated. Thirty-five healthy volunteers were recruited as controls for a baseline comparison of NTs. All patients were followed up after 6 weeks to evaluate the changes in NT levels and correlate it with the change in MADRS scores. RESULTS: At baseline, NT levels were significantly lower in patients with depression in comparison with healthy control. In group 1, serum NGF, NT-3, and NT-4 level were found to increase significantly after treatment, whereas changes in groups 2 and 3 were statistically not significant. Montgomery-Asberg Depression Rating Scale score and serum NGF at baseline had an inverse relation (r = -0.648), whereas the change in MADRS score in sertraline group had a positive correlation (r = 0.86) with the change of serum NGF. CONCLUSIONS: Monotherapy with sertraline increased the level of non-BDNF NTs; however, treatment with dosulepin and venlafaxine did not produce any significant changes in patients with depression.

Biomarkers to predict the response to cardiac resynchronization therapy.

Cardiac resynchronization therapy (CRT) is an established non-pharmacological treatment for selected heart failure patients with wide QRS duration. However, there is a persistent number of non-responders throughout. The prediction of the CRT response is paramount to adequately select the correct patients for CRT. One of the expanding fields of research is the development of biomarkers that predict the response to CRT. A review of the available literature on biomarkers in CRT patients has been performed to formulate a critical appraisal of the available data. The main conclusion of our review is that biomarker research in this patient population is very fragmented and broad. This results in the use of non-uniform endpoints to define the CRT response, which precludes an in-depth comparison of the available data. To improve research development in this field, a uniform definition of the CRT response and relevant endpoints is necessary to better predict the CRT response.

Activation of Complement by Pigment Epithelium-Derived Factor in Rheumatoid Arthritis.

The aim of this study was to identify molecules that trigger complement activation in rheumatic joints. C4d, the final cleavage product of C4 activation, is found in the diseased joint and can bind covalently to complement-activating molecules. By using a highly specific Ab against a cleavage neoepitope in C4d, several molecules that were specifically bound to C4d were identified from pooled synovial fluid (SF) from four rheumatoid arthritis (RA) patients. One of these molecules, pigment epithelium-derived factor (PEDF), is a broadly expressed multifunctional member of the serine proteinase inhibitor family. Using ELISA, we confirmed the presence of various amounts of complexes between PEDF and C4d in the SF from 30 RA patients, whereas none were detected in SF from control subjects. Correlation analyses suggested that, in arthritis patients, C4d-PEDF complexes found in sera arise from the joints, as well as from other tissues, and levels of the complexes did not differ in sera of RA patients and healthy controls. When immobilized, recombinant PEDF expressed in eukaryotic cells activated the classical complement pathway but not the alternative or lectin pathways. C1q protein was demonstrated to bind immobilized PEDF, and PEDF was shown to bind to immobilized C1q, in particular its head regions, which are known to interact with other activators of the classical pathway. Our results call for further investigation into the role of PEDF in inflammatory processes in the joint, which, in combination with classical complement activation, appears to be part of a (patho-)physiologic response.