Production of IL-16 correlates with CD4+ Th1 inflammation and phosphorylation of axonal cytoskeleton in multiple sclerosis lesions

Background  

Multiple sclerosis (MS) is a central nervous system-specific autoimmune, demyelinating and neurodegenerative disease. Infiltration of lesions by autoaggressive, myelin-specific CD4+Th1 cells correlates with clinical manifestations of disease. The cytokine IL-16 is a CD4+ T cell-specific chemoattractant that is biased towards CD4+ Th1 cells. IL-16 precursor is constitutively expressed in lymphocytes and during CD4+ T cell activation; active caspase-3 cleaves and releases C-terminal bioactive IL-16. Previously, we used an animal model of MS to demonstrate an important role for IL-16 in regulation of autoimmune inflammation and subsequent axonal damage. This role of IL-16 in MS is largely unexplored. Here we examine the regulation of IL-16 in relation to CD4+ Th1 infiltration and inflammation-related changes of axonal cytoskeleton in MS lesions.     

The relationship between the dim light melatonin onset and sleep on a regular schedule in young healthy adults

The endogenous melatonin onset in dim light (DLMO) is a marker of circadian phase that can be used to appropriately time the administration of bright light or exogenous melatonin in order to elicit a desired phase shift. Determining an individual's circadian phase can be costly and time-consuming. We examined the relationship between the DLMO and sleep times in 16 young healthy individuals who slept at their habitual times for a week. The DLMO occurred about 2 hours before bedtime and 14 hours after wake. Wake time and midpoint of sleep were significantly associated with the DLMO (r = 0.77, r = 0.68 respectively), but bedtime was not (r = 0.36). The possibility of predicting young healthy normally entrained people's DLMOs from their sleep times is discussed.     

Characteristics of N400 component elicited in patients who have migraine with aura

BackgroundThis study aimed to examine the N400 effect and event-related potentials (ERPs) elicited from congruent and incongruent stimuli in patients who have migraines with aura (MwA).MethodsA total of 33 MwA patients and 20 healthy controls (HCs) were studied. They were balanced in age (35.12 ± 8.94 vs 34.70 ± 9.59 years, p = 0.872) and sex (69.7 vs 75.0% females, p = 0.761). ERPs were measured in response to both stimuli, where pictures were preceded with an object name that either matched or mismatched with the object. Averaged amplitudes, peaks, peak latencies, difference waves and topography were compared between MwA and HCs.ResultsMwA patients had significantly lower averaged amplitudes at the Fz and F4 sites during incongruent stimuli, as well as reduced peaks at the C3 and Pz sites. Topography showed a more widespread N400 effect over scalp relative to HCs. The difference ERP waveforms did not differ in the N400 effect between groups, but the P600 effect was significantly stronger in the HCs group relative to the MwA group at the Pz (6.52 ± 2.57 vs. 3.50 ± 3.15, p = 0.001) and P4 (5.86 ± 2.79 vs. 3.95 ± 3.64, p = 0.040) sites.ConclusionsPicture-word matching tasks could serve as a potential new method for the investigation of semantic processing in MwA patients.     

Carotid atherosclerosis,coronary atherosclerosis and carotid intima-media thickness in patients with ischemic cerebral disease: Is there any link?

OBJECTIVES: The present study examined the association between carotid atherosclerosis, coronary atherosclerosis and common carotid artery intima-media thickness (CCA-IMT) in patients with incident ischemic stroke and its subtypes (75 cases and 21 controls). METHODS: Cases with ischemic brain infarctions (IBIs) were consecutively recruited and classified into subtypes by computed tomography and Bamford's classification (the size and site of the infarct) as one of the following: total anterior circulation infarcts (TACIs); partial anterior circulation infarcts (PACIs); posterior circulation infarcts (POCIs); and lacunar infarcts. Controls were recruited among individuals hospitalized for a reason other than cerebrovascular disease at the same institutions and matched for age and sex. Patients and controls underwent B-mode ultrasonographic measurements of CCA-IMT, and were evaluated by a qualified internist and neurologist for the presence of ischemic coronary disease and a history of previous stroke or transient ischemic attack. RESULTS: Of the 75 patients with an acute ischemic stroke, 10 (14%) were classified as TACIs, 34 (45%) as PACIs, 12 (16%) as POCIs and 19 (25%) as lacunar infarcts. Mean CCA-IMT was higher in patients (1.03+/-0.18 mm) than in controls (0.85+/-0.18 mm; P<0.0001). The history of cerebrovascular disease was much lower in the patients with POCI and TACI, and the prevalence of ischemic cardiac disease was in the range of 20% in patients with TACIs to more than 40% in patients with PACIs. CONCLUSIONS: An increased CCA-IMT as a marker of general atherosclerosis was associated with IBI and reflects cardiovascular risk. Carotid and coronary atherosclerosis were positively correlated with IBIs, with significant differences across the subtypes.     

Sex differences in patients with mesial temporal lobe epilepsy

Possible sex differences in the pattern of interictalhypometabolism were investigated, and also seizure spread in patients with mesial temporal lobe epilepsy (n=48) and hippocampal sclerosis (MTLE). Male patients (n=21) more often had a frontal lobehypometabolism ipsilateral to the seizure onset (p<0.0001) and aspread of epileptiform activity to this region (p=0.001). By contrast,female patients more often exhibited hypometabolism (p=0.0052) and anictal spread to the contralateral temporal lobe (p=0.0097). Thesefindings suggest sex differences in spatial distribution of braindysfunction in MTLE, perhaps reflecting sexual dimorphism in regionalcerebral connectivity.

     

In vivo demonstration of altered benzodiazepine receptor density in patients with generalised epilepsy.

Electrophysiological data suggest that an abnormal oscillatory pattern of discharge in cortical and thalamic neurons may be the major mechanism underlying primary generalised epilepsy. No neurochemical or anatomical substrate for this theory has hitherto been demonstrated in humans and the pathophysiology of primary generalised epilepsy remains unknown. By means of PET and the benzodiazepine (BZ) ligand [11C]flumazenil it has been previously shown that the BZ receptor density is reduced in the epileptic foci of patients with partial epilepsy. In the present study the method was further developed and used in a comparative analysis of cortical, cerebellar, and subcortical BZ receptor binding in patients with primary generalised tonic and clonic seizures (n = 8), and healthy controls (n = 8). Patients with generalised seizures had an increased BZ receptor density in the cerebellar nuclei (p = 0.006) and decreased density in the thalamus (p = 0.003). No significant changes were seen in the cerebral and cerebellar cortex or in the basal ganglia. The observed alterations suggest that the gamma-amino-butyric acid (GABA)-BZ system may be affected in the cerebello-thalamocortical loop of patients with generalised epilepsy and indicate possible targets for selective pharmacological treatment.     

Regional increases in [11 C]flumazenil binding after epilepsy surgery

Introduction – Animal experiments suggest that epileptic seizures alter the expression of mRNA for neuro-receptors. PET measurements with [¹¹ C]flumazenil show that patients with partial seizures have a reduced density of benzodiazepine (BZ) receptors in the epileptogenic regions (ER) and some of the target areas for seizure activity, the so called projection areas. Recent data suggest that the degree of BZ receptor reduction in ER is correlated to seizure frequency. We therefore hypothesized that seizure activity can alter the BZ receptor binding, and that some of these changes could normalize when the seizures disappeared. Methods – In 4 patients whose seizures were generated by mesial temporal lobe structures, BZ receptor density was measured with [¹¹ C]flumazenil PET before, and 1 year after the epilepsy surgery and cessation of seizures. By use of a computerized anatomical brain atlas the same regions were analyzed in both PET scans, and the results related to data from 7 healthy controls. Results – Presurgical PET scans showed reductions in BZ receptor density in the epileptogenic region and some of its primary projection areas. Other cortical regions had normal values. Postsurgically, the calculated BZ receptor density normalized (29±17% increase) in several of the affected projection areas, whereas the values in other cortical regions remained unaltered. Conclusion – Regional reductions in BZ receptor density may be dynamic and related to seizures. The present preliminary observations encourage further studies on seizure-related changes in regional receptor binding in humans.     

The antitumor immune response in HER-2 positive,metastatic breast cancer patients

The aim of this study was to determine the basis for anti-tumor immune reactivity observed in patients with human epidermal growth factor receptor-2 (HER-2) (3+) breast carcinoma using an in vitro model in which the role of the HER-2-specific monoclonal antibody Herceptin was also investigated. Patients with metastatic breast cancer who had their primary tumor resected were included in this study. Peripheral blood mononuclear cell (PBMC)-dependent cytotoxicity in the presence or absence of Herceptin were assessed using the survival of target breast adenocarcinoma MDA-MB-361 cells as a parameter in a (3-(4,5-dimethyl-2-thiazolyl)-2,5-diphenyl-2H-tetrazolium bromide (MTT) test. We observed a significant increase in PBMC-dependent cytotoxicity when autologous serum was introduced in the assay. Furthermore, the addition of Herceptin significantly increases their cytotoxicity. These data suggest that autologous serum constitutively contains factors that might affect PBMC-dependent cytotoxic activity against HER-2 positive cancer cells.