•iNOS, CD163 and ARG-I were investigated in GBM tumors and in the surrounding parenchyma from the same patients.•CD163 expression was higher within GBM specimens than in surrounding periphery in both ...male and female patients, and was inversely correlated with mean survival times.•A prevailing iNOS-like profile was present within the tumor, at variance with the peripheral parenchyma surrounding the tumor.•No significant association was found between ARG-I or iNOS expression and survival time.
Microglia and macrophages appear to be the most common cells in the GBM microenvironment. In the present study we investigated the status of macrophages/microglia activation in surgical specimens from 41 patients diagnosed with grade IV GBM. For each patient we analyzed both the center of tumor and the parenchyma surrounding the tumor. The specimens were stained for: i) IBA1, a 17-kDa EF hand protein specifically expressed in microglia/macrophages ii) CD163, a cell surface antigen associated with M2 phenotype; iii) iNOS, taken as a functional marker of M1 phenotype, and iv) ARG-I, taken as a functional marker of M2 phenotype. Staining was scored in a double-blinded score on a scale from 0 to 5. Our results suggest that CD163 expression is higher within the tumor than in surrounding periphery in both male and female patients; while iNOS is higher within the tumor in males, no significant difference was found for ARG-1. In addition, analyzing the data in TGCA database, we found that CD163 expression was significantly and inversely correlated with mean survival times, with average survival times ranging from 448days in patients having low expression, to 319 in mid, and 353 in patients with high CD163 expressing tumors. In contrast, no significant association was found between survival time and ARG-1 or iNOS expression.
Agonists of the peroxisome proliferator activated receptor gamma (PPARγ) are currently used for treatment of type 2 diabetes due to their insulin sensitizing and glucose metabolism stabilizing ...effects. More recently some of these same agonists were shown to exert anti-inflammatory and anti-proliferative effects as well. Although PPARγ agonists can operate via receptor-mediated events occurring at the genomic level, thereby causing long lasting changes in gene expression patterns, recent studies demonstrate non-genomic as well as genomic actions, and receptor-dependent as well as receptor-independent effects of the thiazolidinedione (TZD) class of PPARγ agonists. In this review we will summarize data describing some of these novel, receptor independent actions of TZDs, review evidence that TZDs directly influence mitochondrial function, and attempt to reconcile how changes in mitochondrial function could contribute to other receptor-independent actions of these drugs.
Summary
Background
Epidermolysis bullosa (EB) is a group of rare and currently incurable genetic blistering disorders. As more pathogenic‐driven therapies are being developed, there is an important ...need for EB‐specific validated outcomes measures designed for use in clinical trials.
Objectives
To test the reliability and construct validity of an instrument for scoring clinical outcomes of research for EB (iscorEB), a new combined clinician‐ and patient‐reported outcomes tool.
Methods
We conducted an observational study consisting of independent 1‐day assessments (six assessors) at two academic hospitals. The assessments consisted of iscorEB clinician (iscorEB‐c), Birmingham Epidermolysis Bullosa Severity (BEBS) and global severity assessment for physicians; and iscorEB patient (iscorEB‐p), Quality of Life evaluation in Epidermolysis Bullosa and Children's Dermatology Life Quality Index for patients. Construct validity and intraclass correlation coefficients (ICCs) for interobserver, intraobserver and test–retest reliability were calculated.
Results
Overall, 31 patients with a mean age of 19·5 years (1·8–45·2) were included. Disease severity was mild in 42% of cases, moderate in 29% and severe in 29%. The interobserver ICC was 0·96 for both the clinician‐reported section of iscorEB‐c and BEBS. The ICC for intraobserver reliability was 0·91 and 0·70 for the skin and mucosal domains of iscorEB‐c, respectively. Cronbach's alpha for iscorEB‐c was 0·89. The test–retest reliability of iscorEB‐p was 0·97 and Cronbach's alpha was 0·84. The clinical score differentiated between subjects with mild, moderate and severe disease, and both clinical and patient subscores discriminated between recessive dystrophic EB and other EB subtypes.
Conclusions
iscorEB has robust reliability and construct validity, including strong ability to distinguish EB types and severities. Further studies are planned to test its responsiveness to change.
What's already known about this topic?
Outcome measures that test epidermolysis bullosa (EB) severity are limited.
There is a need for valid tools that assess EB severity in the context of clinical trials.
What does this study add
?
The instrument for scoring clinical outcomes of research for EB (iscorEB) is a new combined clinician‐ and patient‐reported outcomes tool.
The iscorEB has robust reliability and construct validity, including a strong ability to distinguish EB types and severities.
Plain language summary available online
Respond to this article
Neuroinflammation in Alzheimer's disease Heneka, Michael T, Prof; Carson, Monica J, Prof; Khoury, Joseph El, Prof ...
Lancet neurology,
04/2015, Volume:
14, Issue:
4
Journal Article
Peer reviewed
Open access
Summary Increasing evidence suggests that Alzheimer's disease pathogenesis is not restricted to the neuronal compartment, but includes strong interactions with immunological mechanisms in the brain. ...Misfolded and aggregated proteins bind to pattern recognition receptors on microglia and astroglia, and trigger an innate immune response characterised by release of inflammatory mediators, which contribute to disease progression and severity. Genome-wide analysis suggests that several genes that increase the risk for sporadic Alzheimer's disease encode factors that regulate glial clearance of misfolded proteins and the inflammatory reaction. External factors, including systemic inflammation and obesity, are likely to interfere with immunological processes of the brain and further promote disease progression. Modulation of risk factors and targeting of these immune mechanisms could lead to future therapeutic or preventive strategies for Alzheimer's disease.
ABSTRACT
We report on the discovery and validation of TOI 813 b (TIC 55525572 b), a transiting exoplanet identified by citizen scientists in data from NASA’s Transiting Exoplanet Survey Satellite ...(TESS) and the first planet discovered by the Planet Hunters TESS project. The host star is a bright (V = 10.3 mag) subgiant ($R_\star =1.94\, R_\odot$, $M_\star =1.32\, M_\odot$). It was observed almost continuously by TESS during its first year of operations, during which time four individual transit events were detected. The candidate passed all the standard light curve-based vetting checks, and ground-based follow-up spectroscopy and speckle imaging enabled us to place an upper limit of $2\, M_{\rm Jup}$ (99 per cent confidence) on the mass of the companion, and to statistically validate its planetary nature. Detailed modelling of the transits yields a period of $83.8911 _{ - 0.0031 } ^ { + 0.0027 }$ d, a planet radius of 6.71 ± 0.38 R⊕ and a semimajor axis of $0.423 _{ - 0.037 } ^ { + 0.031 }$ AU. The planet’s orbital period combined with the evolved nature of the host star places this object in a relatively underexplored region of parameter space. We estimate that TOI 813 b induces a reflex motion in its host star with a semi-amplitude of ∼6 m s−1, making this a promising system to measure the mass of a relatively long-period transiting planet.
Abstract Current treatments used in Multiple Sclerosis (MS) are partly effective in the early stages of the disease but display very limited benefits in patients affected by progressive MS. One ...possible explanation is that these therapies are unable to target the inflammatory component most active during the progressive phase of the disease, and compartmentalized behind the blood–brain barrier. Our findings show that Rapamycin ameliorates clinical and histological signs of chronic EAE when administered during ongoing disease. Moreover, Rapamycin significantly reduced the hyperalgesia observed before clinical development of EAE which, in turn, is completely abolished by the administration of the drug.
Expression of the inducible form of nitric oxide synthase (iNOS) in brain may contribute to neurotoxicity in Alzheimer's disease (AD). Expression of iNOS can be induced in cerebellar granule cells ...(CGCs) in vivo as well as in vitro, allowing these cells to be used to study regulation of neuronal iNOS expression. We report here that microinjection of bacterial lipopolysaccharide and interferon gamma into rat cerebellum induced iNOS expression in CGCs and subsequent cell death assessed by staining for DNA fragmentation. Co-injection of three structurally distinct agonists of the peroxisome proliferator-activated receptor gamma (PPARgamma), including the antidiabetic thiazolidinedione troglitazone, the nonsteroidal anti-inflammatory drug (NSAID) ibuprofen, and the prostanoid 15-deoxy-Delta(12,14) prostaglandin J(2), reduced both iNOS expression and cell death, whereas co-injection of the selective cyclo-oxygenase inhibitor NS-398 had no effect. These data demonstrate that PPARgamma agonists can modulate inflammatory responses in brain. Because sustained medication with NSAIDs reduces the risk and delays the onset of AD, these results further suggest that NSAIDs provide therapeutic value by binding to PPARgamma present in AD brain, thereby preventing iNOS expression and neuronal cell death.
Enzymatically derived nitric oxide (NO) has been implicated in numerous physiological and pathological processes in the brain. Whereas during development NO participates in developmental and ...maturation processes, excess NO production in the adult in response to inflammation, injury, or trauma participates in both cell death and repair. The expression and activity of the inducible isoform of NO synthase (iNOS) play a pivotal role in sustained and elevated NO release. Recent evidence suggests that neurons can respond to proinflammatory stimuli and take part in brain inflammation. Neuronal iNOS expression has been described in different experimental settings, including cytokine stimulation of neuronal cell lines and primary neurons in vitro as well as in animal models of stroke and neurodegeneration. This article outlines different conditions leading to iNOS gene transcription and expression in neurons and neuronal cells and highlights the potential impact on human brain inflammation and neurodegeneration.
Degeneration of locus ceruleus (LC) neurons and reduced levels of norepinephrine (NE) in LC projection areas are well known features of Alzheimer's disease (AD); however, the consequences of those ...losses are not clear. Because inflammatory mediators contribute to AD pathogenesis and because NE can suppress inflammatory gene expression, we tested whether LC loss influenced the brain inflammatory gene expression elicited by amyloid beta (Abeta). Adult rats were injected with the selective neurotoxin N-(2-chloroethyl)-N-ethyl-2 bromobenzylamine (DSP4) to induce LC death and subsequently injected in the cortex with Abeta (aggregated 1-42 peptide). DSP4 treatment potentiated the Abeta-dependent induction of inflammatory nitric oxide synthase (iNOS), interleukin (IL)-1beta, and IL-6 expression compared with control animals. In contrast, the induction of cyclooxygenase-2 expression was not modified by DSP4 treatment. In control animals, injection of Abeta induced iNOS primarily in microglial cells, whereas in DSP4-treated animals, iNOS was localized to neurons, as is observed in AD brains. Injection of Abeta increased IL-1beta expression initially in microglia and at later times in astrocytes, and expression levels were greater in DSP4-treated animals than in controls. The potentiating effects of DSP4 treatment on iNOS and IL-1beta expression were attenuated by coinjection with NE or the beta-adrenergic receptor agonist isoproterenol. These data demonstrate that LC loss and NE depletion augment inflammatory responses to Abeta and suggest that LC loss in AD is permissive for increased inflammation and neuronal cell death.
PDF
