Inflammatory CNS demyelination:histopathologic correlation with in vivo quantitative proton MR spectroscopy

BACKGROUND AND PURPOSE: The mechanisms behind the demyelination that is characteristic of multiple sclerosis (MS) are still poorly understood. The purpose of this study was to compare immunopathologic findings in demyelinating lesions of three patients with in vivo assessments obtained by quantitative proton MR spectroscopy (MRS).METHODS: Between four and seven stereotactic needle brain biopsies were performed in three young adults with diagnostically equivocal findings for MS. Axonal density, gliosis, blood brain–barrier breakdown, and demyelinating activity of lesions were determined. Combined MR/MRS studies were performed (T1-weighted fast low-angle shot and single-voxel stimulated-echo acquisition mode), and absolute metabolite levels were obtained with a user-independent fitting routine. Metabolite control values were obtained from a group of age-matched healthy volunteers (n=40, age range, 20–25 years old). Alterations of metabolite levels of control subjects were considered significant when exceeding two standard deviations.RESULTS: There were parallel decreases of N-acetylaspartate (21%–82%) and reductions of axonal density (44%–74%) in demyelinating plaques. Concomitant increases of choline (75%–152%) and myo-inositol (84%–160%) corresponded to glial proliferation. Elevated lactate was associated with inflammation.CONCLUSION: The present data suggest that in vivo MRS indicates key pathologic features of demyelinating lesions

Circulating Pneumolysin Is a Potent Inducer of Cardiac Injury during Pneumococcal Infection

Streptococcus pneumoniae accounts for more deaths worldwide than any other single pathogen through diverse disease manifestations including pneumonia, sepsis and meningitis. Life-threatening acute cardiac complications are more common in pneumococcal infection compared to other bacterial infections. Distinctively, these arise despite effective antibiotic therapy. Here, we describe a novel mechanism of myocardial injury, which is triggered and sustained by circulating pneumolysin (PLY). Using a mouse model of invasive pneumococcal disease (IPD), we demonstrate that wild type PLY-expressing pneumococci but not PLY-deficient mutants induced elevation of circulating cardiac troponins (cTns), well-recognized biomarkers of cardiac injury. Furthermore, elevated cTn levels linearly correlated with pneumococcal blood counts (r=0.688, p=0.001) and levels were significantly higher in non-surviving than in surviving mice. These cTn levels were significantly reduced by administration of PLY-sequestering liposomes. Intravenous injection of purified PLY, but not a non-pore forming mutant (PdB), induced substantial increase in cardiac troponins to suggest that the pore-forming activity of circulating PLY is essential for myocardial injury in vivo. Purified PLY and PLY-expressing pneumococci also caused myocardial inflammatory changes but apoptosis was not detected. Exposure of cultured cardiomyocytes to PLY-expressing pneumococci caused dose-dependent cardiomyocyte contractile dysfunction and death, which was exacerbated by further PLY release following antibiotic treatment. We found that high PLY doses induced extensive cardiomyocyte lysis, but more interestingly, sub-lytic PLY concentrations triggered profound calcium influx and overload with subsequent membrane depolarization and progressive reduction in intracellular calcium transient amplitude, a key determinant of contractile force. This was coupled to activation of signalling pathways commonly associated with cardiac dysfunction in clinical and experimental sepsis and ultimately resulted in depressed cardiomyocyte contractile performance along with rhythm disturbance. Our study proposes a detailed molecular mechanism of pneumococcal toxin-induced cardiac injury and highlights the major translational potential of targeting circulating PLY to protect against cardiac complications during pneumococcal infections

The role of left and right hemispheres in the comprehension of idiomatic language: an electrical neuroimaging study

<p>Abstract</p> <p>Background</p> <p>The specific role of the two cerebral hemispheres in processing idiomatic language is highly debated. While some studies show the involvement of the left inferior frontal gyrus (LIFG), other data support the crucial role of right-hemispheric regions, and particularly of the middle/superior temporal area. Time-course and neural bases of literal vs. idiomatic language processing were compared. Fifteen volunteers silently read 360 idiomatic and literal Italian sentences and decided whether they were semantically related or unrelated to a following target word, while their EEGs were recorded from 128 electrodes. Word length, abstractness and frequency of use, sentence comprehensibility, familiarity and cloze probability were matched across classes.</p> <p>Results</p> <p>Participants responded more quickly to literal than to idiomatic sentences, probably indicating a difference in task difficulty. Occipito/temporal N2 component had a greater amplitude in response to idioms between 250-300 ms. Related swLORETA source reconstruction revealed a difference in the activation of the left fusiform gyrus (FG, BA19) and medial frontal gyri for the contrast idiomatic-minus-literal. Centroparietal N400 was much larger to idiomatic than to literal phrases (360-550 ms). The intra-cortical generators of this effect included the left and right FG, the left cingulate gyrus, the right limbic area, the right MTG (BA21) and the left middle frontal gyrus (BA46). Finally, an anterior late positivity (600-800 ms) was larger to idiomatic than literal phrases. ERPs also showed a larger right centro-parietal N400 to associated than non-associated targets (not differing as a function of sentence type), and a greater right frontal P600 to idiomatic than literal associated targets.</p> <p>Conclusion</p> <p>The data indicate bilateral involvement of both hemispheres in idiom comprehension, including the right MTG after 350 ms and the right medial frontal gyrus in the time windows 270-300 and 500-780 ms. In addition, the activation of left and right limbic regions (400-450 ms) suggests that they have a role in the emotional connotation of colourful idiomatic language. The data support the view that there is direct access to the idiomatic meaning of figurative language, not dependent on the suppression of its literal meaning, for which the LIFG was previously thought to be responsible.</p

The role of pneumolysin in mediating lung damage in a lethal pneumococcal pneumonia murine model

BACKGROUND: Intranasal inoculation of Streptococcus pneumoniae D39 serotype 2 causes fatal pneumonia in mice. The cytotoxic and inflammatory properties of pneumolysin (PLY) have been implicated in the pathogenesis of pneumococcal pneumonia. METHODS: To examine the role of PLY in this experimental model we performed ELISA assays for PLY quantification. The distribution patterns of PLY and apoptosis were established by immunohistochemical detection of PLY, caspase-9 activity and TUNEL assay on tissue sections from mice lungs at various times, and the results were quantified with image analysis. Inflammatory and apoptotic cells were also quantified on lung tissue sections from antibody treated mice. RESULTS: In bronchoalveolar lavages (BAL), total PLY was found at sublytic concentrations which were located in alveolar macrophages and leukocytes. The bronchoalveolar epithelium was PLY-positive, while the vascular endothelium was not PLY reactive. The pattern and extension of cellular apoptosis was similar. Anti-PLY antibody treatment decreased the lung damage and the number of apoptotic and inflammatory cells in lung tissues. CONCLUSION: The data strongly suggest that in vivo lung injury could be due to the pro-apoptotic and pro-inflammatory activity of PLY, rather than its cytotoxic activity. PLY at sublytic concentrations induces lethal inflammation in lung tissues and is involved in host cell apoptosis, whose effects are important to pathogen survival

Self-Reported Time in Bed and Sleep Quality in Association with Internalizing and Externalizing Symptoms in School-Age Youth

This study investigated the relationship between self-reported time in bed and sleep quality in association with self-reported internalizing and externalizing symptoms in a sample of 285 elementary school students (52% female) recruited from a rural Midwestern elementary school. Path models were used to estimate proposed associations, controlling for grade level and gender. Curvilinear associations were found between time in bed and anxiety, depressive symptoms, and irritability. Marginal curvilinear trends were found between time in bed and emotion dysregulation, reactive aggression, and proactive aggression. Sleep quality was negatively associated with anxiety, depressive symptoms, irritability, reactive aggression, and delinquency engagement. Gender and grade differences were found across models. Findings suggest that examining self-reported time in bed (both linear and quadratic) and sleep quality is important for understanding internalizing and externalizing symptoms associated with sleep in school-age youth. Incorporating self-reported sleep assessments into clinical practice and school-based evaluations may have implications for a child’s adjustment

Increased Glutamine Synthetase immunoreactivity in experimental pneumococcal meningitis

Glutamine synthetase (GS), glial fibrillary acidic protein (GFAP) immunohistochemistry and neuronal apoptotic cell death were evaluated in a rabbit model of pneumococcal meningitis. Meningitis caused an increase of GS immunoreactivity in the cerebral cortex, but not in the hippocampal formation. GFAP immunoreactivity remained unchanged. This may represent a protective mechanism for cortical neurons. The inability of hippocampal GS to counteract the detrimental effects of glutamate may be the cause of neuronal apoptosis observed in the dentate gyrus during meningitis

Intravenous Granulocyte Colony-Stimulating Factor Increases the Release of Tumour Necrosis Factor and Interleukin-1β into the Cerebrospinal Fluid, But Does Not Inhibit the Growth of Streptococcus pneumoniae in Experimental Meningitis

Granulocyte colony-stimulating factor (G-CSF) possesses an antimicrobial effect in several animal models of infection. To evaluate a possible effect of G-CSF on the course of pneumococcal meningitis, rabbits infected intracisternally (i.c.) with Streptococcus pneumoniae type 3 (n = 7) received 50 μg/kg of rhG-CSF intravenously (i.v.) 1 h prior to infection. Seven infected animals served as controls. Uninfected rabbits received 10 μg of G-CSF (n = 3), 2 μg G-CSF (n = 3) or saline (n = 3) i.c. G-CSF injected i.c. did not produce cerebrospinal fluid (CSF) leucocytosis. Compared with the control group, i.v. G-CSF given prior to i.c. infection increased the percentage of granulocytes in blood 6 h and 12 h after infection. Twelve hours after infection, CSF tumour necrosis factor (TNF) activity and CSF interleukin (IL)-1β concentrations were significantly higher in G-CSF-treated animals. G-CSF did not decrease bacterial growth in the subarachnoid space and the CSF leucocyte densities were not influenced. At 24 h after infection, G-CSF did not reduce the CSF concentrations of neurone-specific enolase and the density of apoptotic neurones in the dentate gyrus of the hippocampus. In conclusion, i.v. G-CSF increased the concentration of pro-inflammatory cytokines in the CSF but did not decrease the growth of Streptococcus pneumoniae in the subarachnoid space