The potential role of serotonergic mechanisms in the spinal oxytocin-induced antinociception

The role of oxytocin (OXT) in pain modulation has been suggested. Indeed, hypothalamic paraventricular nuclei (PVN) electrical stimuli reduce the nociceptive neuronal activity (i.e., neuronal discharge associated with activation of Aδ- and C-fibers) of the spinal dorsal horn wide dynamic range (WDR) cells and nociceptive behavior. Furthermore, raphe magnus nuclei lesion reduces the PVN-induced antinociception, suggesting a functional interaction between the OXT and the serotoninergic system. The present study investigated in Wistar rats the potential role of spinal serotonergic mechanisms in the OXT- and PVN-induced antinociception. In long-term secondary mechanical allodynia and hyperalgesia induced by formalin or extracellular unitary recordings of the WDR cells we evaluated the role of 5-hydroxytryptamine (5-HT) effect on the OXT-induced antinociception. All drugs were given intrathecally (i.t.). OXT (1 × 10^− 5–1 × 10^− 4 nmol) or 5-HT (1 × 10^− 3–1 × 10^− 1 nmol) prevented the formalin-induced sensitization, an effect mimicked by PVN stimulation. Moreover, administration of OXT (1 × 10^− 5 nmol) plus 5-HT (1 × 10^− 3 nmol) at ineffective doses, produced antinociception. This effect was antagonized by: (i) d(CH₂)₅[Tyr(Me)²,Thr⁴,Tyr-NH₂⁹]OVT (oxytocin receptor antagonist; 2 × 10^− 2 nmol); or (ii) methiothepin (a non-specific 5-HT_1/2/5/6/7 receptor antagonist; 80 nmol). Similar results were obtained with PVN stimulation plus 5-HT (5 × 10^− 5 nmol). In WDR cell recordings, the PVN-induced antinociception was enhanced by i.t. 5-HT and partly blocked when the spinal cord was pre-treated with methiothepin (80 nmol). Taken together, these results suggest that serotonergic mechanisms at the spinal cord level are partly involved in the OXT-induced antinociception.     

Acute sleep deprivation in healthy young men: Impact on population diversity and function of circulating neutrophils

Lack of sleep greatly affects our immune system. The present study investigates the acute effects of total sleep deprivation on blood neutrophils, the most abundant immune cell in our circulation and the first cell type recruited to sites of infection. Thus, the population diversity and function of circulating neutrophils were compared in healthy young men following one night of total sleep deprivation (TSD) or after 8 h regular sleep. We found that neutrophil counts were elevated after nocturnal wakefulness (2.0 ± 0.2 × 10⁹/l vs. 2.6 ± 0.2 × 10⁹/l, sleep vs. TSD, respectively) and the population contained more immature CD16^dim/CD62L^bright cells (0.11 ± 0.040 × 10⁹/l [5.5 ± 1.1%] vs. 0.26 ± 0.020 × 10⁹/l [9.9 ± 1.4%]). As the rise in numbers of circulating mature CD16^bright/CD62L^bright neutrophils was less pronounced, the fraction of this subpopulation showed a significant decrease (1.8 ± 0.15 × 10⁹/l [88 ± 1.8%] vs. 2.1 ± 0.12 × 10⁹/l [82 ± 2.8%]). The surface expression of receptors regulating mobilization of neutrophils from bone marrow was decreased (CXCR4 and CD49d on immature neutrophils; CXCR2 on mature neutrophils). The receptor CXCR2 is also involved in the production of reactive oxygen species (ROS), and in line with this, total neutrophils produced less ROS. In addition, following sleep loss, circulating neutrophils exhibited enhanced surface levels of CD11b, which indicates enhanced granular fusion and concomitant protein translocation to the membrane. Our findings demonstrate that sleep loss exerts significant effects on population diversity and function of circulating neutrophils in healthy men. To which extent these changes could explain as to why people with poor sleep patterns are more susceptible to infections warrants further investigation.     

Abnormal glucose tolerance,white blood cell count,and telomere length in newly diagnosed,antidepressant-naïve patients with depression

Chronic mood disorders have been associated with a shortened telomere, a marker of increased mortality rate and aging, and impaired cellular immunity. However, treatment may confound these relationships. We examined the relationship of glucose tolerance, white blood cell count and telomere length to depression in newly diagnosed, antidepressant-naïve patients. Subjects with major depression (n = 15), and matched healthy control subjects (n = 70) underwent a two-hour oral glucose tolerance test and evaluation of blood cell count and telomere content. The depression group had significantly higher two-hour glucose concentrations and a lower lymphocyte count than control subjects (respective means [SD] for two-hour glucose were 125.0 mg/dL [67.9] vs 84.6 [25.6] (p < .001); for lymphocyte count 2.1 × 10⁹/L [0.6] vs 2.5 × 10⁹/L [0.7] p = .028). Telomere content was significantly shortened in the depression group (87.9 [7.6]) compared to control subjects (101.0 [14.3]; p < 0.01). Abnormal glucose tolerance, lymphopenia and a shortened telomere are present early in the course of depression independently of the confounding effect of antidepressant treatment, supporting the concept of major depression as an accelerated aging disease.     

Interaction of calcitonin gene related peptide (CGRP) and substance P (SP) in human skin

Calcitonin gene related peptide (CGRP) and substance P (SP) are neuropeptides that are simultaneously released from nociceptive C-fibers. CGRP is a potent vasodilator, inducing a long-lasting increase in superficial skin blood flow, whereas SP induces only a brief vasodilation but a significant plasma extravasation. CGRP and SP may play important roles in the pathophysiology of various pain states but little is known about their interaction.Different concentrations of SP (ranging from 10^− 5 M to 10^− 9 M) were applied to the volar forearm of 24 healthy subjects via dermal microdialysis. SP was applied either alone or in combination with CGRP10^− 9 M and CGRP 10^− 6 M.As expected, SP induced a transient increase in skin blood flow that decayed shortly after application. This transient blood flow peak was blunted with co-application of CGRP 10^− 9 M and inhibited with co-application of CGRP10^− 6 M. SP alone induced plasma protein extravasation (PPE). However, when CGRP10^− 6 M was added, the PPE significantly increased.Our results demonstrate a complex interaction of the neuropeptides CGRP and SP. CGRP10^− 6 M prevented SP-induced early vasodilation but augmented SP-induced PPE. These interactions might explain why vascular symptoms in chronic pain can differ strikingly between individuals.     

Cortical and subcortical connections within the pedunculopontine nucleus of the primate Macaca mulatta determined using probabilistic diffusion tractography

The anatomical connections of the pedunculopontine nucleus (PPN), a brainstem structure associated with locomotion, have been determined recently in healthy humans using probabilistic diffusion tractography (PDT). In order to compare these with histologically demonstrated connections of the PPN in monkeys, and thus to support the use of PDT in humans, we have carried out PDT in a fixed rhesus monkey (Macaca mulatta) brain.Probabilistic diffusion tractography was carried out in a fixed post-mortem rhesus monkey brain using diffusion data acquired at 3T MRI (60 directions × 5 averages, b = 3000 s/mm², matrix size = 104 × 132 × 96, 720 × 720 × 720 μm voxels). We identified the major connections of the PPN from single seed voxels that could be confidently located within the nucleus on the diffusion images. The organisation of these connections within a 3 × 3 × 3 voxel (～10 mm³) region surrounding the initial seed voxel was then examined.PDT confirmed that the rhesus monkey PPN connections with the basal ganglia and motor cortical areas matched those previously demonstrated using conventional anatomical tracing techniques. Furthermore, although the organisation of subcortical connections within the PPN has not been extensively demonstrated in animals, we show here in a rhesus monkey that there are clearly separated connections of the PPN with the thalamus, substantia nigra, and subthalamic nucleus. Thus, in addition to increasing confidence in the accuracy of PDT for tracing PPN connections and determining the organisation of these connections within the PPN in vivo, our observations suggest that diffusion tractography will be a useful new technique to rapidly identify connections in animal brains pre-mortem and post-mortem.     

Stroke in essential thrombocythemia

BackgroundOur aim was to assess the incidence and the special characteristics of stroke, as a severe complication of patients diagnosed with essential thrombocythemia (ET).MethodsA retrospective analysis was carried out on 102 patients with ET enrolled and analyzed from the period between 1999 and 2012. Patients with one or more strokes were selected. The characteristics of stroke events, the medication, and the median platelet counts were revised.ResultsOne or more stroke events were revealed in 11 cases (4 males and 7 females) with a median age of 67 years [range: 45–82 years]. The median platelet count at hematological diagnosis was 658 × 10⁹/L [range: 514–1157 × 10⁹/L], while during the time of stroke it was 450 × 10⁹/L [range: 320–885 × 10⁹/L]. The median follow-up of the patients with stroke was 60 months [range: 19–127 months]. At the time of the stroke, almost all the patients (8/11 cases, 73%) were already on anti-platelet therapy, alone or in combination with cytoreductive therapy (e.g. hydroxyurea). Brain imaging modalities in most cases demonstrated periventricular and/or subcortical and/or basal ganglia lacunes or confluent chronic white matter ischemic lesions in all cerebral arterial regions. Most patients (9/11; 82%) presented at least two serious conventional vascular risk factors, which may have influenced both the clinical course and the morphologic alterations. No correlation was found between the platelet count and the occurrence of stroke.ConclusionOur findings lead us to suppose that ET may be regarded as a risk factor for stroke (mainly of ischemic, small-vessel type), and the early diagnosis and the personalized management of the patient's global vascular risk in the treatment of ET may promote the prevention of further cerebrovascular events.     

Transduction efficiency of AAV 2/6, 2/8 and 2/9 vectors for delivering genes in human corneal fibroblasts

In the present study, cellular tropism and relative transduction efficiency of AAV2/6, AAV2/8 and AAV2/9 vectors have been tested for the cornea using primary cultures of human corneal fibroblasts. The AAV6, AAV8 and AAV9 serotypes having AAV2 ITR plasmid encoding for alkaline phosphatase (AP) gene were generated by transfecting HEK293 cell line with pHelper, pARAP4 and pRep/Cap plasmids. Primary cultures of human corneal fibroblasts were exposed to AAV infectious particles at two different doses (1 × 10⁵ and 2 × 10⁵ MOI). Cytochemistry and enzyme assays were used to measure delivered transgene expression in samples collected at 4 and 30 h after AAV infection by counting AP-stained cells or quantifying AP enzyme activity. Cellular toxicity of AAVs was evaluated with TUNEL and trypan blue assays. All three AAV serotypes transduced human corneal fibroblasts. The order of transduction efficiency was AAV2/6 ? AAV2/9 > AAV2/8. The transduction efficiency of AAV2/6 was 30–50-fold higher (p < 0.001) for the human corneal fibroblasts compared to the AAV2/8 or AAV2/9 at two tested doses. The level of transgene expression at 4 h was considerably low compared to 30 h suggesting that the transgene delivery did not reach its peak at 4 h. Cultures exposed to any of the three AAV serotypes showed more than 97% cellular viability and less than 5 TUNEL positive cells suggesting that tested AAV serotypes do not induce significant cell death and are safe for corneal gene therapy.     

Gaze patterns during scene processing in typical adults and adults with autism spectrum disorders

BackgroundLittle is known about how adults with autism spectrum disorder (ASD) process dynamic social scenes.MethodWe studied gaze behavior in 16 adults with ASD without intellectual impairment and 16 sex- and age-matched controls during passive scene processing.ResultsAdding more characters to a scene resulted in a drop in time spent looking at faces, and an increase in time spent looking at bodies (static trials) or off-person (dynamic trials) [Scene Type × AOI × Mode: F(2, 60) = 3.54, p = .04, η²_p = .11]. Unlike controls, adults with ASD showed only a small drop in the number of fixations made [Mode × Group: F(1, 30) = 11.30, p = .002, η²_p = .27] and no increase in the duration of face fixations [Mode × AOI × Group: F(2, 60) = 3.50, p = .04, η²_p = .11] when dynamic cues were added. Thus, particularly during dynamic trials, adults with ASD spent less time looking at faces and slightly more time looking off-person than did controls [Mode × AOI × Group: F(2, 60) = 3.10 p = .05, η²_p = .09]. Exhibiting more autistic traits and being less empathic were both associated with spending less time fixating on faces [.34 < |r| < .55, p < .05].ConclusionsThese results suggest that adults with ASD may be less sensitive to, or have more difficulty processing, dynamic cues—particularly those conveyed in faces. The findings demonstrate the importance of using dynamic displays in studies involving this clinical population.     

Predictors for changes in various developmental outcomes of children with cerebral palsy—A longitudinal study

We aimed to identify predictors for the changes of various developmental outcomes in preschool children with cerebral palsy (CP). Participants were 78 children (49 boys, 29 girls) with CP (mean age: 3 years, 8 months; SD: 1 year, 7 months; range: 1 year to 5 years, 6 months). We examined eight potential predictors: age, sex, CP subtype, Gross Motor Function Classification System (GMFCS) level, selective motor control, Modified Ashworth Scale, and the spinal alignment (SA) and range of motion subscales of the Spinal Alignment and Range of Motion Measure (SAROMM). Developmental outcomes for cognition, language, self-help, and social and motor functions were measured at baseline and a 6-month follow-up with the Comprehensive Developmental Inventory for Infants and Toddlers. Regression model showed GMFCS level was a negative predictor for change of language (adjusted r² = 0.30, p < .001), motor function (adjusted r² = 0.26, p < .001), social function (adjusted r² = 0.07, p = 0.014), and self-help (adjusted r² = 0.26, p < .001). Age was a negative predictor for change of cognition (adjusted r² = 0.21, p < .001) and language functions (adjusted r² = 0.26, p < .001). SAROMM-SA was a negative predictor for cognitive change (adjusted r² = 0.30, p < .001). The GMFCS levels and age are robust negative predictors for change of most developmental domains in these children.     

Toward clinical application of manganese-enhanced MRI of retinal function

PurposeThe application of manganese-enhanced MRI (MEMRI) to measure retinal function in humans is unclear. To begin to address this gap, we tested the hypothesis that an FDA-approved manganese-based MRI contrast agent, Teslascan, is useful for measuring functional intraretinal ionic regulation.MethodsAnesthetized dark- or light-adapted male healthy Sprague–Dawley rats were infused for 30 min with 10 μmol/kg of Teslascan (clinically relevant dose; n = 5), 100 μmol/kg Teslascan (n = 5), or saline (n = 5). Four hours post-administration, high resolution MEMRI data were collected. Intraretinal signal intensities and enhancements were measured. Modelling was performed to estimate apparent retinal transfer constant K_i and to determine optimal data acquisition parameters.ResultsIn light-adapted rats, intraretinal enhancements responded in a dose–response manner. In addition, in the outer retina the effect of light-adaptation was to reduce significantly Mn²⁺ uptake and K_i compared to dark-adaptation. A non-significant change was also observed in the inner retina. Modelling shows Mn²⁺ plasma concentration reaching a plateau after about 2 h. Apparent K_i values for the clinically relevant dose are 3–6 × 10^?3 min^?1, decreasing to 0.5–0.6 × 10^?3 min^?1 at the higher dose. Intraretinal signal is almost linear with K_i. Optimal TR for a spin-echo sequence is 0.4–1.4 s.ConclusionFirst time evidence is presented that a clinically relevant dose and route of Teslascan can be used to measure intraretinal function. The potential for future clinical application of MEMRI in a broad range of retinopathies is high.     

Effect of new neuronal growth factor on healing of sciatic nerve in rats

ObjectiveThe study aimed to investigate the effect of a new peptide new nerve growth factor (NNGF) on the healing of divided sciatic nerves in rats.Material and methodsTwenty Sprague–Dawley rats of 250–300 g were divided into two groups (group 1 — study group and group 2 — control group). Under ketamine intramuscular anesthesia sciatic nerves were exposed, divided and repaired using 10/0 dexon. Study animals had 10 mg/kg body weight of NNGF added to the repair. Electromyographic studies of the hind libs were carried out after 8 weeks. The average stimulation was 50 mA for 200 μS and four twitches (T) were recorded. The animals were euthanized and the sciatic nerves were removed for histological analysis.ResultsThere were no deaths in either of the groups. Electromyographic study showed that in the control group the average T1–T4 was 0.587 ± 0.17% and in the study group the average was 87.89 ± 5.02% (p value of 0.001). Histologically the control group showed regenerated axons sprouting from the proximal segment of cut nerve with empty endoneurial channels, while in the study group whole nerve trunks were seen within endoneurial channels.ConclusionThis study shows that the NNGF has a positive influence on the experimental healing of sciatic nerves in animals.     

How disabling are pediatric burns? Functional independence in Dutch pediatric patients with burns

Although the attention for functional outcomes after burn injury has grown over the past decades, little is known about functional independence in performing activities of daily living in children after burn injury. Therefore, in this prospective cohort study functional independence was measured by burn care professionals with the WeeFIM^® instrument in 119 pediatric patients with burns (age: 6 months–16 years; 58.8% boys) in the Netherlands. In order to identify whether functional independence was affected, participants’ total scores on the WeeFIM^® instrument were compared to American norm values. Of the participants assessed at 2 weeks post burn (n = 117), 3 months post burn (n = 68) and/or 6 months post burn (n = 38), 22, 9 and 9 participants showed affected performance, respectively. Improvements in WeeFIM^® total scores for the total study population between 2 weeks and 6 months post burn were significant (Wilcoxon T = 2.5; p < .001, effect size = ?0.59). Individual improvements were found to be significant for 30.3% of the assessed participants between 2 weeks and 3 months post burn, and for 12.1% between 3 and 6 months post burn. This study is unique in providing data on functional independence for this large and special population. However, a proportion of participants were lost to follow-up and the use of the WeeFIM^® instrument in this specific population and setting has its limitations. To conclude, burn injury impacts functional independence in children, yet the vast majority of Dutch pediatric patients with burns returns to functional independence typical for age within 6 months post burn.     

Grading meningiomas utilizing multiparametric MRI with inclusion of susceptibility weighted imaging and quantitative susceptibility mapping

Background and purposeThe ability to predict high-grade meningioma preoperatively is important for clinical surgical planning. The purpose of this study is to evaluate the performance of comprehensive multiparametric MRI, including susceptibility weighted imaging (SWI) and quantitative susceptibility mapping (QSM) in predicting high-grade meningioma both qualitatively and quantitatively.MethodsNinety-two low-grade and 37 higher grade meningiomas in 129 patients were included in this study. Morphological characteristics, quantitative histogram analysis of QSM and ADC images, and tumor size were evaluated to predict high-grade meningioma using univariate and multivariate analyses. Receiver operating characteristic (ROC) analyses were performed on the morphological characteristics. Associations between Ki-67 proliferative index (PI) and quantitative parameters were calculated using Pearson correlation analyses.ResultsFor predicting high-grade meningiomas, the best predictive model in multivariate logistic regression analyses included calcification (β = 0.874, P = 0.110), peritumoral edema (β = 0.554, P = 0.042), tumor border (β = 0.862, P = 0.024), tumor location (β = 0.545, P = 0.039) for morphological characteristics, and tumor size (β = 4 × 10⁻⁵, P = 0.004), QSM kurtosis (β = − 5 × 10⁻³, P = 0.058), QSM entropy (β = − 0.067, P = 0.054), maximum ADC (β = − 1.6 × 10⁻³, P = 0.003), ADC kurtosis (β = − 0.013, P = 0.014) for quantitative characteristics. ROC analyses on morphological characteristics resulted in an area under the curve (AUC) of 0.71 (0.61–0.81) for a combination of them. There were significant correlations between Ki-67 PI and mean ADC (r = − 0.277, P = 0.031), 25^th percentile of ADC (r = − 0.275, P = 0.032), and 50^th percentile of ADC (r = − 0.268, P = 0.037).ConclusionsAlthough SWI and QSM did not improve differentiation between low and high-grade meningiomas, combining morphological characteristics and quantitative metrics can help predict high-grade meningioma.     

L’effet modérateur de la pleine conscience dispositionnelle dans la relation entre symptomatologie dépressive,troubles de la personnalité limite et idéations suicidaires chez le jeune adulte

ObjectivesThe aim of the study was to evaluate the influence of dispositional mindfulness on suicidal ideation and its moderating effect on the relationships between depressive symptoms and borderline personality traits, and suicidal ideation.MethodsA sample of 1034 students from France (818 women, mean age = 20.1 ± 2; 216 men, mean age = 20.6 ± 2.2) completed the Five Facets Mindfulness Questionnaire-Short Form (FFMQ-SF), assessing dispositional mindfulness, the Patient Health Questionnaire-9 (PHQ-9) assessing depression symptoms; the borderline personality disorder scale of the Personality Disorder Questionnaire-4th Edition (PDQ-4), and the three-item scale measuring suicidal ideation proposed by Garrison et al. (1991).ResultsAt least occasional wish to kill oneself was reported by 11% of men and 10% of women. Thirty-eight percent of men and 47% of women had moderate to severe depressive symptoms (P < .001). The mean borderline personality traits score for women was higher than for men (33.44 ± 10.56 versus 31.48 ± 10.35; P = .02), and the mean dispositional mindfulness score for men was higher than for women (77.99 ± 12.3 versus 73.4 ± 12.1; P < .001). In order to explore the role of mindfulness as a moderator between depressive symptoms/borderline traits and the wish to kill oneself, multiple regression analyses were performed separately by gender according to the method of Hayes (2013). To assess whether the presence of dispositional mindfulness decreased the risk for persons with depressive symptoms/borderline personality traits to have suicidal ideation, the effect of the interaction between these disorders and dispositional mindfulness was tested by introducing in a second regression the cross product of these two variables. To assert moderation we had to observe that the interaction explained an additional part of the variance of suicidal ideation. For men, in the first multiple regression analysis, the FFMQ-SF score and PHQ-9 score both explained 32% of the variance of suicidal ideation (R² = .32, s.e. = 1.42). In the second analysis, the prediction level of depressive symptoms and dispositional mindfulness scores had decreased. The interaction between dispositional mindfulness and depressive symptoms was a significant predictor in the second stage (β = −.26; t = −4.48, P < .001), accounting for an additional 6% of the variance of suicidal ideation (R² = .38, s.e. = 1.36). For women, in the first multiple regression analysis, the FFMQ-SF score and PHQ-9 score both explained 25% of the variance of suicidal ideation (R² = .25, s.e. = 1.29). In the second analysis, the prediction level of depressive symptoms and dispositional mindfulness scores had slightly decreased. The interaction between dispositional mindfulness and depressive symptoms was a significant predictor in the second stage (β = −.16; t = −5.34, P < .001), accounting for an additional 3% of the variance of suicidal ideation (R² = .28, s.e. = 1.26). For men, in the first multiple regression analysis, the FFMQ-SF score and PDQ-4 subscale score both explained 23% of the variance of suicidal ideation (R² = .23, s.e. = 1.51). In the second analysis, the prediction level of borderline personality traits and dispositional mindfulness scores had decreased. The interaction between dispositional mindfulness and borderline personality traits was a significant predictor in the second stage (β = −.27; t = −4.68, P < .001), accounting for an additional 7% of the variance of suicidal ideation (R² = .30, s.e. = 1.44). For women, in the first multiple regression analysis, the FFMQ-SF score and PDQ-4 subscale score both explained 24% of the variance of suicidal ideation (R² = .24, s.e. = 1.30). In the second analysis, the prediction level of borderline personality traits and dispositional mindfulness scores remained the same. The interaction between dispositional mindfulness and borderline personality traits was a significant predictor in the second stage (β = −.19; t = −6.30, P < .001) accounting for an additional 3% of the variance of suicidal ideation (R² = .27, s.e. = 1.27).ConclusionsDispositional mindfulness appeared to be a moderator between depressive symptoms/borderline personality traits and the wish to kill oneself in both genders. This finding is relevant for prevention and therapy and suggests that mindfulness may be important and useful to reduce suicidal ideation and prevent suicidal attempts in young adults.     

Multifocal frequency-doubling pattern visual evoked responses to dichoptic stimulation

ObjectiveTo examine the feasibility of a multifocal visual evoked potential (mfVEP) binocularly, using a variant of the multifocal frequency-doubling (FD) pattern-electroretinogram (MFP).MethodsStimuli were presented in both monocular and dichoptic conditions at eight visual field locations/eye. The incommensurate stimulus frequencies ranged from 15.45 to 21.51 Hz. Five stimulus conditions differing in spatial frequency and orientation were examined for three viewing conditions. The resulting 15 stimulus conditions were examined in 16 normal subjects who repeated all conditions twice.ResultsSeveral significant independent effects were identified. Response amplitudes were reduced for dichoptic viewing (by 0.85 times, p < 4 × 10⁻¹¹); offset by increases in responses for between eye differences of one octave of spatial frequency: lower (1.15 times, 0.1 cpd); higher (1.29 times, 0.4 cpd), both p < 1.8 × 10⁻⁷. Crossed orientations produced significant effects upon response phase (p = 0.023) but not amplitude (p = 0.062).ConclusionsThe results indicated that dichoptic evoked potentials using multifocal frequency-doubling illusion stimuli are practical. The use of crossed orientation, or differing spatial frequencies, in the two eyes reduced binocular interactions.SignificanceThe results indicate a method wherein several spatial or temporal and frequencies per visual field region can be tested in reasonable time using a multifocal VEP using spatial frequency-doubling stimuli.     

Astrocytes derived from fetal neural progenitor cells as a novel source for therapeutic adenosine delivery

PurposeIntracerebral delivery of anti-epileptic compounds represents a novel strategy for the treatment of refractory epilepsy. Adenosine is a possible candidate for local delivery based on its proven anti-epileptic effects. Neural stem cells constitute an ideal cell source for intracerebral transplantation and long-term drug delivery. In order to develop a cell-based system for the long-term delivery of adenosine, we isolated neural progenitor cells from adenosine kinase deficient mice (Adk^?/?) and compared their differentiation potential and adenosine release properties with corresponding wild-type cells.MethodsFetal neural progenitor cells were isolated from the brains of Adk^?/? and C57BL/6 mice fetuses and expanded in vitro. Before and after neural differentiation, supernatants were collected and assayed for adenosine release using liquid chromatography–tandem mass spectrometry (LC–MS/MS).ResultsAdk^?/? cells secreted significantly more adenosine compared to wild-type cells at any time point of differentiation. Undifferentiated Adk^?/? cells secreted 137 ± 5 ng adenosine per 10⁵ cells during 24 h in culture, compared to 11 ± 1 ng released from corresponding wild-type cells. Adenosine release was maintained after differentiation as differentiated Adk^?/? cells continued to release significantly more adenosine per 24 h (47 ± 1 ng per 10⁵ cells) compared to wild-type cells (3 ± 0.2 ng per 10⁵ cells).ConclusionsFetal neural progenitor cells isolated from Adk^?/? mice – but not those from C57BL/6 mice – release amounts of adenosine considered to be of therapeutic relevance.     

Chronic valproate or levetiracetam treatment does not influence cytokine levels in humans

PurposeThere is growing evidence that complex interactions between seizures and the immune system shape the course of epilepsy. However, systematic analyses of the effects of antiepileptic drugs (AED) on the immune system in humans are rare. We performed a prospective study on the influence of the widely used AED valproate and levetiracetam on interictal immunological parameters.Methods36 patients were prospectively included. 15 were started on valproate (5 female (33%), age 54 ± 27 years, 12 (80%) on monotherapy), 21 on levetiracetam (10 female (48%), age 45 ± 19 years, 17 (81%) on monotherapy). Before treatment and after 3 months, we performed a differential blood count and analyzed the distribution of CD3⁺CD4⁺-, CD3⁺CD8⁺- and CD4⁺CD25⁺-leukocyte subsets using flow cytometry. In addition, we determined the concentrations of IL-1β, IL-6, TNF-α and MCP-1 in the peripheral blood using ELISAs.ResultsValproate intake resulted in a significant decrease of the total white blood count (6.96 ± 1.23/nl vs. 6.13 ± 1.57/nl, p = 0.026) and of absolute count and percentage of neutrophils (4.60 ± 1.05/nl vs. 3.69 ± 1.30/nl, p = 0.01; 65.4 ± 7.9% vs. 59.5 ± 11.5%, p = 0.01, respectively). The percentage of CD3⁺CD4⁺-lymphocytes dropped significantly (50.4 ± 10.9% vs. 45.3 ± 12.3%, p = 0.002). Levetiracetam treatment resulted in a decrease of the percentage of CD4⁺CD25⁺-lymphocytes (26.1 ± 8.0% vs. 21.5 ± 9.2%, p = 0.01) but did not significantly alter absolute counts. Neither valproate nor levetiracetam were associated with significant changes in cytokines.ConclusionValproate intake results in profound changes of white blood cell count and subset distribution. Cytokine levels were not influenced by valproate or levetiracetam.     

Effect of pain on the modulation in discharge rate of sternocleidomastoid motor units with force direction

ObjectiveTo compare the behavior of sternocleidomastoid motor units of patients with chronic neck pain and healthy controls.MethodsNine women (age, 40.4 ± 3.5 yr) with chronic neck pain and nine age- and gender-matched healthy controls participated. Surface and intramuscular EMG were recorded from the sternocleidomastoid muscle bilaterally as subjects performed isometric contractions of 10-s duration in the horizontal plane at a force of 15 N in eight directions (0–360°; 45° intervals) and isometric contractions at 15 and 30 N force with continuous change in force direction in the range 0–360°. Motor unit behavior was monitored during the 10-s contractions and the subsequent resting periods.ResultsThe mean motor unit discharge rate depended on the direction of force in the control subjects (P < 0.05) but not in the patients. Moreover, in three of the nine patients, but in none of the controls, single motor unit activity continued for 8.1 ± 6.1 s upon completion of the contraction. The surface EMG amplitude during the circular contraction at 15 N was greater for the patients (43.5 ± 54.2 μV) compared to controls (16.9 ± 14.9 μV; P < 0.05).ConclusionsThe modulation in discharge rate of individual motor units with force direction is reduced in the sternocleidomastoid muscle in patients with neck pain, with some patients showing prolonged motor unit activity when they were instructed to rest.SignificanceThese observations suggest that chronic neck pain affects the change in neural drive to muscles with force direction.     

Pensamiento catastrófico ante el dolor: presencia en una población de migrañosos

IntroductionCatastrophic thought refers to a negative cognitive and emotional response to pain, and is thought to contribute to pain chronification. We aimed to evaluate pain catastrophising PC in a population of patients with migraine.MethodsWe collected sociodemographic data and clinical data on migraine from patients attended at a tertiary hospital headache unit between January and June 2015. PC was measured with the Spanish-language version of the Pain Catastrophizing Scale (PCS). We compared presence of PC in patients with episodic and chronic migraine, and its correlation with clinical impact (measured by the Headache Impact Test-6 [HIT-6] scale), comorbid depression and anxiety (measured with the Hospital Anxiety and Depression Scale [HADS]), and the presence of medication overuse.ResultsThe study included 96 patients (16 men and 80 women); 67 (69.8%) were diagnosed with chronic migraine and 29 (30.2%) with episodic migraine. Migraine impact was at least moderate (HIT-6 ≥ 56) in 85.4% of cases, and 24% exceeded the cut-off point for anxiety and 9.4% for depression. A total of 34.4% presented PC. Patients with chronic migraine scored higher than those with episodic symptoms on the HADS for anxiety (P < .001) and depression (P < .001) and on the HIT-6 (P < .001).ConclusionsPC is common among patients with migraine. It is related to migraine severity and to comorbid anxiety and depression. PC does not appear to increase the likelihood of migraine chronification or medication overuse.     

Clinical outcomes after craniotomy for unruptured intracranial aneurysm in patients with coronary artery disease

BackgroundCoronary artery disease (CAD) patients receiving antiplatelet agents occasionally undergo craniotomy. We aimed to clarify clinical outcomes after craniotomy for unruptured intracranial aneurysm (UIA) in patients with CAD. We also aimed to identify the possible predictive factors for morbidity and surgical complications in patients on antiplatelet treatment.MethodsWe retrospectively analyzed 401 consecutive patients who had undergone craniotomy for UIA at our institution between January 2006 and December 2016. Forty-three patients (10.7%) received antiplatelet agents during the perioperative period. The underlying reasons for antiplatelet treatment were CAD in 12 patients and other diseases in 31 patients.ResultsSevere morbidity and intracranial hemorrhage occurred more commonly and symptomatic brain infarction occurred less frequently in patients with CAD compared to patients with other underlying diseases (16.7% versus 3.2%, 16.7% versus 9.7%, and 8.3% versus 16.1%, respectively), though differences between the two groups were not significant. Univariate analysis revealed that a low preoperative baseline platelet count was significantly correlated with the occurrence of intracranial hemorrhage (cutoff value, 16.5 × 10⁴/µL; odds ratio (OR), 46.67; 95% confidence interval (CI), 3.88–561.95; p = 0.0005), and a high baseline platelet count tended to correlate with severe morbidity (cutoff value, 29.8 × 10⁴/µL; OR, 11.33; 95% CI, 0.88–145.52; p = 0.0550).ConclusionsOur results suggest that surgical complications and clinical outcomes after craniotomy may depend on the underlying reason for antiplatelet treatment. Moreover, a preoperative platelet count can be useful in predicting the occurrence of intracranial hemorrhage and severe morbidity after craniotomy in patients receiving antiplatelet agents.