Cytomegalovirus infection and interferon-γ modulate major histocompatibility complex class I expression on neural stem cells

Cytomegalovirus (CMV) is the leading transmittable cause of congenital brain abnormalities in children and infection results in fatal ventriculoencephalitis in advanced acquired immunodeficiency syndrome (AIDS) patients. Pathology associated with CMV brain infection is seen predominantly in the periventricular region, an area known to harbor neural stem cells (NSCs). In the present study, using an adult model of murine CMV brain infection, the authors demonstrated that nestin-positive NSCs in the subventricular zone are susceptible to murine CMV infection. Furthermore, primary NSC cultures supported productive murine CMV replication with a 1000-fold increase in viral titers by 5 days post infection (d.p.i). Previous studies from the authors' laboratory demonstrated that CD8 lymphocytes were essential in protecting the brain against murine CMV infection. In the present study, the authors found that interferon (IFN)-gamma treatment increased the expression of major histocompatibility complex (MHC) class I on NSCs. Viral infection, on the other hand, inhibited this IFN-gamma-induced MHC up-regulation. In addition to increasing MHC class I expression, IFN-gamma (but not tumor necrosis factor [TNF]-alpha, interleukin [IL]-1 beta, or IL-10) also suppressed NSC proliferation in vitro. This decrease in proliferation was not accompanied by apoptosis or extracellular release of cellular lactate dehydrogenase (LDH), suggesting that the effects were not due to direct cytotoxicity. These studies demonstrate that NSCs are susceptible to murine CMV infection and inflammatory mediators, such as IFN-gamma, alter cellular characteristics which may have an impact on their reparative functions.     

Effects of interferon-γ, interleukin-1β, and tumor necrosis factor-α on the serotonin metabolism in the nucleus raphe dorsalis of the rat

Summary The effects of the cytokines interferon (IFN)-, interleukin (IL)-1, and tumor necrosis factor (TNF)- on the serotoninergic transmission in the nucleus raphe dorsalis (NRD) were studied after peripheral and central application. The studies were performed in the freely moving rat using differential pulse voltammetry with multicarbon fibre electrodes to study the extracellular levels of the serotonin (5-HT) metabolite 5-hydroxyindoleacetic acid (5-HIAA). The extracellular 5-HIAA levels were not changed in the NRD after peripheral application of rat recombinant IFN-, but elevated by the cytokines IL-1 and TNF-. After intracerebroventricular (i.c.v.) application the cytokines IFN-, IL-1 and TNF- stimulated the serotoninergic transmission in the NRD. Our data suggest that the effect of peripherally elevated cytokine concentrations on the serotonin metabolism in the NRD of the rat is cytokine-dependent. In this respect the T-cell and NK-cell cytokine IFN- acts clearly different when compared to the mainly macrophage-derived cytokines IL-1 and TNF-, and plays a different role in the communication between immune and central nervous system.     

The effects of age on lipopolysaccharide-induced cognitive deficits and interleukin-1β expression

An acute LPS challenge immediately following day 1 of shuttlebox training triggered exacerbated central IL-1β production and disrupted memory consolidation and/or further acquisition of the task in 18-month-old mice, compared to 4-month-old controls. These deficits cannot be attributed to alterations in sickness behavior. The findings suggest that age and immune activation combine to impair learning and memory consolidation processes, and that increased central IL-1β production may play a role.     

Ontogeny and the effects of in utero brain ischemia on interleukin-1β and interleukin-6 protein expression in ovine cerebral cortex and white matter

Interleukin (IL)-1β and IL-6 have been implicated in brain development, injury progression, and fetal/maternal immune interactions. We examined IL-1β and IL-6 protein expression in cerebral cortex (CC) and white matter (WM) from non-ischemic ovine fetuses at 87–90, 122–127, and 135–137 days of gestation, pregnant ewes at 87–90 and 135–137 days of gestation, and fetuses exposed to 48 or 72 h of reperfusion after ischemia. Protein expression was determined by Western immunoblot. In non-ischemic CC, IL-1β was higher (P < 0.05) in adult sheep and fetuses at 135–137 than 87–90 and 122–127 days, and IL-6 higher at 122–127 than 87–90 days, and in adults than fetuses at 87–90, 122–127, and 135–137 days of gestation. In non-ischemic fetal WM, IL-6 was higher at 135–137 than 87–90 days, but IL-1β did not differ. In CC, IL-1β was higher in ewes at 135–137 than 87–90 days and IL-6 at 135–137 days and in non-pregnant adults than ewes at 87–90 days of gestation. In WM, IL-1β was higher in ewes at 135–137 than 87–90 days of gestation, but IL-6 did not differ. Forty-eight and 72 h after ischemia, CC IL-1β was higher than in non-ischemic fetuses. Seventy-two hours after ischemia, IL-1β and IL-6 were higher in WM than CC. In conclusion, IL-1β and IL-6 exhibit developmental regulation in fetal brain, change during gestation in brains of pregnant ewes, show regional differences in normal brains of fetuses and ewes, demonstrate differential responses after ischemia in CC and WM, and IL-1β but not IL-6 increases after ischemia in CC.     

Risky decisions and response reversal: is there evidence of orbitofrontal cortex dysfunction in psychopathic individuals?

This study investigates the performance of psychopathic individuals on tasks believed to be sensitive to dorsolateral prefrontal and orbitofrontal cortex (OFC) functioning. Psychopathic and non-psychopathic individuals, as defined by the Hare psychopathy checklist revised (PCL-R) [Hare, The Hare psychopathy checklist revised, Toronto, Ontario: Multi-Health Systems, 1991] completed a gambling task [Cognition 50 (1994) 7] and the intradimensional/extradimensional (ID/ED) shift task [Nature 380 (1996) 69]. On the gambling task, psychopathic participants showed a global tendency to choose disadvantageously. Specifically, they showed an impaired ability to show learning over the course of the task. On the ID/ED task, the performance of psychopathic individuals was not significantly different from incarcerated controls on attentional set-shifting, but significant impairments were found on response reversal. These results are interpreted with reference to an OFC and amygdala dysfunction explanation of psychopathy.     

Differential effects of interferon-β1b on cytokine patterns of CD4+ and CD8+ T cells derived from RRMS and PPMS patients

The influence of interferon (IFN)-β on cytokine release by immune cells remains controversial. This study compared IFN-β1b effects on mononuclear cells, CD4+ and CD8+ T cells derived from healthy controls and relapsing-remitting multiple sclerosis (RRMS) and primary progressive multiple sclerosis (PPMS) patients. Effects of IFN-β1b (0-10,000 U/ml) on cytokine release were determined in cell culture. IFN-β1b inhibited IFN-γ and induced interleukin (IL)-4 selectively in RRMS-derived CD4+ T cells. IL-10 was significantly induced in all cell populations from RRMS but only marginally in PPMS. IL-5 was always inhibited; IL-17A remained unaltered. These in vitro data parallel clinical observations that IFN-β is most effective in RRMS.     

Frontline clinicians’ perspectives on and utilization of trauma-focused therapy with individuals with eating disorders

With this study, we sought to survey clinicians regarding their perspectives and use of concurrent or integrated psychotherapy for co-occurring eating disorders (EDs) and posttraumatic stress disorder. We conducted a quantitative survey of 184 frontline ED clinicians to investigate whether, and to what extent, they view concurrent EDs and trauma-focused therapy as clinically important. We also assessed clinicians’ specific concerns regarding concurrent EDs and trauma-focused treatment, as well as barriers to implementation of an evidence-based concurrent treatment. On the whole, clinicians reported that addressing trauma-related symptoms in individuals with EDs is highly important and should be administered concurrently. Although clinicians reported anticipating many important benefits of concurrent treatment, they also reported anticipating several potential negative side effects, and they reported a number of perceived barriers to implementation. Clinicians working in hospital settings anticipated more complications, expected fewer benefits, and perceived more barriers to the administration of concurrent treatment.     

Proteomic analysis reveals plasma haptoglobin,interferon-γ, and interleukin-1β as potential biomarkers of pediatric refractory epilepsy

BackgroundChildren with refractory epilepsy (RE) are associated with increased mortality rate, nonfatal injuries, disability, and diminished quality of life. Biomarkers for the early prediction of RE is still an unmet need.MethodsEighteen children with RE and six age-matched unrelated controls were included in this study. Plasma samples were prefractionated by the optimized thermal treatment before proteomic analysis using 2DE-LC-MS/MS. Bioinformatic analysis was carried out using STRING protein network. Immunoassay of unprocessed plasma was applied to confirm changes of proteins of interest. P-value < 0.05 was considered statistically significant.ResultsProteomic analysis (n = 6 each group) revealed nine differentially expressed proteins, i.e., haptoglobin, S100A9, serpin B1, apolipoprotein A-I, apolipoprotein A-IV, apolipoprotein C-II, alpha-1-acid glycoprotein 1 and 2, and transthyretin. Western immunoblotting confirmed haptoglobin upregulation in the RE group. STRING protein network predicted the inflammatory cytokines, i.e., interferon gamma (IFN-γ), interleukin-1 beta (IL-1β) and tumor necrosis factor alpha (TNF-α), play roles in pathophysiology in RE patients. Cytokine immunoassay (n = 24, 18 RE vs. 6 controls) exhibited plasma IFN-γ was upregulated in RE patients as compared to the healthy individuals (median [IQR]; 2.9 [2.9, 4.9] vs. 1.32 [0.8, 1.5] pg/mL, p = 0.0013), and plasma IL-1β was significantly downregulated in patients (1.0 [0.2, 1.9] vs. 4.5 [1.9, 11.0] pg/mL, p = 0.01). TNF-α had no difference between groups. The results suggest that haptoglobin may be associated with oxidative brain damage, while IFN-γ and IL-1β may be involved with neuroinflammation.ConclusionsAlterations in plasma haptoglobin, IFN-γ, and IL-1β were associated with RE patients. Future studies using a combination of these candidate biomarkers may help predict the intractability of epilepsy in pediatric populations.     

Effect of interferon-α on DOI-induced wet-dog shakes in rats

Summary Acute (1h) intraperitoneal (ip) treatment with interferon (IFN)--2a (300IU/g) significantly inhibited wet-dog shakes (WDS) induced by (±)-1-(2,5-dimethoxy-4-iodophenyl)-2 aminopropane (DOI; 0.5, 1.0mg/kg), which is mediated by serotonin (5-hydroxytryptamine; 5-HT)₂ receptor in rats. IFN- did not affect spontaneous locomotion. The inhibition of DOI (0.5mg/kg)-induced WDS by IFN- was dose (90–300 IU/g)- and time (1–6 h)-dependent, and was prevented by 30 min pretreatment with naltrexone (NLTX; 1.0mg/kg, ip), an opioid receptor antagonist. Acute (1h) intracerebroventricular (icv) treatment with IFN- (1,500IU/rat) also inhibited DOI (0.5mg/kg)-induced WDS, and the effect was blocked by NLTX (50g/rat, icv). These results suggest that IFN- may modulate 5-HT₂ receptor-mediated behavior through opioid receptors in the central nervous system.Abbreviations CNS central nervous system - DOI (±)-1-(2,5-dimethoxy-4-iodophenyl)-2 aminopropane - 5-HT 5-hydroxytryptamine (serotonin) - icv intracerebroventricular - IFN interferon - ip intraperitoneal - IU international unit - NLTX naltrexone - sc subcutaneous - WDS wet-dog shakes     

Effect of neuropeptide Y on white matter demyelination and serum interleukin-4 and gamma-interferon levels in the guinea pig with experimental allergic encephalomyelitis★

BACKGROUND： Neuropeptide Y （NPY） may influence differentiation of Th cells immunological pathology of experimental allergic encephalomyelitis （EAE） is differentiation of Th cells It is assumed that the related to abnormal OBJECTIVE： To investigate the effect of NPY on white matter demyelination, the serum levels interleukin-4 （IL-4） and gamma-interferon （IFN-γ ）, as well as EAE pathogenesis in an EAE guinea pig model following NPY injection into the lateral cerebral ventricle. DESIGN, TIME AND SETTING： A randomized controlled animal study, which was performed in the Infection Immunity Animal Laboratory, Affiliated Hospital of Luzhou Medical College, China, from October 2005 to April 2006. MATERIALS： Thirty healthy female guinea pigs of 8-12 weeks of age, and 10 healthy female rats of three months of age were used. NPY was provided by Sigma Company, USA. NPY kit was provided by Beijing Huaying Biotechnology Institute, China. METHODS： Thirty guinea pigs were randomly divided into three groups： normal control group, EAE model group, and NPY intervention group （n =10 per group）. Normal control group and EAE model group： Saline （10μ L, once） was injected into the lateral cerebral ventricle. After one week, the same volume of Freund＇s adjuvant complete was either injected subcutaneously into two post-palms or EAE was modeled. NPY intervention group： EAE was modeled after one week and NPY was injected （10 μ L of 6 nmol NPY, once） into the lateral cerebral ventricle. Myelin basic protein （MBP） antigen made from rat spinal cord homogenate and Freund＇s adjuvant complete were injected subcutaneously into both post-palms （0.2 mL per palm） to establish the EAE model. MAIN OUTCOME MEASURES： White matter demyelination of the cerebrum, cerebellum, brain stem, and spinal cord were observed by light microscopy after HE staining. Levels of serum IFN-γ and IL-4 were detected by the double antibody sandwich ABC-ELISA technique. NPY content was detected by radioimmunoassay.     

Functional neuroanatomy of response inhibition in bipolar disorders – Combined voxel based and cognitive performance meta-analysis

Objectives

Impaired response inhibition underlies symptoms and altered functioning in patients with bipolar disorders (BD). The interpretation of fMRI studies requires an accurate estimation of neurocognitive performance, for which individual studies are typically underpowered. Thus, we performed the first combined meta-analysis of fMRI activations and neurocognitive performance in studies investigating response inhibition in BD.

Methods

We used signed differential mapping to combine anatomical coordinates of activation and standardized differences between means to evaluate neurocognitive performance in 30 fMRI studies of response inhibition comparing controls (n = 667) and patients with BD (n = 635).

Results

Relative to controls, BD patients underactivated the right inferior frontal gyrus (rIFG) regardless of current mood state and behavioral performance. Unique to euthymia were cortical hyperactivations (left superior temporal, right middle frontal gyri) combined with subcortical hypoactivations (basal ganglia), whereas unique to mania were subcortical hyperactivations (bilateral basal ganglia), combined with cortical hypoactivations (right inferior and medial frontal gyri). The fMRI changes in euthymia were associated with normal cognitive performance, whereas manic patients committed more errors during response inhibition.

Conclusions

The rIFG hypoactivations were congruent with a BD trait, which may underlie the impaired response inhibition in mania. Euthymic BD subjects may compensate for the rIFG hypoactivations by hyperactivations of adjacent cortical areas, yielding comparable performance in inhibitory functions and suggesting possibilities for neuromodulation treatment of these cognitive impairments. The reversal of the activation pattern between mania and euthymia has implications for monitoring of treatment response and identification of imminent relapse.     

Effect of interferon-β1α therapy on multiple sclerosis based on gadolinium-enhancing or active T2 magnetic resonance imaging outcomes: a meta-analysis

Objectives: Interferon-beta1alpha (IFN-β1α) is widely used to modify the course of relapsing-remitting multiple sclerosis. However, many patients have relapses. The purpose of this study was to evaluate magnetic resonance imaging (MRI) as a predictor of IFN-β1α treatment efficacy in patients with MS.

Methods: PubMed, Embase, and the Cochrane Library were searched to identify eligible studies. Manual searches were also conducted. All eligible trials included MS patients who received IFN-β1α based on gadolinium-enhancing or active T2 MRI lesions for determination of relapse rates.

Results: Of 499 identified studies, we included 10 trials reporting data on 6,037 MS patients. IFN-β1α therapy significantly reduced the risk of relapse (RR: 0.87; 95% confidence intervals (CI): 0.76–0.99; p = 0.032). Furthermore, baseline median T2 lesion volume was found to be related to IFN-β1α therapy and relapse (p = 0.018). Subgroup analysis suggested that IFN-β1α therapy was associated with reduced risk of relapse (RR: 0.82; 95%CI: 0.71–0.94; p = 0.005 versus placebo). However, there was no significant difference in the risk of relapse compared to treatment with low dose IFN-β1α (RR: 0.93; 95%CI: 0.80–1.08; p = 0.337) or glatiramer acetate (RR: 0.93; 95%CI: 0.77–1.14; p = 0.506). Finally, IFN-β1α therapy significantly increased the risk of injection-site disorders, influenza-like syndrome, and alanine transferase elevation.

Discussion: Effects of IFN-β1α therapy are associated with a statistically significant impact on baseline median T2 lesion volume. However, the safety outcomes are significantly worse in patients who receive IFN-β1α therapy.     

The effects of modified spaced-retrieval training on learning and retention of face–name associations by individuals with dementia

The purpose of this project was to assess the effects of spaced-retrieval training (SRT) on learning of new and previously known associations by individuals with dementia in two treatment conditions: one in which the recall intervals were filled with activities unrelated to the information being learned (unrelated condition) and one in which the intervals were filled with related activities (related condition). Thirty-two individuals with mild to moderate dementia (30 with a diagnosis of Alzheimer's disease; two with vascular dementia) participated in the study. On average, participants learned the associations in fewer than four sessions and retained the information for variable amounts of time, up to 6 weeks. Previously known associations were learned significantly faster than new associations. The modified SRT format, in which the within-session recall intervals were filled with information related to the target association, did not result in faster learning or longer retention of learned associations. Participants learned previously known associations in the standard SRT format (with unrelated information in the recall intervals) significantly faster than new associations taught in the modified SRT condition. Cognitive impairment, as measured by the Mini-Mental State Examination, was significantly correlated with time to learn new associations, but did not explain a large proportion of the variance in new learning. Theoretical and clinical implications are discussed.     

Classification of hydrocephalus: critical analysis of classification categories and advantages of ��Multi-categorical Hydrocephalus Classification�� (Mc HC)

Objective  

Hydrocephalus is a complex pathophysiology with disturbed cerebrospinal fluid (CSF) circulation. There are numerous numbers of classification trials published focusing on various criteria, such as associated anomalies/underlying lesions, CSF circulation/intracranial pressure patterns, clinical features, and other categories. However, no definitive classification exists comprehensively to cover the variety of these aspects. The new classification of hydrocephalus, “Multi-categorical Hydrocephalus Classification” (Mc HC), was invented and developed to cover the entire aspects of hydrocephalus with all considerable classification items and categories.