Current concepts on the expression of neurotrophins in the greater omentum

The omentum has been utilized in Neurosurgery since the late 1960s. Its overwhelming effects on fibroblast and peripheral nerve growths were soon noticed. However, there was no direct evidence of production of any of the growth factors by the omentum, although substances were shown to be present in the omentum. Three animals were used in the study. After removal of the omentum in one, the tissue was submitted to PCR for BDNF, NT3/4 and NT5. Water was the negative control utilized. There was marked expression of all neurotrophins in the omentum, indicating local production of all those substances. The omentum has, for the first time, demonstrated to produce and not only accumulate neurotrophins. Utilization of this concept may permit transplant or transposition of parts of the omentum into the central nervous system for the management of multiple diseases, including vascular dementia, strokes, Alzheimer's disease or Moya-Moya disease.     

Permeability of the blood–brain barrier to neurotrophins

To evaluate the feasibility of applying blood-borne neurotrophins to promote normal function of the central nervous system (CNS) and to rescue neuronal degeneration, we characterized the permeability of the blood–brain barrier (BBB) to neurotrophins. We report here that some members of the neurotrophin family (NGF, βNGF, NT3, and NT5) can cross the BBB of mice in vivo to arrive at the brain parenchyma. BBB permeability differed among individual neurotrophins in that NGF had the fastest influx rate (K_i) and NT3 the slowest, and that the entry rate of NGF was twice that of its smaller bioactive subunit βNGF. BBB permeability also differed at various CNS regions in that the cervical spinal cord had the greatest rate of influx, whereas brain had the lowest. Saturability of influx was suggested by self-inhibition studies for NT3 in vivo, and for NGF in an in situ brain perfusion system, indicating the presence of saturable transport systems. The results suggest that peripheral administration of neurotrophins could have therapeutic effects within the CNS.     

Neuropeptides and neurotrophins in neonatal blood of children with autism or mental retardation

There has been little exploration of major biologic regulators of cerebral development in autism. In archived neonatal blood of children with autistic spectrum disorders (n = 69), mental retardation without autism (n = 60), or cerebral palsy (CP, n = 63) and of control children (n = 54), we used recycling immunoaffinity chromatography to measure the neuropeptides substance P (SP), vasoactive intestinal peptide (VIP), pituitary adenylate cyclase-activating polypeptide (PACAP), calcitonin gene-related peptide (CGRP), and the neurotrophins nerve growth factor (NGF), brain-derived neurotrophic factor (BDNF), neurotrophin 3 (NT3), and neurotrophin 4/5 (NT4/5). Neonatal concentrations of VIP, CGRP, BDNF, and NT4/5 were higher (ANOVA, all p values < 0.0001 by Scheffe test for pairwise differences) in children in the autistic spectrum and in those with mental retardation without autism than in control children. In 99% of children with autism and 97% with mental retardation, levels of at least one of these substances exceeded those of all control children. Concentrations were similar in subgroups of the autistic spectrum (core syndrome with or without mental retardation, other autistic spectrum disorders with or without mental retardation) and in the presence or absence of a history of regression. Among children with mental retardation, concentrations did not differ by severity or known cause (n = 11, including 4 with Down syndrome). Concentrations of measured substances were similar in children with CP as compared with control subjects. SP, PACAP, NGF, and NT3 were not different by diagnostic group. No measured analyte distinguished children with autism from children with mental retardation alone. In autism and in a heterogeneous group of disorders of cognitive function, overexpression of certain neuropeptides and neurotrophins was observed in peripheral blood drawn in the first days of life.     

Flow cytometry analysis of T-cell subsets in cerebrospinal fluid of narcolepsy type 1 patients with long-lasting disease

BackgroundType 1 narcolepsy (NT1) is a central hypersomnia linked to the destruction of hypocretin-producing neurons. A great body of genetic and epidemiological data points to likely autoimmune disease aetiology. Recent reports have characterized peripheral blood T-cell subsets in NT1, whereas data regarding the cerebrospinal fluid (CSF) immune cell composition are lacking. The current study aimed to characterize the T-cell and natural killer (NK) cell subsets in NT1 patients with long disease course.MethodsImmune cell subsets from CSF and peripheral blood mononuclear cell (PBMC) samples were analysed by flow cytometry in two age-balanced and sex-balanced groups of 14 NT1 patients versus 14 healthy controls. The frequency of CSF cell groups was compared with PBMCs. Non-parametric tests were used for statistical analyses.ResultsThe NT1 patients did not show significant differences of CSF immune cell subsets compared to controls, despite a trend towards higher CD4⁺ terminally differentiated effector memory T cells. T cells preferentially displayed a memory phenotype in the CSF compared to PBMCs. Furthermore, a reduced frequency of CD4⁺ terminally differentiated effector memory T cells and an increased frequency of NK CD56^bright cells was observed in PBMCs from patients compared to controls. Finally, the ratio between CSF and peripheral CD4⁺ terminally differentiated effector memory T cells was two-fold increased in NT1 patients versus controls.ConclusionsSignificant differences in PBMCs and in CSF/PBMC ratios of immune cell profile were found in NT1 patients compared to healthy controls. These differences might have arisen from the different HLA status, or be primary or secondary to hypocretin deficiency. Further functional studies in patients close to disease onset are required to understand NT1 pathophysiology.     

A review on microelectrode recording selection of features for machine learning in deep brain stimulation surgery for Parkinson’s disease

ObjectiveThis study seeks to systematically review the selection of features and algorithms for machine learning and automation in deep brain stimulation surgery (DBS) for Parkinson’s disease. This will assist in consolidating current knowledge and accuracy levels to allow greater understanding and research to be performed in automating this process, which could lead to improved clinical outcomes.MethodsA systematic literature review search was conducted for all studies that utilized machine learning and DBS in Parkinson’s disease.ResultsTen studies were identified from 2006 utilizing machine learning in DBS surgery for Parkinson’s disease. Different combinations of both spike independent and spike dependent features have been utilized with different machine learning algorithms to attempt to delineate the subthalamic nucleus (STN) and its surrounding structures.ConclusionThe state-of-the-art algorithms achieve good accuracy and error rates with relatively short computing time, however, the currently achievable accuracy is not sufficiently robust enough for clinical practice. Moreover, further research is required for identifying subterritories of the STN.SignificanceThis is a comprehensive summary of current machine learning algorithms that discriminate the STN and its adjacent structures for DBS surgery in Parkinson’s disease.     

Reliability and validity of the Chinese version of Narcolepsy Severity Scale in adult patients with narcolepsy type 1

ObjectiveTo evaluate reliability and validity of the Chinese version of Narcolepsy Severity Scale (NSS) in adult patients with narcolepsy type 1 (NT1).MethodsOne hundred and fifty-one adult patients (≥18 years) with NT1 were recruited. All filled out the 15-item Chinese version of NSS. Item analysis included critical ratio and correlation analysis. The validity of NSS was assessed by exploratory factor analysis, discriminant validity and convergent validity. Reliability of NSS was assessed by Cronbach's α coefficient, spilt-half reliability and test-retest reliability.ResultsCritical value of all 15 items ranged from 3.01 to 13.36. Each item was significantly correlated with the total score by a correlation coefficient (r) ranging from 0.219 to 0.700. Three common domains were extracted and 15 items explained 54.86% of the total variance. There was a shift in domains compared to the English version likely due to cultural differences. Cronbach's α coefficient for the total scale of 15 items was 0.821 and for three factors was 0.726, 0.748 and 0.760 respectively. The NSS had good correlation with Epworth sleepiness scale scores, Insomnia severity index scores and moderate correlation with mean the sleep latency of polysomnographic recording, and European Quality of Life-5 Dimensions Questionnaire. The Chinese version of NSS showed good spilt-half reliability and test-retest reliability.ConclusionThe Chinese version of NSS shows satisfactory psychometric properties with good validity and reliability. It is applicable to evaluate the severity and consequences of symptoms in Chinese adult patients with NT1.     

Narcolepsy type 1 patients have lower levels of effector memory CD4+ T cells compared to their siblings when controlling for H1N1-(Pandemrix™)-vaccination and HLA DQB1106:02 status

Study objectivesEvidence suggests a cell-mediated autoimmune pathogenesis for narcolepsy type 1 (NT1), but it is not clear whether the disease is associated with overall changes in T cell subsets. The increase in NT1 incidence after H1N1 vaccination campaign with the Pandemrix™ vaccine suggests that disease-relevant changes in the immune system following this vaccination were important. In this study, we aimed to investigate differentiated T cell subsets and levels of CD25 and CD69 activation markers in a cohort of mainly Pandemrix™-vaccinated NT1 patients compared with their vaccinated and unvaccinated siblings.MethodsPeripheral blood mononuclear cells were collected in parallel and analysed with flow cytometry in 31 NT1 patients with disease onset after the 2009 influenza A (H1N1) pandemic and/or Pandemrix™ vaccination and 45 of their non-narcoleptic siblings (29/31 and 34/45 vaccinated, respectively).ResultsWe observed significantly lower effector memory CD4⁺ T cell levels in NT1 patients compared to their siblings, when controlling for HLA DQB1106:02 and vaccination status. Further, within the sibling group, vaccination status significantly affected frequencies of central memory and CD8⁺CD25⁺ T cells, and HLA DQB1106:02 status significantly affected frequencies of CD4⁺CD25⁺ T cells.ConclusionWe confirm that NT1 is associated with lower levels of effector memory CD4⁺ T cells in peripheral blood. Importantly, this finding was only significant when controlling for vaccination and HLA status in both patients and controls. We thus demonstrate the importance of characterizing such factors (eg HLA and vaccination) when studying T cell subsets in NT1. This might explain earlier conflicting results.     

Increased intra-subject variability of neural activity during speech production in people with autism spectrum disorder

BackgroundCommunication difficulties are a core deficit in many people with autism spectrum disorder (ASD). The current study evaluated neural activation in participants with ASD and neurotypical (NT) controls during a speech production task.MethodsNeural activities of participants with ASD (N = 15, M = 16.7 years, language abilities ranged from low verbal abilities to verbally fluent) and NT controls (N = 12, M = 17.1 years) was examined using functional magnetic resonance imaging with a sparse-sampling paradigm.ResultsThere were no differences between the ASD and NT groups in average speech activation or inter-subject run-to-run variability in speech activation. Intra-subject run-to-run neural variability was greater in the ASD group and was positively correlated with autism severity in cortical areas associated with speech.ConclusionsThese findings highlight the importance of understanding intra-subject neural variability in participants with ASD.     

Increased monocyte chemoattractant protein-1 and nitrotyrosine are associated with increased body weight in patients with rheumatoid arthritis after etanercept therapy

ObjectivesEtanercept, a tumor necrosis factor inhibitor, is an effective drug for patients with active rheumatoid arthritis (RA). Monocyte chemoattractant protein-1 (MCP-1) and nitrotyrosine (NT) are pro-inflammatory biomolecules associated with satiety and increased body weight. We evaluated whether MCP-1 and NT are associated with decreased inflammation or increased body mass during etanercept therapy in active RA patients.MethodsRA patients with moderate to high disease activity were enrolled to receive add-on etanercept (25 mg subcutaneous injection, biweekly) for at least one year, combined with sustained treatment with conventional synthetic disease-modifying anti-rheumatic drugs (csDMARDs).ResultsForty patients received add-on etanercept and 15 received DMARDs alone. At the end of one year, etanercept significantly reduced the disease activity score of 28 joints, C-reactive protein, and erythrocyte sedimentation rate. Moreover, etanercept significantly increased the body weight, body mass index (BMI), as well as MCP-1 and NT levels, compared to that in the csDMARD-only group.ConclusionsIncreased serum MCP-1 and NT levels in RA patients with moderate to high disease activity, who underwent one-year etanercept treatment, might be attributed to increase in body weight and BMI rather than induction of more severe autoimmune inflammation.     

Attenuation of pain perception after transposition of the greater omentum to the cauda equina region of rats—a preliminary observation

Abstract

Background: This paper addresses a specific experimental design to suggest the possible role of the greater omentum in the modulation of pain in rats.

Methods: Fifteen male Sprague–Dawley rats weighing between 275 and 325 g were selected. The animals were randomized and then anesthetized with pentobarbital (35 mg/kg) and divided into three groups: (1) sham: laparotomy followed by laminectomy with exposure of the spinal epidural space (n=5); (2) transposition of pedicled omentum (n=5) to the cauda equina epidural space; and (3) transposition of pedicled omentum (n=5) to the cauda equina intradural space. The animals were operated upon and once more randomized by an independent investigator, so that the groups were thought to be similar during post-operative testing. The latency of paw withdrawal to noxious heat stimulation was tested and the values (seconds) plotted for 1, 3, 6, 11, 14 and 30 days after surgery. Randomization codes were open after the animals were euthanized. The analysis of variance (ANOVA) without replication was applied for each of the dataset and comparisons established among the different study groups involved. The omenta were removed and standard immunohistochemistry was performed for gamma-amino-butyric acid (GABA), serotonin, calcitonin-gene related protein (CGRP), vascular intestinal peptide (VIP) and Met-enkephalin.

Results: The response to high heating rates of stimulation favored intradural versus sham and epidural omental transpositions. High and low noxious heat stimulation suggested an increased threshold to noxious stimulation after the 3 and 30 days of omental transposition. In the low heat stimulation series, responses were comparatively higher than in the sham animals.

Conclusions: The suggested increased threshold of response to noxious stimulation after transposition of the greater omentum onto the spinal cord of rats suggested a novel role of the omentum and a potential future application in the clinical arena.     

Vitamin D deficiency in type 1 narcolepsy: a reappraisal

ObjectivesNarcolepsy type 1 (NT1) is considered to be an immune-mediated disease in which environmental factors, such as vitamin D, might play a major role. The association between NT1 and vitamin D deficiency has previously been reported. The aim of this case–control study was to reassess vitamin D levels in a large clinic-based adult and paediatric population of patients with NT1 by considering several potential confounding factors.MethodsThe serum level of 25-hydroxyvitamin D (25OHD) was measured in 174 Caucasian patients with NT1 and 174 controls. Demographic and clinical features, body mass index (BMI), Pandemrix® vaccination, age, and season at the time of blood sampling were recorded. Between-group comparisons were made using univariate and multivariate logistic regression analyses. When appropriate, interaction terms were tested using the Wald Chi-squared test.ResultsAge, BMI, and season of blood sampling were different between groups. Conversely, the 25OHD level and fraction of subjects with vitamin D deficiency (serum level <75 nmol/L: 46.6% of patients vs 48.3% of controls; <50 nmol/L: 20.7% vs 17.2%) did not differ between patients with NT1 and controls. Overall, vitamin D deficiency was more frequent in men, obese subjects, and in samples collected in winter, without any association with NT1. In the patients group, no significant association was found between vitamin D deficiency, NT1 duration and severity, treatment, and Pandemrix® vaccination.ConclusionsVitamin D levels were not associated with NT1 in a large case–control population when potential demographic and clinical confounding factors were taken into account.     

Exploring the association between depression,suicidality and serum neurotrophin levels in adolescents

Abstract

Objective: The aim of this study was to identify potential differences in serum brain-derived neurotrophic factor (BDNF), glial-derived neurotrophic factor (GDNF), nerve growth factor (NGF) and neurotrophin-3 (NTF3) levels in adolescents with major depressive disorder (MDD) compared to healthy controls. The possible relationship between serum neurotrophin levels and suicidality in adolescents with MDD was also addressed.

Methods: A total of 70 treatment-free adolescents with MDD and 40 healthy controls aged 11 to 19?years were enrolled. The severity of suicidality was determined using the Columbia-Suicide Severity Rating Scale, and the severity of depression and anxiety symptoms were evaluated by self-report inventories. Serum levels of neurotrophins were measured using an enzyme-linked immunosorbent assay.

Results: The mean serum BDNF levels were significantly higher in adolescents with MDD than in control subjects; no significant difference was found between the groups for serum GDNF, NGF and NTF3 levels. No correlations were found between the levels of serum neurotrophins and the severity of depression or suicidality.

Conclusions: The study results suggest that elevated serum BDNF levels may be related to MDD in adolescents. However, our findings did not support a role for neurotrophins in suicidality.

• Key points

• Serum BDNF levels were higher in adolescents with MDD than in controls.

• No significant alterations of serum levels of GDNF, NGF and NTF3 were evident in adolescents with MDD.

• Neurotrophin levels were not associated with suicidal ideation and behaviours.

     

The evolution of omentum transposition: from lymphedema to spinal cord,stroke and Alzheimer's disease

Abstract

It is now well established that the omentum incorporates into its tissues a variety of biological factors that exert a favorable effect on the central nervous system. Physiological characteristics of the omentum include edema absorption, fibrotic inhibition, blood–brain barrier penetration and, of major importance, angiogenic activity. Over several decades, studies have shown increasing clinical uses of the omentum following its placement on various structures within the body. This paper details the evolution of omental transposition (OT) up to the present at which time OT is being applied to the brain of Alzheimer disease (AD) patients. Success in this area raises the possibility that the omentum may prove to be a present-day treatment for patients with AD until future pharmaceutical and/or genetic forms of treatment are developed.     

Effects of exercise and muscle type on BDNF,NT‐4/5, and TrKB expression in skeletal muscle

Muscle‐derived neurotrophins are thought to contribute to the adaptation of skeletal muscle to exercise, but the effects of brief exercise interventions on BDNF, NT‐4/5, and trkB are not understood. RNA was extracted for RT‐PCR from soleus and medial gastrocnemius of Sprague‐Dawley rats exercised on a treadmill at speeds up to 20 m/min at 5% incline for 5 or 10 days. BDNF expression was elevated in soleus following 5 days (184%, P < 0.001) but not 10 days of exercise. NT‐4/5 and trkB were not affected at either time‐point. BDNF mRNA was significantly higher in soleus at rest when compared with medial gastrocnemius (193%, P < 0.05). No significant effects of muscle type were detected for NT‐4/5 and trkB. Our results indicate differential control of BDNF expression between soleus and medial gastrocnemius following 5 days of exercise. BDNF may be a protein with an uncharacterized contribution to the acute adaptation of skeletal muscle to exercise, whereas NT‐4/5 shows no response. Muscle Nerve, 2009     

Expression of neurotrophins in the adult spinal cord in vivo

Potential roles of trophins in the normal and injured spinal cord are largely undefined. However, a number of recent studies suggest that adult spinal cord expresses neurotrophin receptors and responds to the neurotrophins, brain-derived neurotrophic factor (BDNF) and neurotrophin 3 (NT3), particularly after injury. The data indicate that trophins may enhance regrowth after damage and may represent a new therapeutic approach to injury. Neurotrophins are reportedly present in the spinal cord, but the cellular localization is unknown. This information is critical to begin delineating mechanisms of actions. To approach this problem, we examined whether spinal cord glia express BDNF and NT3 in vivo and have begun to define cellular distribution. Specific antibodies directed against the neurotrophins were utilized to visualize neurotrophin protein. Initial studies indicated that small cells in the white matter of adult rat spinal cord express BDNF and NT3. Large neurotrophin-positive neurons were also identified in the ventral cord. To identify the neurotrophin-positive cells, co-localization studies were performed utilizing neurotrophin polyclonal antisera together with monoclonal antibodies directed against the astrocyte marker, glial fibrillary acidic protein (GFAP). In the white matter of adult spinal cord, GFAP-positive and GFAP-negative cells expressed BDNF and NT3. Our study suggests that astrocyte and non-astrocyte cells provide trophic support to the adult spinal cord.     

Narrative Therapy vs. Cognitive-Behavioral Therapy for moderate depression: Empirical evidence from a controlled clinical trial

Abstract

Background: Systematic studies of the efficacy of Narrative Therapy (NT) for depression are sparse. Objective: To evaluate the efficacy of individual NT for moderate depression in adults compared to Cognitive-Behavioral Therapy (CBT). Method: Sixty-three depressed clients were assigned to either NT or CBT. The Beck Depression Inventory-II (BDI-II) and Outcome Questionnaire-45.2 (OQ-45.2) were used as outcome measures. Results: We found a significant symptomatic reduction in both treatments. Group differences favoring CBT were found on the BDI-II, but not on the OQ-45.2. Conclusions: Pre- to post-treatment effect sizes for completers in both groups were superior to benchmarked waiting-list control groups.     

Distinct populations of hypothalamic dopaminergic neurons exhibit differential responses to brain-derived neurotrophic factor (BDNF) and neurotrophin-3 (NT3)

We have previously demonstrated that differentiation of hypothalamic dopaminergic (DA) neurons can be induced in culture by their pituitary intermediate lobe target cells, through both membrane and diffusible factors. We also showed that subpopulations of DA neurons from the arcuate nucleus only, not the periventricular area, can respond to the target. Here we investigated the possibility that both neuronal subsets could also respond differentially to brain-derived neurotrophic factor (BDNF) or neurotrophin-3 (NT3). Addition of NT3, but not BDNF, enhanced growth and branching of neurites, tyrosine hydroxylase (TH) as well as increasing levels of cultured arcuate DA neurons. Conversely, BDNF, but not NT3, affected the same parameters in cultured periventricular DA neurons. The neurotrophins thus affect DA neurons in a structure and neuronal type-selective manner, since general neuronal markers were not affected by either neurotrophin. Neurotrophin effects were reversed by addition of specific antibodies directed against them or their respective receptors, TrkB or TrkC. By themselves, the antibodies inhibited development of DA neurons below that of control cultures, suggesting involvement of endogenous neurotrophins. BDNF and NT3 were indeed found in both arcuate and periventricular neurons and in the intermediate lobe. BDNF was always present as the mature peptide. The mature form of NT3 was only detected in the periventricular area; a precursor-like heavier form was present in all tissues studied. The present data suggest that NT3, but not BDNF, could participate in the differentiating action of intermediate lobe cells on arcuate DA neurons.     

Long-term survival of autologous adrenal medulla grafts in the great omentum of the rat

Abstract

The omentum, a rich source for trophic and angiogenic factors, was explored as a potential intermediate transplant site to facilitate long-term survival of chromaffin tissue. Autologous rat adrenal medullas were grafted into omental pockets. All grafts became densely vascularized. The grafted chromaffin tissue exhibited strong immunoreactivities for tyrosine hydroxylase, synaptophysin and chromogranin A throughout the observation period of 16 weeks. The expression of these markers implies that grafted chromaffin cells retained the key enzyme for catecholamine biosynthesis and the organelles required for catecholamine secretion. Moreover, intermediate transplant of chromaffin tissue to the omentum could provide a favourable conditioning microenvironment thus augmenting the potential for survival of functional chromaffin tissue. [Neurol Res 1993; 15: 269-272]