Roles of inflammation and apoptosis in experimental brain death-induced right ventricular failure.

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Belhaj, Asmae; Dewachter, Laurence; Rorive, Sandrine; Remmelink, Myriam; Weynand, Birgit; Melot, Christian; Galanti, Laurence; Hupkens, Emeline; Sprockeels, Thomas; Dewachter, Céline; Creteur, Jacques; McEntee, Kathleen; Naeije, Robert; Rondelet, Benoît

2016-12-01

Right ventricular (RV) dysfunction remains the leading cause of early death after cardiac transplantation. Methylprednisolone is used to improve graft quality; however, evidence for that remains empirical. We sought to determine whether methylprednisolone, acting on inflammation and apoptosis, might prevent brain death-induced RV dysfunction. After randomization to placebo (n = 11) or to methylprednisolone (n = 8; 15 mg/kg), 19 pigs were assigned to a brain-death procedure. The animals underwent hemodynamic evaluation at 1 and 5 hours after Cushing reflex (i.e., hypertension and bradycardia). The animals euthanized, and myocardial tissue was sampled. This was repeated in a control group (n = 8). At 5 hours after the Cushing reflex, brain death resulted in increased pulmonary artery pressure (27 ± 2 vs 18 ± 1 mm Hg) and in a 30% decreased ratio of end-systolic to pulmonary arterial elastances (Ees/Ea). Cardiac output and right atrial pressure did not change. This was prevented by methylprednisolone. Brain death-induced RV dysfunction was associated with increased RV expression of heme oxygenase-1, interleukin (IL)-6, IL-10, IL-1β, tumor necrosis factor (TNF)-α, IL-1 receptor-like (ST)-2, signal transducer and activator of transcription-3, intercellular adhesion molecules-1 and -2, vascular cell adhesion molecule-1, and neutrophil infiltration, whereas IL-33 expression decreased. RV apoptosis was confirmed by terminal deoxynucleotide transferase-mediated deoxy uridine triphosphate nick-end labeling staining. Methylprednisolone pre-treatment prevented RV-arterial uncoupling and decreased RV expression of TNF-α, IL-1 receptor-like-2, intercellular adhesion molecule-1, vascular cell adhesion molecule-1, and neutrophil infiltration. RV Ees/Ea was inversely correlated to RV TNF-α and IL-6 expression. Brain death-induced RV dysfunction is associated with RV activation of inflammation and apoptosis and is partly limited by methylprednisolone. Copyright © 2016

Cerebral volumes, neuronal integrity and brain inflammation measured by MRI in patients receiving PI monotherapy or triple therapy.

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Valero, Ignacio Pérez; Baeza, Alicia Gonzalez; Hernandez-Tamames, Juan Antonio; Monge, Susana; Arnalich, Francisco; Arribas, Jose Ramon

2014-01-01

Penetration of protease inhibitors (PI) in the central nervous system (CNS) is limited. Therefore, there are concerns about the capacity of PI monotherapy (MT) to control HIV in CNS and preserve brain integrity. Exploratory case-control study designed to compare neuronal integrity and brain inflammation in HIV-suppressed patients (>2 years) with and without neurocognitive impairment (NI), treated with MT or triple therapy (TT), 3-Tesla cerebral magnetic resonance image (MRI) and spectroscopy (MRS) were used to evaluate neuronal integrity (volume of cerebral structures and MRS levels of N-acetyl-aspartate (NAA)) and brain inflammation (MRS levels of myo-inositol (MI) and choline (CHO)). MRS biomarkers were measured in 4 voxels located in basal ganglia, frontal (2) and parietal lobes. A comprehensive battery of tests (14 tests - 7 domains) was used to diagnose neurocognitive impairment (1). We included 18 neurocognitively impaired patients (MT: 10, TT: 8) and 21 without NI (MT: 9; TT: 12, Table 1). Subset of patients with NI: cerebral volumes and MRS biomarkers were mostly similar between MT and TT with exception of the right cingulate nucleolus volume (MT: 8854±1851 vs TT: 10482±1107 mm(3); p<0.04), CHO levels in basal ganglia (MT: 0.44±0.05 vs TT: 0.37±0.03 MMOL/L; p<0.01) and the NAA levels in parietal lobe (MT: 1.49±0.12 vs 1.70±0.13 MMOL/L; p<0.01). Subset of patients without NI: cerebral volumes and MRS biomarkers were mostly similar between MT and TT with exception of MI levels in frontal lobe (MT: 1.20±0.36 vs 0.81±0.25 MMOL/L; p=0.01). We did not find significant differences in cerebral volumes or MRS biomarkers in most areas of the brain. However, we found higher levels of inflammation and neuronal damage in some brain areas of patients who received MT. This observation has to be taken into caution while we could not adjust our results by potential confounders. Further investigation is needed to confirm these preliminary results.

MALT1 Controls Attenuated Rabies Virus by Inducing Early Inflammation and T Cell Activation in the Brain.

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Kip, E; Staal, J; Verstrepen, L; Tima, H G; Terryn, S; Romano, M; Lemeire, K; Suin, V; Hamouda, A; Kalai, M; Beyaert, R; Van Gucht, S

2018-04-15

MALT1 is involved in the activation of immune responses, as well as in the proliferation and survival of certain cancer cells. MALT1 acts as a scaffold protein for NF-κB signaling and a cysteine protease that cleaves substrates, further promoting the expression of immunoregulatory genes. Deregulated MALT1 activity has been associated with autoimmunity and cancer, implicating MALT1 as a new therapeutic target. Although MALT1 deficiency has been shown to protect against experimental autoimmune encephalomyelitis, nothing is known about the impact of MALT1 on virus infection in the central nervous system. Here, we studied infection with an attenuated rabies virus, Evelyn-Rotnycki-Abelseth (ERA) virus, and observed increased susceptibility with ERA virus in MALT1 -/- mice. Indeed, after intranasal infection with ERA virus, wild-type mice developed mild transient clinical signs with recovery at 35 days postinoculation (dpi). Interestingly, MALT1 -/- mice developed severe disease requiring euthanasia at around 17 dpi. A decreased induction of inflammatory gene expression and cell infiltration and activation was observed in MALT1 -/- mice at 10 dpi compared to MALT1 +/+ infected mice. At 17 dpi, however, the level of inflammatory cell activation was comparable to that observed in MALT1 +/+ mice. Moreover, MALT1 -/- mice failed to produce virus-neutralizing antibodies. Similar results were obtained with specific inactivation of MALT1 in T cells. Finally, treatment of wild-type mice with mepazine, a MALT1 protease inhibitor, also led to mortality upon ERA virus infection. These data emphasize the importance of early inflammation and activation of T cells through MALT1 for controlling the virulence of an attenuated rabies virus in the brain. IMPORTANCE Rabies virus is a neurotropic virus which can infect any mammal. Annually, 59,000 people die from rabies. Effective therapy is lacking and hampered by gaps in the understanding of virus pathogenicity. MALT1 is an intracellular

Caspase Activation in Fetal Rat Brain Following Experimental Intrauterine Inflammation

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Sharangpani, Aditi; Takanohashi, Asako; Bell, Michael J.

2009-01-01

Intrauterine inflammation has been implicated in developmental brain injuries, including the development of periventricular leukomalacia (PVL) and cerebral palsy (CP). Previous studies in our rat model of intrauterine inflammation demonstrated apoptotic cell death in fetal brains within the first 5 days after lipopolysaccharide (LPS) administration to mothers and eventual dysmyelination. Cysteine-containing, aspartate-specific proteases, or caspases, are proteins involved with apoptosis through both intracellular (intrinsic pathway) and extracellular (extrinsic pathway) mechanisms. We hypothesized that cell death in our model would occur mainly via activation of the extrinsic pathway. We further hypothesized that Fas, a member of the tumor necrosis factor receptor (TNFR) superfamily, would be increased and the death inducing signaling complex (DISC) would be detectable. Pregnant rats were injected intracervically with LPS at E15 and immunoblotting, immunohistochemical and immunoprecipitation analyses were performed. The presence of the activated form of the effector caspase (caspase-3) was observed 24 h after LPS administration. Caspase activity assays demonstrated rapid increases in (i) caspases-9 and -10 within 1 h, (ii) caspase-8 at 2 h and (iii) caspase-3 at 4 h. At 24 h after LPS, activated caspase-3+/Fas+ cells were observed within the developing white matter. Lastly, the DISC complex (caspase-8, Fas and Fas-associated Death Domain (FADD)) was observed within 30 min by immunoprecipitation. Apoptosis in our model occurs via both extrinsic and intrinsic pathways, and activation of Fas may play a role. Understanding the mechanisms of cell death in models of intrauterine inflammation may affect development of future strategies to mitigate these injuries in children. PMID:18289516

White matter hyperintensities, systemic inflammation, brain growth, and cognitive functions in children exposed to air pollution.

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Calderón-Garcidueñas, Lilian; Mora-Tiscareño, Antonieta; Styner, Martin; Gómez-Garza, Gilberto; Zhu, Hongtu; Torres-Jardón, Ricardo; Carlos, Esperanza; Solorio-López, Edelmira; Medina-Cortina, Humberto; Kavanaugh, Michael; D'Angiulli, Amedeo

2012-01-01

Air pollution exposures are linked to neuroinflammation and neuropathology in young urbanites. Forty percent of exposed children and young adults exhibit frontal tau hyperphosphorylation and 51% have amyloid-β diffuse plaques compared to 0% in low pollution controls. In older adults, white matter hyperintensities (WMH) are associated with cognitive deficits while inflammatory markers correlate with greater atrophy than expected for age. We investigated patterns of WMH, magnetic resonance imaging (MRI) volume growth, blood inflammatory mediators, and cognition in matched children from two urban cohorts: one severely and one minimally exposed to air pollution. Baseline and one year follow-up measurements of cognitive abilities, brain MRI volumes, and blood were collected in 20 Mexico City (MC) children (10 with WMH+, and 10 without WMH-) and 10 matched controls (WMH-). MC WMH- children display the profile of classical pro-inflammatory defensive responses: high interleukin 12, production of powerful pro-inflammatory cytokines, and low concentrations of key cytokines and chemokines associated with neuroprotection. MC WMH+ children exhibit a response involved in resolution of inflammation, immunoregulation, and tissue remodeling. The MC WMH+ group responded to the air pollution-associated brain volumetric alterations with white and grey matter volume increases in temporal, parietal, and frontal regions and better cognitive performance compared to MC WMH-. We conclude that complex modulation of cytokines and chemokines influences children's central nervous system structural and volumetric responses and cognitive correlates resulting from environmental pollution exposures. Identification of biomarkers associating systemic inflammation to brain growth is critical for detecting children at higher risk for cognitive deficits and neurodegeneration, thereby warranting early implementation of neuroprotective measures.

Alterations in Brain Inflammation, Synaptic Proteins, and Adult Hippocampal Neurogenesis during Epileptogenesis in Mice Lacking Synapsin2.

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Deepti Chugh

Full Text Available Synapsins are pre-synaptic vesicle-associated proteins linked to the pathogenesis of epilepsy through genetic association studies in humans. Deletion of synapsins causes an excitatory/inhibitory imbalance, exemplified by the epileptic phenotype of synapsin knockout mice. These mice develop handling-induced tonic-clonic seizures starting at the age of about 3 months. Hence, they provide an opportunity to study epileptogenic alterations in a temporally controlled manner. Here, we evaluated brain inflammation, synaptic protein expression, and adult hippocampal neurogenesis in the epileptogenic (1 and 2 months of age and tonic-clonic (3.5-4 months phase of synapsin 2 knockout mice using immunohistochemical and biochemical assays. In the epileptogenic phase, region-specific microglial activation was evident, accompanied by an increase in the chemokine receptor CX3CR1, interleukin-6, and tumor necrosis factor-α, and a decrease in chemokine keratinocyte chemoattractant/ growth-related oncogene. Both post-synaptic density-95 and gephyrin, scaffolding proteins at excitatory and inhibitory synapses, respectively, showed a significant up-regulation primarily in the cortex. Furthermore, we observed an increase in the inhibitory adhesion molecules neuroligin-2 and neurofascin and potassium chloride co-transporter KCC2. Decreased expression of γ-aminobutyric acid receptor-δ subunit and cholecystokinin was also evident. Surprisingly, hippocampal neurogenesis was reduced in the epileptogenic phase. Taken together, we report molecular alterations in brain inflammation and excitatory/inhibitory balance that could serve as potential targets for therapeutics and diagnostic biomarkers. In addition, the regional differences in brain inflammation and synaptic protein expression indicate an epileptogenic zone from where the generalized seizures in synapsin 2 knockout mice may be initiated or spread.

Early Effects of Lipopolysaccharide-Induced Inflammation on Foetal Brain Development in Rat

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Cristina A Ghiani

2011-10-01

Full Text Available Studies in humans and animal models link maternal infection and imbalanced levels of inflammatory mediators in the foetal brain to the aetiology of neuropsychiatric disorders. In a number of animal models, it was shown that exposure to viral or bacterial agents during a period that corresponds to the second trimester in human gestation triggers brain and behavioural abnormalities in the offspring. However, little is known about the early cellular and molecular events elicited by inflammation in the foetal brain shortly after maternal infection has occurred. In this study, maternal infection was mimicked by two consecutive intraperitoneal injections of 200 μg of LPS (lipopolysaccharide/kg to timed-pregnant rats at GD15 (gestational day 15 and GD16. Increased thickness of the CP (cortical plate and hippocampus together with abnormal distribution of immature neuronal markers and decreased expression of markers for neural progenitors were observed in the LPS-exposed foetal forebrains at GD18. Such effects were accompanied by decreased levels of reelin and the radial glial marker GLAST (glial glutamate transporter, and elevated levels of pro-inflammatory cytokines in maternal serum and foetal forebrains. Foetal inflammation elicited by maternal injections of LPS has discrete detrimental effects on brain development. The early biochemical and morphological changes described in this work begin to explain the sequelae of early events that underlie the neurobehavioural deficits reported in humans and animals exposed to prenatal insults.

NF-kB as a mediator of brain inflammation in AD.

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Hong, Jin Tae

2017-08-07

Alzheimer's disease is the most common form of dementia. It is characterized by beta-amyloid peptide fibrils which are extracellular deposition of a specific protein, and is accompanied by extensive neuroinflammation. Various studies show the presence of a number of inflammation markers in the AD brain: elevated inflammatory cytokines and chemokines, and an accumulation of activated microglia in the damaged regions. NF-kB is a redox of transcriptional factors, and it is known to be located in the genes involved in amyloidogenesis and inflammation. Epidemiological studies have shown that NF-kB is elevated in the AD patient brain, and long-term use of non-steroidal anti-inflammatory drugs suppresses the progression of AD and delays its onset, suggesting that there is a close correlation between NF-kB and AD pathogenesis. This study is (1) to assess the association between NF-kB activity and AD through discussion of a variety of experimental and clinical studies on AD and (2) to review treatment strategies designed to treat or prevent AD with NF-kB inhibitors. Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.org.

Early Brain Injury Associated with Systemic Inflammation After Subarachnoid Hemorrhage.

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Savarraj, Jude; Parsha, Kaushik; Hergenroeder, Georgene; Ahn, Sungho; Chang, Tiffany R; Kim, Dong H; Choi, H Alex

2018-04-01

Early brain injury (EBI) after aneurysmal subarachnoid hemorrhage (aSAH) is defined as brain injury occurring within 72 h of aneurysmal rupture. Although EBI is the most significant predictor of outcomes after aSAH, its underlying pathophysiology is not well understood. We hypothesize that EBI after aSAH is associated with an increase in peripheral inflammation measured by cytokine expression levels and changes in associations between cytokines. aSAH patients were enrolled into a prospective observational study and were assessed for markers of EBI: global cerebral edema (GCE), subarachnoid hemorrhage early brain edema score (SEBES), and Hunt-Hess grade. Serum samples collected at ≤ 48 h of admission were analyzed using multiplex bead-based assays to determine levels of 13 pro- and anti-inflammatory cytokines. Pairwise correlation coefficients between cytokines were represented as networks. Cytokine levels and differences in correlation networks were compared between EBI groups. Of the 71 patients enrolled in the study, 17 (24%) subjects had GCE, 31 (44%) subjects had SEBES ≥ 3, and 21 (29%) had HH ≥ 4. IL-6 was elevated in groups with GCE, SEBES ≥ 3, and HH ≥ 4. MIP1β was independently associated with high-grade SEBES. Correlation network analysis suggests higher systematic inflammation in subjects with SEBES ≥ 3. EBI after SAH is associated with increased levels of specific cytokines. Peripheral levels of IL-10, IL-6, and MIP1β may be important markers of EBI. Investigating systematic correlations in addition to expression levels of individual cytokines may offer deeper insight into the underlying mechanisms related to EBI.

Minocycline Protects Against NLRP3 Inflammasome-Induced Inflammation and P53-Associated Apoptosis in Early Brain Injury After Subarachnoid Hemorrhage.

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Li, Jianru; Chen, Jingsen; Mo, Hangbo; Chen, Jingyin; Qian, Cong; Yan, Feng; Gu, Chi; Hu, Qiang; Wang, Lin; Chen, Gao

2016-05-01

Minocycline has beneficial effects in early brain injury (EBI) following subarachnoid hemorrhage (SAH); however, the molecular mechanisms underlying these effects have not been clearly identified. This study was undertaken to determine the influence of minocycline on inflammation and neural apoptosis and the possible mechanisms of these effects in early brain injury following subarachnoid hemorrhage. SAH was induced by the filament perforation model of SAH in male Sprague-Dawley rats. Minocycline or vehicle was given via an intraperitoneal injection 1 h after SAH induction. Minocycline treatment markedly attenuated brain edema secondary to blood-brain barrier (BBB) dysfunction by inhibiting NLRP3 inflammasome activation, which controls the maturation and release of pro-inflammatory cytokines, especially interleukin-1β (IL-1β). Minocycline treatment also markedly reduced the number of terminal deoxynucleotidyl transferase-mediated deoxyuridine triphosphate nick-end labeling (TUNEL)-positive cells. To further identify the potential mechanisms, we demonstrated that minocycline increased Bcl2 expression and reduced the protein expression of P53, Bax, and cleaved caspase-3. In addition, minocycline reduced the cortical levels of reactive oxygen species (ROS), which are closely related to both NLRP3 inflammasome and P53 expression. Minocycline protects against NLRP3 inflammasome-induced inflammation and P53-associated apoptosis in early brain injury following SAH. Minocycline's anti-inflammatory and anti-apoptotic effect may involve the reduction of ROS. Minocycline treatment may exhibit important clinical potentials in the management of SAH.

Disruption in the Blood-Brain Barrier: The Missing Link between Brain and Body Inflammation in Bipolar Disorder?

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Jay P. Patel

2015-01-01

Full Text Available The blood-brain barrier (BBB regulates the transport of micro- and macromolecules between the peripheral blood and the central nervous system (CNS in order to maintain optimal levels of essential nutrients and neurotransmitters in the brain. In addition, the BBB plays a critical role protecting the CNS against neurotoxins. There has been growing evidence that BBB disruption is associated with brain inflammatory conditions such as Alzheimer’s disease and multiple sclerosis. Considering the increasing role of inflammation and oxidative stress in the pathophysiology of bipolar disorder (BD, here we propose a novel model wherein transient or persistent disruption of BBB integrity is associated with decreased CNS protection and increased permeability of proinflammatory (e.g., cytokines, reactive oxygen species substances from the peripheral blood into the brain. These events would trigger the activation of microglial cells and promote localized damage to oligodendrocytes and the myelin sheath, ultimately compromising myelination and the integrity of neural circuits. The potential implications for research in this area and directions for future studies are discussed.

Cerebral amyloid angiopathy-related inflammation presenting with steroid-responsive higher brain dysfunction: case report and review of the literature

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Maeda Yasushi

2011-09-01

Full Text Available Abstract A 56-year-old man noticed discomfort in his left lower limb, followed by convulsion and numbness in the same area. Magnetic resonance imaging (MRI showed white matter lesions in the right parietal lobe accompanied by leptomeningeal or leptomeningeal and cortical post-contrast enhancement along the parietal sulci. The patient also exhibited higher brain dysfunction corresponding with the lesions on MRI. Histological pathology disclosed β-amyloid in the blood vessels and perivascular inflammation, which highlights the diagnosis of cerebral amyloid angiopathy (CAA-related inflammation. Pulse steroid therapy was so effective that clinical and radiological findings immediately improved. CAA-related inflammation is a rare disease, defined by the deposition of amyloid proteins within the leptomeningeal and cortical arteries associated with vasculitis or perivasculitis. Here we report a patient with CAA-related inflammation who showed higher brain dysfunction that improved with steroid therapy. In cases with atypical radiological lesions like our case, cerebral biopsy with histological confirmation remains necessary for an accurate diagnosis.

Glucose transport in brain - effect of inflammation.

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Jurcovicova, J

2014-01-01

membrane to transport glucose into cells, and GLUT8 from cytosol to rough endoplasmic reticulum to recover redundant glucose to cytosol after protein glycosylation. In autoimmune diseases, the enhanced glucose uptake was found in inflamed peripheral tissue, mainly due to proliferating fibroblasts and activated macrophages. In our experimental model of rheumatoid arthritis (adjuvant arthritis), enhanced 2-deoxy-2[F-18]fluoro-D-glucose was found in the hippocampus and amygdala two days after the induction of the disease which, similarly as in the peripheral joints, can be ascribed to the activated macrophages. The knowledge on the glucose transport and the role of glucose transporters in the brain during systemic autoimmune inflammation is still incomplete and needs further investigations.

Brain "fog," inflammation and obesity : key aspects of neuropsychiatric disorders improved by luteolin

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Theoharis Constantin Theoharides

2015-07-01

Full Text Available Brain fog is a constellation of symptoms that include reduced cognition, inability to concentrate and multitask, as well as loss of short and long term memory. Brain fog characterizes patients with autism spectrum disorders (ASDs, celiac disease, chronic fatigue syndrome, fibromyalgia, mastocytosis and postural tachycardia syndrome (POTS, as well as minimal cognitive impairment, an early clinical presentation of Alzheimer’s disease (AD, and other neuropsychiatric disorders. Brain fog may be due to inflammatory molecules, including adipocytokines and histamine released from mast cells (MCs further stimulating microglia activation, and causing focal brain inflammation. Recent reviews have described the potential use of natural flavonoids for the treatment of neuropsychiatric and neurodegenerative diseases. The flavone luteolin has numerous useful actions that include: anti-oxidant, anti-inflammatory, microglia inhibition, neuroprotection, and memory increase. A liposomal luteolin formulation in olive fruit extract improved attention in children with ASDs and brain fog in mastocytosis patients. Methylated luteolin analogues with increased activity and better bioavailability could be developed into effective treatments for neuropsychiatric disorders and brain fog.

Brain "fog," inflammation and obesity: key aspects of neuropsychiatric disorders improved by luteolin.

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Theoharides, Theoharis C; Stewart, Julia M; Hatziagelaki, Erifili; Kolaitis, Gerasimos

2015-01-01

Brain "fog" is a constellation of symptoms that include reduced cognition, inability to concentrate and multitask, as well as loss of short and long term memory. Brain "fog" characterizes patients with autism spectrum disorders (ASDs), celiac disease, chronic fatigue syndrome, fibromyalgia, mastocytosis, and postural tachycardia syndrome (POTS), as well as "minimal cognitive impairment," an early clinical presentation of Alzheimer's disease (AD), and other neuropsychiatric disorders. Brain "fog" may be due to inflammatory molecules, including adipocytokines and histamine released from mast cells (MCs) further stimulating microglia activation, and causing focal brain inflammation. Recent reviews have described the potential use of natural flavonoids for the treatment of neuropsychiatric and neurodegenerative diseases. The flavone luteolin has numerous useful actions that include: anti-oxidant, anti-inflammatory, microglia inhibition, neuroprotection, and memory increase. A liposomal luteolin formulation in olive fruit extract improved attention in children with ASDs and brain "fog" in mastocytosis patients. Methylated luteolin analogs with increased activity and better bioavailability could be developed into effective treatments for neuropsychiatric disorders and brain "fog."

Treatment with gelsolin reduces brain inflammation and apoptotic signaling in mice following thermal injury.

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Zhang, Qing-Hong; Chen, Qi; Kang, Jia-Rui; Liu, Chen; Dong, Ning; Zhu, Xiao-Mei; Sheng, Zhi-Yong; Yao, Yong-Ming

2011-09-21

Burn survivors develop long-term cognitive impairment with increased inflammation and apoptosis in the brain. Gelsolin, an actin-binding protein with capping and severing activities, plays a crucial role in the septic response. We investigated if gelsolin infusion could attenuate neural damage in burned mice. Mice with 15% total body surface area burns were injected intravenously with bovine serum albumin as placebo (2 mg/kg), or with low (2 mg/kg) or high doses (20 mg/kg) of gelsolin. Samples were harvested at 8, 24, 48 and 72 hours postburn. The immune function of splenic T cells was analyzed. Cerebral pathology was examined by hematoxylin/eosin staining, while activated glial cells and infiltrating leukocytes were detected by immunohistochemistry. Cerebral cytokine mRNAs were further assessed by quantitative real-time PCR, while apoptosis was evaluated by caspase-3. Neural damage was determined using enzyme-linked immunosorbent assay of neuron-specific enolase (NSE) and soluble protein-100 (S-100). Finally, cerebral phospho-ERK expression was measured by western blot. Gelsolin significantly improved the outcomes of mice following major burns in a dose-dependent manner. The survival rate was improved by high dose gelsolin treatment compared with the placebo group (56.67% vs. 30%). Although there was no significant improvement in outcome in mice receiving low dose gelsolin (30%), survival time was prolonged against the placebo control (43.1 ± 4.5 h vs. 35.5 ± 5.0 h; P Burn-induced T cell suppression was greatly alleviated by high dose gelsolin treatment. Concurrently, cerebral abnormalities were greatly ameliorated as shown by reduced NSE and S-100 content of brain, decreased cytokine mRNA expressions, suppressed microglial activation, and enhanced infiltration of CD11b+ and CD45+ cells into the brain. Furthermore, the elevated caspase-3 activity seen following burn injury was remarkably reduced by high dose gelsolin treatment along with down-regulation of

Attenuating brain inflammation, ischemia, and oxidative damage by hyperbaric oxygen in diabetic rats after heat stroke

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Kai-Li Lee

2013-08-01

Conclusion: Our results suggest that, in diabetic animals, HBO2 therapy may improve outcomes of HS in part by reducing heat-induced activated inflammation and ischemic and oxidative damage in the hypothalamus and other brain regions.

Modulation of experimental arthritis by vagal sensory and central brain stimulation.

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Bassi, Gabriel Shimizu; Dias, Daniel Penteado Martins; Franchin, Marcelo; Talbot, Jhimmy; Reis, Daniel Gustavo; Menezes, Gustavo Batista; Castania, Jaci Airton; Garcia-Cairasco, Norberto; Resstel, Leonardo Barbosa Moraes; Salgado, Helio Cesar; Cunha, Fernando Queiróz; Cunha, Thiago Mattar; Ulloa, Luis; Kanashiro, Alexandre

2017-08-01

Articular inflammation is a major clinical burden in multiple inflammatory diseases, especially in rheumatoid arthritis. Biological anti-rheumatic drug therapies are expensive and increase the risk of systemic immunosuppression, infections, and malignancies. Here, we report that vagus nerve stimulation controls arthritic joint inflammation by inducing local regulation of innate immune response. Most of the previous studies of neuromodulation focused on vagal regulation of inflammation via the efferent peripheral pathway toward the viscera. Here, we report that vagal stimulation modulates arthritic joint inflammation through a novel "afferent" pathway mediated by the locus coeruleus (LC) of the central nervous system. Afferent vagal stimulation activates two sympatho-excitatory brain areas: the paraventricular hypothalamic nucleus (PVN) and the LC. The integrity of the LC, but not that of the PVN, is critical for vagal control of arthritic joint inflammation. Afferent vagal stimulation suppresses articular inflammation in the ipsilateral, but not in the contralateral knee to the hemispheric LC lesion. Central stimulation is followed by subsequent activation of joint sympathetic nerve terminals inducing articular norepinephrine release. Selective adrenergic beta-blockers prevent the effects of articular norepinephrine and thereby abrogate vagal control of arthritic joint inflammation. These results reveals a novel neuro-immune brain map with afferent vagal signals controlling side-specific articular inflammation through specific inflammatory-processing brain centers and joint sympathetic innervations. Copyright © 2017 Elsevier Inc. All rights reserved.

More inflammation but less brain-derived neurotrophic factor in antisocial personality disorder.

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Wang, Tzu-Yun; Lee, Sheng-Yu; Hu, Ming-Chuan; Chen, Shiou-Lan; Chang, Yun-Hsuan; Chu, Chun-Hsien; Lin, Shih-Hsien; Li, Chia-Ling; Wang, Liang-Jen; Chen, Po See; Chen, Shih-Heng; Huang, San-Yuan; Tzeng, Nian-Sheng; Lee, I Hui; Chen, Kao Chin; Yang, Yen Kuang; Hong, Jau-Shyong; Lu, Ru-Band

2017-11-01

Antisocial personality disorder (ASPD) is highly comorbid with substance use disorders (SUDs). We hypothesize that chronic neuroinflammation and the loss of neurotrophic factors prompts the pathogenesis of both disorders. We used ELISA to measure plasma levels of proinflammatory (tumor necrosis factor-α [TNF-α], C-reactive protein [CRP]) and anti-inflammatory factors (transforming growth factor-β1 [TGF-β1] and interleukin-10 [IL-10]), and brain-derived neurotrophic factor (BDNF) in male patients with ASPD (n=74), SUDs (n=168), ASPD comorbid with SUDs (ASPD+SUDs) (n=438), and Healthy Controls (HCs) (n=81). A multivariate analysis of covariance (MANCOVA) controlled for possible confounders was used to compare cytokines and BDNF levels between groups. The results of MANCOVA adjusted for age showed a significant (pdisorder (OUD) and other SUDs groups showed that the IL-10 levels were specifically higher in OUD and ASPD±OUD groups than other SUDs (P≤0.001). We conclude that uncontrolled inflammation and losing neurotrophic factors, with or without comorbid SUDs, underlies ASPD. IL-10 expression might be more specifically associated with OUD. Copyright © 2017 Elsevier Ltd. All rights reserved.

Influence of age on brain edema formation, secondary brain damage and inflammatory response after brain trauma in mice.

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Ralph Timaru-Kast

Full Text Available After traumatic brain injury (TBI elderly patients suffer from higher mortality rate and worse functional outcome compared to young patients. However, experimental TBI research is primarily performed in young animals. Aim of the present study was to clarify whether age affects functional outcome, neuroinflammation and secondary brain damage after brain trauma in mice. Young (2 months and old (21 months male C57Bl6N mice were anesthetized and subjected to a controlled cortical impact injury (CCI on the right parietal cortex. Animals of both ages were randomly assigned to 15 min, 24 h, and 72 h survival. At the end of the observation periods, contusion volume, brain water content, neurologic function, cerebral and systemic inflammation (CD3+ T cell migration, inflammatory cytokine expression in brain and lung, blood differential cell count were determined. Old animals showed worse neurological function 72 h after CCI and a high mortality rate (19.2% compared to young (0%. This did not correlate with histopathological damage, as contusion volumes were equal in both age groups. Although a more pronounced brain edema formation was detected in old mice 24 hours after TBI, lack of correlation between brain water content and neurological deficit indicated that brain edema formation is not solely responsible for age-dependent differences in neurological outcome. Brains of old naïve mice were about 8% smaller compared to young naïve brains, suggesting age-related brain atrophy with possible decline in plasticity. Onset of cerebral inflammation started earlier and primarily ipsilateral to damage in old mice, whereas in young mice inflammation was delayed and present in both hemispheres with a characteristic T cell migration pattern. Pulmonary interleukin 1β expression was up-regulated after cerebral injury only in young, not aged mice. The results therefore indicate that old animals are prone to functional deficits and strong ipsilateral cerebral

Brain acetylcholinesterase activity controls systemic cytokine levels through the cholinergic anti-inflammatory pathway

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Pavlov, Valentin A.; Parrish, William R.; Rosas-Ballina, Mauricio; Ochani, Mahendar; Puerta, Margot; Ochani, Kanta; Chavan, Sangeeta; Al-Abed, Yousef; Tracey, Kevin J.

2015-01-01

The excessive release of cytokines by the immune system contributes importantly to the pathogenesis of inflammatory diseases. Recent advances in understanding the biology of cytokine toxicity led to the discovery of the “cholinergic anti-inflammatory pathway,” defined as neural signals transmitted via the vagus nerve that inhibit cytokine release through a mechanism that requires the alpha7 subunit-containing nicotinic acetylcholine receptor (α7nAChR). Vagus nerve regulation of peripheral functions is controlled by brain nuclei and neural networks, but despite considerable importance, little is known about the molecular basis for central regulation of the vagus nerve-based cholinergic anti-inflammatory pathway. Here we report that brain acetylcholinesterase activity controls systemic and organ specific TNF production during endotoxemia. Peripheral administration of the acetylcholinesterase inhibitor galantamine significantly reduced serum TNF levels through vagus nerve signaling, and protected against lethality during murine endotoxemia. Administration of a centrally-acting muscarinic receptor antagonist abolished the suppression of TNF by galantamine, indicating that suppressing acetylcholinesterase activity, coupled with central muscarinic receptors, controls peripheral cytokine responses. Administration of galantamine to α7nAChR knockout mice failed to suppress TNF levels, indicating that the α7nAChR-mediated cholinergic anti-inflammatory pathway is required for the anti-inflammatory effect of galantamine. These findings show that inhibition of brain acetylcholinesterase suppresses systemic inflammation through a central muscarinic receptor-mediated and vagal- and α7nAChR-dependent mechanism. Our data also indicate that a clinically used centrally-acting acetylcholinesterase inhibitor can be utilized to suppress abnormal inflammation to therapeutic advantage. PMID:18639629

Extracellular vesicle-mediated transfer of genetic information between the hematopoietic system and the brain in response to inflammation.

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Kirsten Ridder

2014-06-01

Full Text Available Mechanisms behind how the immune system signals to the brain in response to systemic inflammation are not fully understood. Transgenic mice expressing Cre recombinase specifically in the hematopoietic lineage in a Cre reporter background display recombination and marker gene expression in Purkinje neurons. Here we show that reportergene expression in neurons is caused by intercellular transfer of functional Cre recombinase messenger RNA from immune cells into neurons in the absence of cell fusion. In vitro purified secreted extracellular vesicles (EVs from blood cells contain Cre mRNA, which induces recombination in neurons when injected into the brain. Although Cre-mediated recombination events in the brain occur very rarely in healthy animals, their number increases considerably in different injury models, particularly under inflammatory conditions, and extend beyond Purkinje neurons to other neuronal populations in cortex, hippocampus, and substantia nigra. Recombined Purkinje neurons differ in their miRNA profile from their nonrecombined counterparts, indicating physiological significance. These observations reveal the existence of a previously unrecognized mechanism to communicate RNA-based signals between the hematopoietic system and various organs, including the brain, in response to inflammation.

Hypothalamic inflammation: a double-edged sword to nutritional diseases

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Cai, Dongsheng; Liu, Tiewen

2015-01-01

The hypothalamus is one of the master regulators of various physiological processes, including energy balance and nutrient metabolism. These regulatory functions are mediated by discrete hypothalamic regions that integrate metabolic sensing with neuroendocrine and neural controls of systemic physiology. Neurons and non-neuronal cells in these hypothalamic regions act supportively to execute metabolic regulations. Under conditions of brain and hypothalamic inflammation, which may result from overnutrition-induced intracellular stresses or disease-associated systemic inflammatory factors, extracellular and intracellular environments of hypothalamic cells are disrupted, leading to central metabolic dysregulations and various diseases. Recent research has begun to elucidate the effects of hypothalamic inflammation in causing diverse components of metabolic syndrome leading to diabetes and cardiovascular disease. These new understandings have provocatively expanded previous knowledge on the cachectic roles of brain inflammatory response in diseases, such as infections and cancers. This review describes the molecular and cellular characteristics of hypothalamic inflammation in metabolic syndrome and related diseases as opposed to cachectic diseases, and also discusses concepts and potential applications of inhibiting central/hypothalamic inflammation to treat nutritional diseases. PMID:22417140

Global loss of acetylcholinesterase activity with mitochondrial complexes inhibition and inflammation in brain of hypercholesterolemic mice.

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Paul, Rajib; Borah, Anupom

2017-12-20

There exists an intricate relationship between hypercholesterolemia (elevated plasma cholesterol) and brain functions. The present study aims to understand the impact of hypercholesterolemia on pathological consequences in mouse brain. A chronic mouse model of hypercholesterolemia was induced by giving high-cholesterol diet for 12 weeks. The hypercholesterolemic mice developed cognitive impairment as evident from object recognition memory test. Cholesterol accumulation was observed in four discrete brain regions, such as cortex, striatum, hippocampus and substantia nigra along with significantly damaged blood-brain barrier by hypercholesterolemia. The crucial finding is the loss of acetylcholinesterase activity with mitochondrial dysfunction globally in the brain of hypercholesterolemic mice, which is related to the levels of cholesterol. Moreover, the levels of hydroxyl radical were elevated in the regions of brain where the activity of mitochondrial complexes was found to be reduced. Intriguingly, elevations of inflammatory stress markers in the cholesterol-rich brain regions were observed. As cognitive impairment, diminished brain acetylcholinesterase activity, mitochondrial dysfunctions, and inflammation are the prima facie pathologies of neurodegenerative diseases, the findings impose hypercholesterolemia as potential risk factor towards brain dysfunction.

Maternal Inflammation Contributes to Brain Overgrowth and Autism-Associated Behaviors through Altered Redox Signaling in Stem and Progenitor Cells

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Janel E. Le Belle

2014-11-01

Full Text Available A period of mild brain overgrowth with an unknown etiology has been identified as one of the most common phenotypes in autism. Here, we test the hypothesis that maternal inflammation during critical periods of embryonic development can cause brain overgrowth and autism-associated behaviors as a result of altered neural stem cell function. Pregnant mice treated with low-dose lipopolysaccharide at embryonic day 9 had offspring with brain overgrowth, with a more pronounced effect in PTEN heterozygotes. Exposure to maternal inflammation also enhanced NADPH oxidase (NOX-PI3K pathway signaling, stimulated the hyperproliferation of neural stem and progenitor cells, increased forebrain microglia, and produced abnormal autism-associated behaviors in affected pups. Our evidence supports the idea that a prenatal neuroinflammatory dysregulation in neural stem cell redox signaling can act in concert with underlying genetic susceptibilities to affect cellular responses to environmentally altered cellular levels of reactive oxygen species.

Linking Inflammation, Cardiorespiratory Variability, and Neural Control in Acute Inflammation via Computational Modeling.

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Dick, Thomas E; Molkov, Yaroslav I; Nieman, Gary; Hsieh, Yee-Hsee; Jacono, Frank J; Doyle, John; Scheff, Jeremy D; Calvano, Steve E; Androulakis, Ioannis P; An, Gary; Vodovotz, Yoram

2012-01-01

Acute inflammation leads to organ failure by engaging catastrophic feedback loops in which stressed tissue evokes an inflammatory response and, in turn, inflammation damages tissue. Manifestations of this maladaptive inflammatory response include cardio-respiratory dysfunction that may be reflected in reduced heart rate and ventilatory pattern variabilities. We have developed signal-processing algorithms that quantify non-linear deterministic characteristics of variability in biologic signals. Now, coalescing under the aegis of the NIH Computational Biology Program and the Society for Complexity in Acute Illness, two research teams performed iterative experiments and computational modeling on inflammation and cardio-pulmonary dysfunction in sepsis as well as on neural control of respiration and ventilatory pattern variability. These teams, with additional collaborators, have recently formed a multi-institutional, interdisciplinary consortium, whose goal is to delineate the fundamental interrelationship between the inflammatory response and physiologic variability. Multi-scale mathematical modeling and complementary physiological experiments will provide insight into autonomic neural mechanisms that may modulate the inflammatory response to sepsis and simultaneously reduce heart rate and ventilatory pattern variabilities associated with sepsis. This approach integrates computational models of neural control of breathing and cardio-respiratory coupling with models that combine inflammation, cardiovascular function, and heart rate variability. The resulting integrated model will provide mechanistic explanations for the phenomena of respiratory sinus-arrhythmia and cardio-ventilatory coupling observed under normal conditions, and the loss of these properties during sepsis. This approach holds the potential of modeling cross-scale physiological interactions to improve both basic knowledge and clinical management of acute inflammatory diseases such as sepsis and trauma.

Silver nanoparticles reduce brain inflammation and related neurotoxicity through induction of H2S-synthesizing enzymes

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Gonzalez-Carter, Daniel A.; Leo, Bey Fen; Ruenraroengsak, Pakatip; Chen, Shu; Goode, Angela E.; Theodorou, Ioannis G.; Chung, Kian Fan; Carzaniga, Raffaella; Shaffer, Milo S. P.; Dexter, David T.; Ryan, Mary P.; Porter, Alexandra E.

2017-03-01

Silver nanoparticles (AgNP) are known to penetrate into the brain and cause neuronal death. However, there is a paucity in studies examining the effect of AgNP on the resident immune cells of the brain, microglia. Given microglia are implicated in neurodegenerative disorders such as Parkinson’s disease (PD), it is important to examine how AgNPs affect microglial inflammation to fully assess AgNP neurotoxicity. In addition, understanding AgNP processing by microglia will allow better prediction of their long term bioreactivity. In the present study, the in vitro uptake and intracellular transformation of citrate-capped AgNPs by microglia, as well as their effects on microglial inflammation and related neurotoxicity were examined. Analytical microscopy demonstrated internalization and dissolution of AgNPs within microglia and formation of non-reactive silver sulphide (Ag2S) on the surface of AgNPs. Furthermore, AgNP-treatment up-regulated microglial expression of the hydrogen sulphide (H2S)-synthesizing enzyme cystathionine-γ-lyase (CSE). In addition, AgNPs showed significant anti-inflammatory effects, reducing lipopolysaccharide (LPS)-stimulated ROS, nitric oxide and TNFα production, which translated into reduced microglial toxicity towards dopaminergic neurons. Hence, the present results indicate that intracellular Ag2S formation, resulting from CSE-mediated H2S production in microglia, sequesters Ag+ ions released from AgNPs, significantly limiting their toxicity, concomitantly reducing microglial inflammation and related neurotoxicity.

Influence of a brief episode of anesthesia during the induction of experimental brain trauma on secondary brain damage and inflammation.

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Clara Luh

Full Text Available It is unclear whether a single, brief, 15-minute episode of background anesthesia already modulates delayed secondary processes after experimental brain injury. Therefore, this study was designed to characterize three anesthesia protocols for their effect on molecular and histological study endpoints. Mice were randomly separated into groups that received sevoflurane (sevo, isoflurane (iso or an intraperitoneal anesthetic combination (midazolam, fentanyl and medetomidine; comb prior to traumatic brain injury (controlled cortical impact, CCI; 8 m/s, 1 mm impact depth, 3 mm diameter. Twenty-four hours after insult, histological brain damage, neurological function (via neurological severity score, cerebral inflammation (via real-time RT-PCR for IL6, COX-2, iNOS and microglia (via immunohistochemical staining for Iba1 were determined. Fifteen minutes after CCI, the brain contusion volume did not differ between the anesthetic regimens (sevo = 17.9±5.5 mm(3; iso = 20.5±3.7 mm(3; comb = 19.5±4.6 mm(3. Within 24 hours after injury, lesion size increased in all groups (sevo = 45.3±9.0 mm(3; iso = 31.5±4.0 mm(3; comb = 44.2±6.2 mm(3. Sevo and comb anesthesia resulted in a significantly larger contusion compared to iso, which was in line with the significantly better neurological function with iso (sevo = 4.6±1.3 pts.; iso = 3.9±0.8 pts.; comb = 5.1±1.6 pts.. The expression of inflammatory marker genes was not significantly different at 15 minutes and 24 hours after CCI. In contrast, significantly more Iba1-positive cells were present in the pericontusional region after sevo compared to comb anesthesia (sevo = 181±48/mm(3; iso = 150±36/mm(3; comb = 113±40/mm(3. A brief episode of anesthesia, which is sufficient for surgical preparations of mice for procedures such as delivering traumatic brain injury, already has a significant impact on the extent of secondary brain damage.

Donor dopamine treatment in brain dead rats is associated with an improvement in renal function early after transplantation and a reduction in renal inflammation

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Hoeger, Simone; Reisenbuechler, Anke; Gottmann, Uwe; Doyon, Fabian; Braun, Claude; Kaya, Ziya; Seelen, Marc A.; van Son, Willem J.; Waldherr, Ruediger; Schnuelle, Peter; Yard, Benito A.

Brain death (BD) is associated with tissue inflammation. As dopamine treatment of BD donor rats reduces renal monocyte infiltration, we tested if this treatment affects renal function and inflammation in recipients. BD was induced in F344 rats and was maintained for 6 h in all experiments. Dopamine

Association between brain natriuretic peptide, markers of inflammation and the objective and subjective response to cardiac resynchronization therapy

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Brouwers, Corline; Versteeg, Henneke; Meine, Mathias

2014-01-01

Introduction: Studies suggest that cardiac resynchronization therapy (CRT) can induce a decrease in brain natriuretic peptide (BNP) and systemic inflammation, which may be associated with CRT-response. However, the evidence is inconclusive. We examined levels of BNP and inflammatory markers from...... ventricular end systolic volume; subjective CRT-response was defined as an improvement of ⩾10 points in patient-reported health status assessed with the Kansas City Cardiomyopathy Questionnaire. Plasma BNP and markers of inflammation (CRP, IL-6, TNFα, sTNFr1 and sTNFr2) were measured at three time points...... is not automatically related to a stronger overall decrease in inflammation. Large-scale studies are warranted that further examine the relation between the clinical effects of CRT on inflammatory markers, as the latter have been associated with poor prognosis in heart failure....

Attenuation of prostaglandin E2 elimination across the mouse blood-brain barrier in lipopolysaccharide-induced inflammation and additive inhibitory effect of cefmetazole

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Akanuma Shin-ichi

2011-10-01

Full Text Available Abstract Background Peripheral administration of lipopolysaccharide (LPS induces inflammation and increases cerebral prostaglandin E2 (PGE2 concentration. PGE2 is eliminated from brain across the blood-brain barrier (BBB in mice, and this process is inhibited by intracerebral or intravenous pre-administration of anti-inflammatory drugs and antibiotics such as cefmetazole and cefazolin that inhibit multidrug resistance-associated protein 4 (Mrp4/Abcc4-mediated PGE2 transport. The purpose of this study was to examine the effect of LPS-induced inflammation on PGE2 elimination from brain, and whether antibiotics further inhibit PGE2 elimination in LPS-treated mice. Methods [3H]PGE2 elimination across the BBB of intraperitoneally LPS-treated mice was assessed by the brain efflux index (BEI method. Transporter protein amounts in brain capillaries were quantified by liquid chromatography-tandem mass spectrometry. Results The apparent elimination rate of [3H]PGE2 from brain was lower by 87%, in LPS-treated mice compared with saline-treated mice. The Mrp4 protein amount was unchanged in brain capillaries of LPS-treated mice compared with saline-treated mice, while the protein amounts of organic anion transporter 3 (Oat3/Slc22a8 and organic anion transporting polypeptide 1a4 (Oatp1a4/Slco1a4 were decreased by 26% and 39%, respectively. Either intracerebral or intravenous pre-administration of cefmetazole further inhibited PGE2 elimination in LPS-treated mice. However, intracerebral or intravenous pre-administration of cefazolin had little effect on PGE2 elimination in LPS-treated mice, or in LPS-untreated mice given Oat3 and Oatp1a4 inhibitors. These results indicate that peripheral administration of cefmetazole inhibits PGE2 elimination across the BBB in LPS-treated mice. Conclusion PGE2 elimination across the BBB is attenuated in an LPS-induced mouse model of inflammation. Peripheral administration of cefmetazole further inhibits PGE2 elimination in LPS

Exercise and taurine in inflammation, cognition, and peripheral markers of blood-brain barrier integrity in older women.

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Chupel, Matheus Uba; Minuzzi, Luciele Guerra; Furtado, Guilherme; Santos, Mário Leonardo; Hogervorst, Eef; Filaire, Edith; Teixeira, Ana Maria

2018-07-01

Immunosenescence contribute to increase the blood-brain barrier (BBB) permeability, leading cognitive impairment and neurodegeneration. Thus, we investigated the anti-inflammatory effect of exercise and taurine supplementation on peripheral markers of BBB, inflammation, and cognition of elderly women. Forty-eight elderly women (age, 83.58 ± 6.9 years) participated in the study, and were allocated into combined exercise training (CET: n = 13), taurine supplementation (TAU: n = 12), exercise training associated with taurine (CET+TAU: n = 11), or control (CG: n = 12) groups. Exercise was applied twice a week (multi-modal exercise). Taurine ingestion was 1.5 g., once a day. Participants were evaluated before and after 14-weeks of intervention. Plasma levels of interleukin (IL)-1β, IL-1ra, IL-6, IL-10, IL-17, tumor necrosis factor alpha (TNF-α), and serum concentration of S100β and neuron specific enolase (NSE) were determined. The mini mental state examination (MMSE) was also applied. Concentrations of S100β were maintained in all intervention groups, while a subtle increase in the CG was found. NSE levels increased only in TAU group (p < 0.05). CET reduced TNF-α, IL-6, and IL-1β/IL-1ra, IL-6/IL10, and TNF-α/IL-10 ratios (p < 0.05). TAU decreased the IL-1β/IL-1ra ratio (p < 0.05). MMSE score increased only in the CET+TAU group (p < 0.05). Multiple regression analysis showed that there was a trend for changes in IL-1β and the Charlson Comorbidity Index to be independently associated with changes in S100β. Exercise and taurine decreased inflammation, and maintained the BBB integrity in elderly women. Exercise emerged as an important tool to improve brain health even when started at advanced ages.

Nutrients, Microglia Aging, and Brain Aging

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Zhou Wu

2016-01-01

Full Text Available As the life expectancy continues to increase, the cognitive decline associated with Alzheimer’s disease (AD becomes a big major issue in the world. After cellular activation upon systemic inflammation, microglia, the resident immune cells in the brain, start to release proinflammatory mediators to trigger neuroinflammation. We have found that chronic systemic inflammatory challenges induce differential age-dependent microglial responses, which are in line with the impairment of learning and memory, even in middle-aged animals. We thus raise the concept of “microglia aging.” This concept is based on the fact that microglia are the key contributor to the acceleration of cognitive decline, which is the major sign of brain aging. On the other hand, inflammation induces oxidative stress and DNA damage, which leads to the overproduction of reactive oxygen species by the numerous types of cells, including macrophages and microglia. Oxidative stress-damaged cells successively produce larger amounts of inflammatory mediators to promote microglia aging. Nutrients are necessary for maintaining general health, including the health of brain. The intake of antioxidant nutrients reduces both systemic inflammation and neuroinflammation and thus reduces cognitive decline during aging. We herein review our microglia aging concept and discuss systemic inflammation and microglia aging. We propose that a nutritional approach to controlling microglia aging will open a new window for healthy brain aging.

Nutrients, Microglia Aging, and Brain Aging.

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Wu, Zhou; Yu, Janchun; Zhu, Aiqin; Nakanishi, Hiroshi

2016-01-01

As the life expectancy continues to increase, the cognitive decline associated with Alzheimer's disease (AD) becomes a big major issue in the world. After cellular activation upon systemic inflammation, microglia, the resident immune cells in the brain, start to release proinflammatory mediators to trigger neuroinflammation. We have found that chronic systemic inflammatory challenges induce differential age-dependent microglial responses, which are in line with the impairment of learning and memory, even in middle-aged animals. We thus raise the concept of "microglia aging." This concept is based on the fact that microglia are the key contributor to the acceleration of cognitive decline, which is the major sign of brain aging. On the other hand, inflammation induces oxidative stress and DNA damage, which leads to the overproduction of reactive oxygen species by the numerous types of cells, including macrophages and microglia. Oxidative stress-damaged cells successively produce larger amounts of inflammatory mediators to promote microglia aging. Nutrients are necessary for maintaining general health, including the health of brain. The intake of antioxidant nutrients reduces both systemic inflammation and neuroinflammation and thus reduces cognitive decline during aging. We herein review our microglia aging concept and discuss systemic inflammation and microglia aging. We propose that a nutritional approach to controlling microglia aging will open a new window for healthy brain aging.

Neurobehavioral comorbidities of epilepsy: Role of inflammation.

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Mazarati, Andrey M; Lewis, Megan L; Pittman, Quentin J

2017-07-01

Epilepsy is associated with a high incidence of comorbid neurologic and psychiatric disorders. This review focuses on the association of epilepsy with autism spectrum disorder (ASD) and depression. There is high concordance of these behavioral pathologies with epilepsy. We review data that unambiguously reveal that epilepsy, ASD, and depression are associated with elevated brain inflammatory markers and that these may interact with serotoninergic pathways. Interference with inflammatory pathways or actions can reduce the severity of seizures, depression, and ASD-like behavior. Inflammation in the brain can be induced by seizure activity as well as by behavioral, environmental, and physiologic stressors. Furthermore, induction of inflammation at an early time point during gestation and in early neonatal life can precipitate both an ASD-like phenotype as well as a more excitable brain. It appears likely that priming of the brain due to early inflammation could provide a means by which subsequent inflammatory processes associated with epilepsy, ASD, and depression may lead to comorbidity. Wiley Periodicals, Inc. © 2017 International League Against Epilepsy.

Local Effect of Neurotrophin-3 in Neuronal Inflammation of Allergic Rhinitis: Preliminary Report.

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İsmi, Onur; Özcan, Cengiz; Karabacak, Tuba; Polat, Gürbüz; Vayisoğlu, Yusuf; Güçlütürk, Taylan; Görür, Kemal

2015-10-01

Allergic rhinitis is a common inflammatory nasal mucosal disease characterized by sneezing, watery nasal discharge, nasal obstruction and itching. Although allergen-specific antibodies play a main role in the allergic airway inflammation, neuronal inflammation may also contribute to the symptoms of allergic rhinitis. Neuronal inflammation is primarily caused by the stimulation of sensory nerve endings with histamine. It has been shown that neurotrophins may also have a role in allergic reactions and neuronal inflammation. Nerve growth factor, neurotrophin 3 (NT-3), neurotrophin 4/5 and brain-derived neurotrophic factor are members of the neurotrophin family. Although nerve growth factor and brain-derived neurotrophic factor are well studied in allergic rhinitis patients, the exact role of Neurotrophin-3 is not known. To investigate the possible roles of neurotrophin-3 in allergic rhinitis patients. Case-control study. Neurotrophin-3 levels were studied in the inferior turbinate and serum samples of 20 allergic rhinitis and 13 control patients. Neurotrophin-3 staining of nasal tissues was evaluated by immunohistochemistry and ELISA was used for the determination of serum Neurotrophin-3 levels. Neurotrophin-3 staining scores were statistically higher in the study group than in the control patients (p=0.001). Regarding serum Neurotrophin-3 levels, no statistically significant difference could be determined between allergic rhinitis and control patients (p=0.156). When comparing the serum NT-3 levels with tissue staining scores, there were no statistically significant differences in the allergic rhinitis and control groups (p=0.254 for allergic rhinitis and p=0.624 for control groups). We suggest that Neurotrophin-3 might affect the nasal mucosa locally without being released into the systemic circulation in allergic rhinitis patients.

Bacterial lipopolysaccharide-induced systemic inflammation alters perfusion of white matter-rich regions without altering flow in brain-irrigating arteries: Relationship to blood-brain barrier breakdown?

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Dhaya, Ibtihel; Griton, Marion; Raffard, Gérard; Amri, Mohamed; Hiba, Bassem; Konsman, Jan Pieter

2018-01-15

To better understand brain dysfunction during sepsis, cerebral arterial blood flow was assessed with Phase Contrast Magnetic Resonance Imaging, perfusion with Arterial Spin Labeling and structure with diffusion-weighted Magnetic Resonance Imaging in rats after intraperitoneal administration of bacterial lipopolysaccharides. Although cerebral arterial flow was not altered, perfusion of the corpus callosum region and diffusion parallel to its fibers were higher after lipopolysaccharide administration as compared to saline injection. In parallel, lipopolysaccharide induced perivascular immunoglobulin-immunoreactivity in white matter. These findings indicate that systemic inflammation can result in increased perfusion, blood-brain barrier breakdown and altered water diffusion in white matter. Copyright © 2017 Elsevier B.V. All rights reserved.

Inflammation in Parkinson’s disease: Role of glucocorticoids

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Maria Trinidad eHerrero

2015-04-01

Full Text Available Chronic inflammation is a major characteristic feature of Parkinson’s disease (PD. Studies in PDpatients show evidence of augmented levels of potent pro-inflammatory molecules e.g. TNF-α, iNOS,IL-1β whereas in experimental Parkinsonism it has been consistently demonstrated that dopaminergicneurons are particularly vulnerable to activated glia releasing these toxic factors. Recent geneticstudies point to the role of immune system in the etiology of PD, thus in combination withenvironmental factors, both peripheral and CNS-mediated immune responses could play importantroles in onset and progression of PD. Whereas microglia, astrocytes and infiltrating T cells are knownto mediate chronic inflammation, the roles of other immune-competent cells are less well understood.Inflammation is a tightly controlled process. One major effector system of regulation is HPA axis.Glucocorticoids released from adrenal glands upon stimulation of HPA axis, in response to either cellinjury or presence of pathogen, activate their receptor, GR. GR regulates inflammation both throughdirect transcriptional action on target genes and by indirectly inhibiting transcriptional activities oftranscriptional factors such as NF-kB, AP-1 or interferon regulatory factors. In PD patients, the HPAaxis is unbalanced and the cortisol levels are significantly increased, implying a deregulation of GRfunction in immune cells. In experimental Parkinsonism, the activation of microglial GR has a crucialeffect in diminishing microglial cell activation and reducing dopaminergic degeneration. Moreover,glucocorticoids are also known to regulate human brain vasculature as well as blood brain barrierpermeability, any dysfunction in their actions may influence infiltration of cytotoxic moleculesresulting in increased vulnerability of dopamine neurons in PD. Overall, deregulation ofGR actions is likely important in dopamine neuron degeneration throughestablishment of chronic inflammation.

Nanoparticle-Based Strategies to Treat Neuro-Inflammation

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Rémy Poupot

2018-02-01

Full Text Available Neuro-inflammation is a pivotal physio-pathological feature of brain disorders, including neurodegenerative diseases. As such, it is a relevant therapeutic target against which drugs have to be proposed. Targeting neuro-inflammation implies crossing the Blood-Brain Barrier (BBB to reach the Central Nervous System (CNS. Engineered nanoparticles (ENPs are promising candidates to carry and deliver drugs to the CNS by crossing the BBB. There are several strategies to design ENPs intended for crossing through the BBB. Herein, we first put nanotechnologies back in their historical context and introduce neuro-inflammation and its consequences in terms of public health. In a second part, we explain how ENPs can get access to the brain and review this area by highlighting recent papers in the field. Finally, after pointing out potential guidelines for preclinical studies involving ENPs, we conclude by opening the debate on the questions of nanosafety and toxicity of these ENPs and in particular on ecotoxicity related to regulatory issues and public concerns.

Bidirectional brain-gut interactions and chronic pathological changes after traumatic brain injury in mice.

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Ma, Elise L; Smith, Allen D; Desai, Neemesh; Cheung, Lumei; Hanscom, Marie; Stoica, Bogdan A; Loane, David J; Shea-Donohue, Terez; Faden, Alan I

2017-11-01

Traumatic brain injury (TBI) has complex effects on the gastrointestinal tract that are associated with TBI-related morbidity and mortality. We examined changes in mucosal barrier properties and enteric glial cell response in the gut after experimental TBI in mice, as well as effects of the enteric pathogen Citrobacter rodentium (Cr) on both gut and brain after injury. Moderate-level TBI was induced in C57BL/6mice by controlled cortical impact (CCI). Mucosal barrier function was assessed by transepithelial resistance, fluorescent-labelled dextran flux, and quantification of tight junction proteins. Enteric glial cell number and activation were measured by Sox10 expression and GFAP reactivity, respectively. Separate groups of mice were challenged with Cr infection during the chronic phase of TBI, and host immune response, barrier integrity, enteric glial cell reactivity, and progression of brain injury and inflammation were assessed. Chronic CCI induced changes in colon morphology, including increased mucosal depth and smooth muscle thickening. At day 28 post-CCI, increased paracellular permeability and decreased claudin-1 mRNA and protein expression were observed in the absence of inflammation in the colon. Colonic glial cell GFAP and Sox10 expression were significantly increased 28days after brain injury. Clearance of Cr and upregulation of Th1/Th17 cytokines in the colon were unaffected by CCI; however, colonic paracellular flux and enteric glial cell GFAP expression were significantly increased. Importantly, Cr infection in chronically-injured mice worsened the brain lesion injury and increased astrocyte- and microglial-mediated inflammation. These experimental studies demonstrate chronic and bidirectional brain-gut interactions after TBI, which may negatively impact late outcomes after brain injury. Copyright © 2017 Elsevier Inc. All rights reserved.

Experimental inflammation following dural application of complete Freund's adjuvant or inflammatory soup does not alter brain and trigeminal microvascular passage.

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Lundblad, Cornelia; Haanes, Kristian A; Grände, Gustaf; Edvinsson, Lars

2015-01-01

Migraine is a paroxysmal, disabling primary headache that affects 16 % of the adult population. In spite of decades of intense research, the origin and the pathophysiology mechanisms involved are still not fully known. Although triptans and gepants provide effective relief from acute migraine for many patients, their site of action remains unidentified. It has been suggested that during migraine attacks the leakiness of the blood-brain barrier (BBB) is altered, increasing the passage of anti-migraine drugs. This study aimed to investigate the effect of experimental inflammation, following dural application of complete Freund's adjuvant (CFA) or inflammatory soup (IS) on brain and trigeminal microvascular passage. In order to address this issue, we induced local inflammation in male Sprague-Dawley-rats dura mater by the addition of CFA or IS directly on the dural surface. Following 2, 24 or 48 h of inflammation we calculated permeability-surface area product (PS) for [(51)Cr]-EDTA in the trigeminal ganglion (TG), spinal trigeminal nucleus, cortex, periaqueductal grey and cerebellum. We observed that [(51)Cr]-EDTA did not pass into the central nervous system (CNS) in a major way. However, [(51)Cr]-EDTA readily passed the TG by >30 times compared to the CNS. Application of CFA or IS did not show altered transfer constants. With these experiments we show that dural IS/CFA triggered TG inflammation, did not increase the BBB passage, and that the TG is readily exposed to circulating molecules. The TG could provide a site of anti-migraine drug interaction with effect on the trigeminal system.

Controlling the complement system in inflammation.

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Kirschfink, M

1997-12-01

Inappropriate or excessive activation of the complement system can lead to harmful, potentially life-threatening consequences due to severe inflammatory tissue destruction. These consequences are clinically manifested in various disorders, including septic shock, multiple organ failure and hyperacute graft rejection. Genetic complement deficiencies or complement depletion have been proven to be beneficial in reducing tissue injury in a number of animal models of severe complement-dependent inflammation. It is therefore believed that therapeutic inhibition of complement is likely to arrest the process of certain diseases. Attempts to efficiently inhibit complement include the application of endogenous soluble complement inhibitors (C1-inhibitor, recombinant soluble complement receptor 1- rsCR1), the administration of antibodies, either blocking key proteins of the cascade reaction (e.g. C3, C5), neutralizing the action of the complement-derived anaphylatoxin C5a, or interfering with complement receptor 3 (CR3, CD18/11b)-mediated adhesion of inflammatory cells to the vascular endothelium. In addition, incorporation of membrane-bound complement regulators (DAF-CD55, MCP-CD46, CD59) has become possible by transfection of the correspondent cDNA into xenogeneic cells. Thereby, protection against complement-mediated inflammatory tissue damage could be achieved in various animal models of sepsis, myocardial as well as intestinal ischemia/reperfusion injury, adult respiratory distress syndrome, nephritis and graft rejection. Supported by results from first clinical trials, complement inhibition appears to be a suitable therapeutic approach to control inflammation. Current strategies to specifically inhibit complement in inflammation have been discussed at a recent meeting on the 'Immune Consequences of Trauma, Shock and Sepsis', held from March 4-8, 1997, in Munich, Germany. The Congress (chairman: E. Faist, Munich, Germany), which was held in close cooperation with various

Experimental inflammation following dural application of complete Freund's adjuvant or inflammatory soup does not alter brain and trigeminal microvascular passage

DEFF Research Database (Denmark)

Lundblad, Cornelia; Haanes, Kristian A; Grände, Gustaf

2015-01-01

, following dural application of complete Freund's adjuvant (CFA) or inflammatory soup (IS) on brain and trigeminal microvascular passage. METHODS: In order to address this issue, we induced local inflammation in male Sprague-Dawley-rats dura mater by the addition of CFA or IS directly on the dural surface...

Inflammation of the Penis

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... Inflammation of the Penis (Balanitis; Posthitis; Balanoposthitis) By Patrick J. Shenot, MD, Associate Professor and Deputy Chair, ... of stimuli to nerves, blood vessels, and the brain. Which of the following happens to blood during ...

Radioisotopic Imaging of Neuro-inflammation

International Nuclear Information System (INIS)

Winkeler, A.; Boisgard, R.; Martin, M.; Tavitian, B.

2010-01-01

Inflammatory responses are closely associated with many neurologic disorders and influence their outcome. In vivo imaging can document events accompanying neuro-inflammation, such as changes in blood flow, vascular permeability, tightness of the blood-to-brain barrier, local metabolic activity, and expression of specific molecular targets. Here, we briefly review current methods for imaging neuro-inflammation, with special emphasis on nuclear imaging techniques. (authors)

Risk factors for idiopathic orbital inflammation: a case-control study

NARCIS (Netherlands)

Bijlsma, Ward R.; van Gils, Carla H.; Paridaens, Dion; Mourits, Maarten P.; Kalmann, Rachel

2011-01-01

Objective To identify risk factors involved in the development of idiopathic orbital inflammation (IOI). Methods Case-control study of 69 adults who had had a first episode of IOI and 296 adult controls with rhegmatogenous retinal detachment (RD) selected from three orbital centres in The

Effects of the PPAR-β agonist GW501516 in an in vitro model of brain inflammation and antibody-induced demyelination

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Honegger Paul

2009-05-01

Full Text Available Abstract Background Brain inflammation plays a central role in numerous brain pathologies, including multiple sclerosis (MS. Microglial cells and astrocytes are the effector cells of neuroinflammation. They can be activated also by agents such as interferon-γ (IFN-γ and lipopolysaccharide (LPS. Peroxisome proliferator-associated receptor (PPAR pathways are involved in the control of the inflammatory processes, and PPAR-β seems to play an important role in the regulation of central inflammation. In addition, PPAR-β agonists were shown to have trophic effects on oligodendrocytes in vitro, and to confer partial protection in experimental autoimmune encephalomyelitis (EAE, an animal model of MS. In the present work, a three-dimensional brain cell culture system was used as in vitro model to study antibody-induced demyelination and inflammatory responses. GW 501516, a specific PPAR-β agonist, was examined for its capacity to protect from antibody-mediated demyelination and to prevent inflammatory responses induced by IFN-γ and LPS. Methods Aggregating brain cells cultures were prepared from embryonal rat brain, and used to study the inflammatory responses triggered by IFN-γ and LPS and by antibody-mediated demyelination induced by antibodies directed against myelin-oligodendrocyte glycoprotein (MOG. The effects of GW 501516 on cellular responses were characterized by the quantification of the mRNA expression of tumor necrosis factor-α (TNF-α, interleukin-6 (IL-6, inducible NO synthase (i-NOS, PPAR-β, PPAR-γ, glial fibrillary acidic protein (GFAP, myelin basic protein (MBP, and high molecular weight neurofilament protein (NF-H. GFAP expression was also examined by immunocytochemistry, and microglial cells were visualized by isolectin B4 (IB4 and ED1 labeling. Results GW 501516 decreased the IFN-γ-induced up-regulation of TNF-α and iNOS in accord with the proposed anti-inflammatory effects of this PPAR-β agonist. However, it increased IL

Fingolimod against endotoxin-induced fetal brain injury in a rat model.

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Yavuz, And; Sezik, Mekin; Ozmen, Ozlem; Asci, Halil

2017-11-01

Fingolimod is a sphingosine-1-phosphate receptor modulator used for multiple sclerosis treatment and acts on cellular processes such as apoptosis, endothelial permeability, and inflammation. We hypothesized that fingolimod has a positive effect on alleviating preterm fetal brain injury. Sixteen pregnant rats were divided into four groups of four rats each. On gestational day 17, i.p. endotoxin was injected to induce fetal brain injury, followed by i.p. fingolimod (4 mg/kg maternal weight). Hysterotomy for preterm delivery was performed 6 h after fingolimod. The study groups included (i) vehicle controls (i.p. normal saline only); (ii) positive controls (endotoxin plus saline); (iii) saline plus fingolimod; and (iv) endotoxin plus fingolimod treatment. Brain tissues of the pups were dissected for evaluation of interleukin (IL)-6, caspase-3, and S100β on immunohistochemistry. Maternal fingolimod treatment attenuated endotoxin-related fetal brain injury and led to lower immunoreactions for IL-6, caspase-3, and S100β compared with endotoxin controls (P < 0.0001 for all comparisons). Antenatal maternal fingolimod therapy had fetal neuroprotective effects by alleviating preterm birth-related fetal brain injury with inhibitory effects on inflammation and apoptosis. © 2017 Japan Society of Obstetrics and Gynecology.

The Role of Brain Inflammation in Epileptogenesis in TSC

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2014-07-01

future challenges. Epilepsia 2007;48:617- 630. 2. Ravizza T, Balosso S, Vezzani A. Inflammation and prevention of epileptogenesis. Neurosci Lett...development. Neurobiol Dis 2006;24:128-143. 7. Aronica E, Crino PB. Inflammation in epilepsy: clinical observations. Epilepsia 2011;52(Suppl.3);26

Inflammation and Alzheimer's disease

NARCIS (Netherlands)

Akiyama, H.; Barger, S.; Barnum, S.; Bradt, B.; Bauer, J.; Cole, G. M.; Cooper, N. R.; Eikelenboom, P.; Emmerling, M.; Fiebich, B. L.; Finch, C. E.; Frautschy, S.; Griffin, W. S.; Hampel, H.; Hull, M.; Landreth, G.; Lue, L.; Mrak, R.; Mackenzie, I. R.; McGeer, P. L.; O'Banion, M. K.; Pachter, J.; Pasinetti, G.; Plata-Salaman, C.; Rogers, J.; Rydel, R.; Shen, Y.; Streit, W.; Strohmeyer, R.; Tooyoma, I.; van Muiswinkel, F. L.; Veerhuis, R.; Walker, D.; Webster, S.; Wegrzyniak, B.; Wenk, G.; Wyss-Coray, T.

2000-01-01

Inflammation clearly occurs in pathologically vulnerable regions of the Alzheimer's disease (AD) brain, and it does so with the full complexity of local peripheral inflammatory responses. In the periphery, degenerating tissue and the deposition of highly insoluble abnormal materials are classical

Prophylactic effects of sulforaphane on depression-like behavior and dendritic changes in mice after inflammation.

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Zhang, Ji-Chun; Yao, Wei; Dong, Chao; Yang, Chun; Ren, Qian; Ma, Min; Han, Mei; Wu, Jin; Ushida, Yusuke; Suganuma, Hiroyuki; Hashimoto, Kenji

2017-01-01

Inflammation plays a role in the pathophysiology of depression. Sulforaphane (SFN), an isothiocyanate compound derived from broccoli, is a potent activator of the NF-E2-related factor-2 (Nrf2), which plays a role in inflammation. In this study, we examined whether the prevention effects of SFN in lipopolysaccharide (LPS) induced depression-like behavior in mice. Pretreatment with SFN significantly blocked an increase in the serum tumor necrosis factor-α (TNF-α) level and an increase in microglial activation of brain regions after a single administration of LPS (0.5 mg/kg). Furthermore, SFN significantly potentiated increased serum levels of IL-10 after LPS administration. In the tail-suspension test and forced swimming test, SFN significantly attenuated an increase of the immobility time after LPS administration. In addition, SFN significantly recovered to control levels for LPS-induced alterations in the proteins such as brain-derived neurotrophic factor, postsynaptic density protein 95 and AMPA receptor 1 (GluA1) and dendritic spine density in the brain regions. Finally, dietary intake of 0.1% glucoraphanin (a glucosinolate precursor of SFN) food during the juvenile and adolescence could prevent the onset of LPS-induced depression-like behaviors and dendritic spine changes in the brain regions at adulthood. In conclusion, these findings suggest that dietary intake of SFN-rich broccoli sprout has prophylactic effects on inflammation-related depressive symptoms. Therefore, supplementation of SFN-rich broccoli sprout could be prophylactic vegetable to prevent or minimize the relapse by inflammation in the remission state of depressed patients. Copyright © 2016 Elsevier Inc. All rights reserved.

HMGB1 a-Box Reverses Brain Edema and Deterioration of Neurological Function in a Traumatic Brain Injury Mouse Model

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Lijun Yang

2018-05-01

Full Text Available Background/Aims: Traumatic brain injury (TBI is a complex neurological injury in young adults lacking effective treatment. Emerging evidences suggest that inflammation contributes to the secondary brain injury following TBI, including breakdown of the blood brain barrier (BBB, subsequent edema and neurological deterioration. High mobility group box-1 (HMGB1 has been identified as a key cytokine in the inflammation reaction following TBI. Here, we investigated the therapeutic efficacy of HMGB1 A-box fragment, an antagonist competing with full-length HMGB1 for receptor binding, against TBI. Methods: TBI was induced by controlled cortical impact (CCI in adult male mice. HMGB1 A-box fragment was given intravenously at 2 mg/kg/day for 3 days after CCI. HMGB1 A-box-treated CCI mice were compared with saline-treated CCI mice and sham mice in terms of BBB disruption evaluated by Evan’s blue extravasation, brain edema by brain water content, cell death by propidium iodide staining, inflammation by Western blot and ELISA assay for cytokine productions, as well as neurological functions by the modified Neurological Severity Score, wire grip and beam walking tests. Results: HMGB1 A-box reversed brain damages in the mice following TBI. It significantly reduced brain edema by protecting integrity of the BBB, ameliorated cell degeneration, and decreased expression of pro-inflammatory cytokines released in injured brain after TBI. These cellular and molecular effects were accompanied by improved behavioral performance in TBI mice. Notably, HMGB1 A-box blocked IL-1β-induced HMGB1 release, and preferentially attenuated TLR4, Myd88 and P65 in astrocyte cultures. Conclusion: Our data suggest that HMGB1 is involved in CCI-induced TBI, which can be inhibited by HMGB1 A-box fragment. Therefore, HMGB1 A-box fragment may have therapeutic potential for the secondary brain damages in TBI.

HMGB1 a-Box Reverses Brain Edema and Deterioration of Neurological Function in a Traumatic Brain Injury Mouse Model.

Science.gov (United States)

Yang, Lijun; Wang, Feng; Yang, Liang; Yuan, Yunchao; Chen, Yan; Zhang, Gengshen; Fan, Zhenzeng

2018-01-01

Traumatic brain injury (TBI) is a complex neurological injury in young adults lacking effective treatment. Emerging evidences suggest that inflammation contributes to the secondary brain injury following TBI, including breakdown of the blood brain barrier (BBB), subsequent edema and neurological deterioration. High mobility group box-1 (HMGB1) has been identified as a key cytokine in the inflammation reaction following TBI. Here, we investigated the therapeutic efficacy of HMGB1 A-box fragment, an antagonist competing with full-length HMGB1 for receptor binding, against TBI. TBI was induced by controlled cortical impact (CCI) in adult male mice. HMGB1 A-box fragment was given intravenously at 2 mg/kg/day for 3 days after CCI. HMGB1 A-box-treated CCI mice were compared with saline-treated CCI mice and sham mice in terms of BBB disruption evaluated by Evan's blue extravasation, brain edema by brain water content, cell death by propidium iodide staining, inflammation by Western blot and ELISA assay for cytokine productions, as well as neurological functions by the modified Neurological Severity Score, wire grip and beam walking tests. HMGB1 A-box reversed brain damages in the mice following TBI. It significantly reduced brain edema by protecting integrity of the BBB, ameliorated cell degeneration, and decreased expression of pro-inflammatory cytokines released in injured brain after TBI. These cellular and molecular effects were accompanied by improved behavioral performance in TBI mice. Notably, HMGB1 A-box blocked IL-1β-induced HMGB1 release, and preferentially attenuated TLR4, Myd88 and P65 in astrocyte cultures. Our data suggest that HMGB1 is involved in CCI-induced TBI, which can be inhibited by HMGB1 A-box fragment. Therefore, HMGB1 A-box fragment may have therapeutic potential for the secondary brain damages in TBI. © 2018 The Author(s). Published by S. Karger AG, Basel.

Chronic inflammation in refractory hippocampal sclerosis-related temporal lobe epilepsy.

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Gales, Jordan M; Prayson, Richard A

2017-10-01

Emerging evidence suggests chronic inflammation may play a role in hippocampal sclerosis-associated temporal lobe epilepsy. We sought to systematically evaluate for its presence in a group of 315 patients who underwent surgery for medically-refractory epilepsy and who had hippocampal sclerosis. Upon histologic review of hematoxylin and eosin stained tissue sections, 95 (41%) cases demonstrated the presence of lymphocytes within the perivascular region and diffusely within the brain parenchyma. Those cases with chronic inflammation evident on hematoxylin and eosin staining were significantly more likely to experience a post-operative seizure recurrence than those without it (p=0.03). In 9 cases of hippocampi with chronic inflammation observed on hematoxylin and eosin stained sections, there was a mixture of both T (CD3+) and B (CD20+) lymphocytes located around blood vessels and interspersed within the brain parenchyma and a predominance of CD4 positive T cells versus CD8 positive cells. Ten hippocampi, apparently devoid of chronic inflammation upon inspection with hematoxylin and eosin stained sections, were stained with the lymphocyte common antigen CD45. In all 10 cases, scattered lymphoid cells were observed in the brain parenchyma, suggesting some level of chronic inflammation may be present in more cases than casual inspection might suggest. This study was the first to evaluate the incidence of chronic inflammation within a large temporal lobe epilepsy population. The study findings suggest chronic inflammation may be a more common component of hippocampal sclerosis -associated temporal lobe epilepsy than previously believed. Copyright © 2017 Elsevier Inc. All rights reserved.

Inflammation and oxidative stress are elevated in the brain, blood, and adrenal glands during the progression of post-traumatic stress disorder in a predator exposure animal model.

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Wilson, C Brad; McLaughlin, Leslie D; Nair, Anand; Ebenezer, Philip J; Dange, Rahul; Francis, Joseph

2013-01-01

This study sought to analyze specific pathophysiological mechanisms involved in the progression of post-traumatic stress disorder (PTSD) by utilizing an animal model. To examine PTSD pathophysiology, we measured damaging reactive oxygen species and inflammatory cytokines to determine if oxidative stress and inflammation in the brain, adrenal glands, and systemic circulation were upregulated in response to constant stress. Pre-clinical PTSD was induced in naïve, male Sprague-Dawley rats via a predator exposure/psychosocial stress regimen. PTSD group rats were secured in Plexiglas cylinders and placed in a cage with a cat for one hour on days 1 and 11 of a 31-day stress regimen. In addition, PTSD group rats were subjected to psychosocial stress whereby their cage cohort was changed daily. This model has been shown to cause heightened anxiety, exaggerated startle response, impaired cognition, and increased cardiovascular reactivity, all of which are common symptoms seen in humans with PTSD. At the conclusion of the predator exposure/psychosocial stress regimen, the rats were euthanized and their brains were dissected to remove the hippocampus, amygdala, and pre-frontal cortex (PFC), the three areas commonly associated with PTSD development. The adrenal glands and whole blood were also collected to assess systemic oxidative stress. Analysis of the whole blood, adrenal glands, and brain regions revealed oxidative stress increased during PTSD progression. In addition, examination of pro-inflammatory cytokine (PIC) mRNA and protein demonstrated neurological inflammatory molecules were significantly upregulated in the PTSD group vs. controls. These results indicate oxidative stress and inflammation in the brain, adrenal glands, and systemic circulation may play a critical role in the development and further exacerbation of PTSD. Thus, PTSD may not be solely a neurological pathology but may progress as a systemic condition involving multiple organ systems.

Self-Control and the Developing Brain

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Tarullo, Amanda R.; Obradovic, Jelena; Gunnar, Megan R.

2009-01-01

Self-control is a skill that children need to succeed academically, socially, and emotionally. Brain regions essential to self-control are immature at birth and develop slowly throughout childhood. From ages 3 to 6 years, as these brain regions become more mature, children show improved ability to control impulses, shift their attention flexibly,…

NLRP3-inflammasome activating DAMPs stimulate an inflammatory response in glia in the absence of priming which contributes to brain inflammation after injury

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Catherine Diane Savage

2012-09-01

Full Text Available Inflammation in the absence of infection (sterile inflammation contributes to acute injury and chronic disease. Cerebral ischaemia is a devastating condition in which the primary injury is caused by reduced blood supply and is therefore sterile. The cytokine interleukin-1β (IL-1β is a key contributor to ischaemic brain injury and central inflammatory responses. The release of IL-1β is regulated by the protease caspase-1, and its activating complex, the inflammasome. Of the known inflammasomes the best characterised, and one that is perceived to sense sterile injury is formed by a pattern recognition receptor called NLRP3. A key feature of NLRP3-inflammasome dependent responses in vitro in macrophages is the requirement of an initial priming stimulus by a pathogen (PAMP, or damage associated molecular pattern (DAMP respectively. We sought to determine the inflammatory responses of NLRP3-activating DAMPs on brain derived mixed glial cells in the absence of an initial priming stimulus in vitro. In cultured mouse mixed glia the DAMPs ATP, MSU and CPPD crystals had no effect on the expression of IL-1α or IL-1β and induced release only when the cells were primed with a PAMP. In the absence of priming, these DAMPs did however induce inflammation via the production of IL-6 and CXCL1, and the release of the lysosomal protease cathepsin B. Furthermore, the acute phase protein serum amyloid A (SAA acted as a priming stimulus on glial cells resulting in levels of IL-1 expression comparable to those induced by the PAMP LPS. In vivo, after cerebral ischaemia, IL-1 production contributed to increased IL-6 and CXCL1 since these cytokines were profoundly reduced in the ischaemic hemispheres from IL-1α/β double KO mice, although injury-induced cytokine responses were not abolished. Thus, DAMPs augment brain inflammation by directly stimulating production of glial derived inflammatory mediators. This is markedly enhanced by DAMP-induced IL-1-release

Systemic inflammation and resting state connectivity of the default mode network.

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Marsland, Anna L; Kuan, Dora C-H; Sheu, Lei K; Krajina, Katarina; Kraynak, Thomas E; Manuck, Stephen B; Gianaros, Peter J

2017-05-01

The default mode network (DMN) encompasses brain systems that exhibit coherent neural activity at rest. DMN brain systems have been implicated in diverse social, cognitive, and affective processes, as well as risk for forms of dementia and psychiatric disorders that associate with systemic inflammation. Areas of the anterior cingulate cortex (ACC) and surrounding medial prefrontal cortex (mPFC) within the DMN have been implicated specifically in regulating autonomic and neuroendocrine processes that relate to systemic inflammation via bidirectional signaling mechanisms. However, it is still unclear whether indicators of inflammation relate directly to coherent resting state activity of the ACC, mPFC, or other areas within the DMN. Accordingly, we tested whether plasma interleukin (IL)-6, an indicator of systemic inflammation, covaried with resting-state functional connectivity of the DMN among 98 adults aged 30-54 (39% male; 81% Caucasian). Independent component analyses were applied to resting state fMRI data to generate DMN connectivity maps. Voxel-wise regression analyses were then used to test for associations between IL-6 and DMN connectivity across individuals, controlling for age, sex, body mass index, and fMRI signal motion. Within the DMN, IL-6 covaried positively with connectivity of the sub-genual ACC and negatively with a region of the dorsal medial PFC at corrected statistical thresholds. These novel findings offer evidence for a unique association between a marker of systemic inflammation (IL-6) and ACC and mPFC functional connectivity within the DMN, a network that may be important for linking aspects of immune function to psychological and behavioral states in health and disease. Copyright © 2017 Elsevier Inc. All rights reserved.

Study on Control of Brain Temperature for Brain Hypothermia Treatment

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Gaohua, Lu; Wakamatsu, Hidetoshi

The brain hypothermia treatment is an attractive therapy for the neurologist because of its neuroprotection in hypoxic-ischemic encephalopathy patients. The present paper deals with the possibility of controlling the brain and other viscera in different temperatures from the viewpoint of system control. It is theoretically attempted to realize the special brain hypothermia treatment to cool only the head but to warm the body by using the simple apparatus such as the cooling cap, muffler and warming blanket. For this purpose, a biothermal system concerning the temperature difference between the brain and the other thoracico-abdominal viscus is synthesized from the biothermal model of hypothermic patient. The output controllability and the asymptotic stability of the system are examined on the basis of its structure. Then, the maximum temperature difference to be realized is shown dependent on the temperature range of the apparatus and also on the maximum gain determined from the coefficient matrices A, B and C of the biothermal system. Its theoretical analysis shows the realization of difference of about 2.5°C, if there is absolutely no constraint of the temperatures of the cooling cap, muffler and blanket. It is, however, physically unavailable. Those are shown by simulation example of the optimal brain temperature regulation using a standard adult database. It is thus concluded that the surface cooling and warming apparatus do no make it possible to realize the special brain hypothermia treatment, because the brain temperature cannot be cooled lower than those of other viscera in an appropriate temperature environment. This study shows that the ever-proposed good method of clinical treatment is in principle impossible in the actual brain hypothermia treatment.

Soluble CD40 ligand contributes to blood-brain barrier breakdown and central nervous system inflammation in multiple sclerosis and neuromyelitis optica spectrum disorder.

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Masuda, Hiroki; Mori, Masahiro; Uchida, Tomohiko; Uzawa, Akiyuki; Ohtani, Ryohei; Kuwabara, Satoshi

2017-04-15

Soluble CD40 ligand (sCD40L) is reported to disrupt the blood-brain barrier (BBB). Cerebrospinal fluid (CSF) and serum sCD40L levels were measured in 29 multiple sclerosis (MS), 29 neuromyelitis optica spectrum disorder (NMOSD), and 27 disease control (DC) patients. In MS, serum sCD40L levels were higher than in DCs and positively correlated with the CSF/serum albumin ratio (Qalb). In NMOSD, CSF sCD40L levels were significantly increased compared to DCs, and were correlated to Qalb, CSF cell counts, protein concentrations, and interleukin-6 levels. sCD40L could be involved in BBB disruption in MS, whereas it may contribute to CNS inflammation in NMOSD. Copyright © 2017 Elsevier B.V. All rights reserved.

Neurobiology of inflammation-associated anorexia

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Laurent Gautron

2010-01-01

Full Text Available Compelling data demonstrate that inflammation-associated anorexia directly results from the action of pro-inflammatory factors, primarily cytokines and prostaglandins E2, on the nervous system. For instance, the aforementioned pro-inflammatory factors can stimulate the activity of peripheral sensory neurons, and induce their own de novo synthesis and release into the brain parenchyma and cerebrospinal fluid. Ultimately, it results in the mobilization of a specific neural circuit that shuts down appetite. The present article describes the different cell groups and neurotransmitters involved in inflammation-associated anorexia and examines how they interact with neural systems regulating feeding such as the melanocortin system. A better understanding of the neurobiological mechanisms underlying inflammation-associated anorexia will help to develop appetite stimulants for cancer and AIDS patients.

Atopic diseases and inflammation of the brain in the pathogenesis of autism spectrum disorders.

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Theoharides, T C; Tsilioni, I; Patel, A B; Doyle, R

2016-06-28

benefits most from treatment with the natural flavonoid luteolin. Atopic diseases may create a phenotype susceptible to ASD and formulations targeting focal inflammation of the brain could have great promise in the treatment of ASD.

Mice Lacking Free Fatty Acid Receptor 1 (GPR40/FFAR1) are Protected Against Conjugated Linoleic Acid-Induced Fatty Liver but Develop Inflammation and Insulin Resistance in the Brain.

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Sartorius, Tina; Drescher, Andrea; Panse, Madhura; Lastovicka, Petr; Peter, Andreas; Weigert, Cora; Kostenis, Evi; Ullrich, Susanne; Häring, Hans-Ulrich

2015-01-01

Conjugated linoleic acids (CLAs) affect body fat distribution, induce insulin resistance and stimulate insulin secretion. The latter effect is mediated through the free fatty acid receptor-1 (GPR40/FFAR1). This study examines whether GPR40/FFAR1 interacts with tissue specific metabolic changes induced by CLAs. After chronic application of CLAs C57BL/6J wild type (WT) and GPR40/FFAR1 (Ffar1(-/-)) knockout mice developed insulin resistance. Although CLAs accumulated in liver up to 46-fold genotype-independently, hepatic triglycerides augmented only in WT mice. This triglyceride deposition was not associated with increased inflammation. In contrast, in brain of CLA fed Ffar1(-/-) mice mRNA levels of TNF-α were 2-fold higher than in brain of WT mice although CLAs accumulated genotype-independently in brain up to 4-fold. Concomitantly, Ffar1(-/-) mice did not respond to intracerebroventricular (i.c.v.) insulin injection with an increase in cortical activity while WT mice reacted as assessed by radiotelemetric electrocorticography (ECoG) measurements. In vitro incubation of primary murine astrocytes confirmed that CLAs stimulate neuronal inflammation independent of GPR40/FFAR1. This study discloses that GPR40/FFAR1 indirectly modulates organ-specific effects of CLAs: the expression of functional GPR40/FFAR1 counteracts CLA-induced inflammation and insulin resistance in the brain, but favors the development of fatty liver. © 2015 S. Karger AG, Basel.

Metallothionein-I overexpression alters brain inflammation and stimulates brain repair in transgenic mice with astrocyte-targeted interleukin-6 expression

DEFF Research Database (Denmark)

Penkowa, Milena; Camats, Jordi; Giralt, Mercedes

2003-01-01

injury, such as a cryolesion, demonstrate a neuroprotective role of IL-6. Thus, the GFAP-IL-6 mice showed faster tissue repair and decreased oxidative stress and apoptosis compared with control litter-mate mice. The neuroprotective factors metallothionein-I+II (MT-I+II) were upregulated by the cryolesion...... the inflammatory response, decreased oxidative stress and apoptosis significantly, and increased brain tissue repair in comparison with either GFAP-IL-6 or control litter-mate mice. Overall, the results demonstrate that brain MT-I+II proteins are fundamental neuroprotective factors....

[Vascular depression in the elderly. Does inflammation play a role?].

Science.gov (United States)

Viscogliosi, Giovanni; Andreozzi, Paola; Chiriac, Iulia Maria; Ettorre, Evaristo; Vulcano, Achiropita; Servello, Adriana; Marigliano, Benedetta; Marigliano, Vincenzo

2011-06-01

Vascular depression in the elderly. Does inflammation play a role?Depression is the most common comorbidity in the elderly, and it is a major determinant of disability. The late-onset depression in highly associated to cardiovascular disease. Depressive symptoms may follow vascular brain damage, especially when mood regulating areas are affected. However depression is strongly associated to vascular disease even when there is no manifest brain damage. Recently great attention has been given to chronic inflammation, both related to depression and vascular disease. Both experimental and clinical evidence shows that a rise in the concentrations of proinflammatory cytokines and glucocorticoids in depressed patients is associated with defect in serotonergic function. Chronic inflammation may underlie many forms of depression associated with vascular disease and metabolic syndrome. The importance of the inflammation hypothesis of depression lies is that psychotropic drugs may have central anti-inflammatory action, and that new generation of central anti-inflammatory drugs may be useful in depression treatment.

Evaluation of Perifollicular Inflammation of Donor Area during Hair Transplantation in Androgenetic Alopecia and its Comparison with Controls

OpenAIRE

Nirmal, Balakrishnan; Somiah, Savitha; Sacchidanand, Sarvajnamurthy A; Biligi, Dayananda S; Palo, Seetu

2013-01-01

Background: Mild perifollicular inflammation is seen in both androgenetic alopecia (AGA) cases and normal controls, whereas moderate or dense inflammation with concentric layers of collagen, is seen in AGA cases but only in very few normal controls, and may lessen the response to topical minoxidil. Moderate or dense lymphocytic inflammation and perifollicular fibrosis have poor hair growth following transplantation. Aim: The purpose of the study is to evaluate the perifollicular lymphocytic i...

Infections, inflammation and epilepsy

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Vezzani, Annamaria; Fujinami, Robert S.; White, H. Steve; Preux, Pierre-Marie; Blümcke, Ingmar; Sander, Josemir W.; Löscher, Wolfgang

2016-01-01

Epilepsy is the tendency to have unprovoked epileptic seizures. Anything causing structural or functional derangement of brain physiology may lead to seizures, and different conditions may express themselves solely by recurrent seizures and thus be labelled “epilepsy.” Worldwide, epilepsy is the most common serious neurological condition. The range of risk factors for the development of epilepsy varies with age and geographic location. Congenital, developmental and genetic conditions are mostly associated with the development of epilepsy in childhood, adolescence and early adulthood. Head trauma, infections of the central nervous system (CNS) and tumours may occur at any age and may lead to the development of epilepsy. Infections of the CNS are a major risk factor for epilepsy. The reported risk of unprovoked seizures in population-based cohorts of survivors of CNS infections from developed countries is between 6.8 and 8.3 %, and is much higher in resource-poor countries. In this review, the various viral, bacterial, fungal and parasitic infectious diseases of the CNS which result in seizures and epilepsy are discussed. The pathogenesis of epilepsy due to brain infections, as well as the role of experimental models to study mechanisms of epileptogenesis induced by infectious agents, is reviewed. The sterile (non-infectious) inflammatory response that occurs following brain insults is also discussed, as well as its overlap with inflammation due to infections, and the potential role in epileptogenesis. Furthermore, autoimmune encephalitis as a cause of seizures is reviewed. Potential strategies to prevent epilepsy resulting from brain infections and non-infectious inflammation are also considered. PMID:26423537

Role of Inflammation and Oxidative Stress Mediators in Gliomas

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Alfredo Conti

2010-04-01

Full Text Available Gliomas are the most common primary brain tumors of the central nervous system. Despite relevant progress in conventional treatments, the prognosis of such tumors remains almost invariably dismal. The genesis of gliomas is a complex, multistep process that includes cellular neoplastic transformation, resistance to apoptosis, loss of control of the cell cycle, angiogenesis, and the acquisition of invasive properties. Among a number of different biomolecular events, the existence of molecular connections between inflammation and oxidative stress pathways and the development of this cancer has been demonstrated. In particular, the tumor microenvironment, which is largely orchestrated by inflammatory molecules, is an indispensable participant in the neoplastic process, promoting proliferation, survival and migration of such tumors. Proinflammatory cytokines, such as tumor necrosis factor-alpha, interleukin-1beta, and interferon-gamma, as well as chemokines and prostaglandins, are synthesized by resident brain cells and lymphocytes invading the affected brain tissue. Key mediators of cancer progression include nuclear factor-kappaB, reactive oxygen and nitrogen species, and specific microRNAs. The collective activity of these mediators is largely responsible for a pro-tumorigenic response through changes in cell proliferation, cell death, cellular senescence, DNA mutation rates, DNA methylation and angiogenesis. We provide a general overview of the connection between specific inflammation and oxidative stress pathway molecules and gliomas. The elucidation of specific effects and interactions of these factors may provide the opportunity for the identification of new target molecules leading to improved diagnosis and treatment.

Role of Inflammation and Oxidative Stress Mediators in Gliomas

Energy Technology Data Exchange (ETDEWEB)

Conti, Alfredo, E-mail: alfredo.conti@unime.it; Gulì, Carlo; La Torre, Domenico; Tomasello, Chiara; Angileri, Filippo F.; Aguennouz, M’Hammed [Department of Neuroscience and Department of Oncology, University of Messina, Policlinico Universitario, Via Consolare Valeria 1, 98125, Messina (Italy)

2010-04-26

Gliomas are the most common primary brain tumors of the central nervous system. Despite relevant progress in conventional treatments, the prognosis of such tumors remains almost invariably dismal. The genesis of gliomas is a complex, multistep process that includes cellular neoplastic transformation, resistance to apoptosis, loss of control of the cell cycle, angiogenesis, and the acquisition of invasive properties. Among a number of different biomolecular events, the existence of molecular connections between inflammation and oxidative stress pathways and the development of this cancer has been demonstrated. In particular, the tumor microenvironment, which is largely orchestrated by inflammatory molecules, is an indispensable participant in the neoplastic process, promoting proliferation, survival and migration of such tumors. Proinflammatory cytokines, such as tumor necrosis factor-alpha, interleukin-1beta, and interferon-gamma, as well as chemokines and prostaglandins, are synthesized by resident brain cells and lymphocytes invading the affected brain tissue. Key mediators of cancer progression include nuclear factor-kappaB, reactive oxygen and nitrogen species, and specific microRNAs. The collective activity of these mediators is largely responsible for a pro-tumorigenic response through changes in cell proliferation, cell death, cellular senescence, DNA mutation rates, DNA methylation and angiogenesis. We provide a general overview of the connection between specific inflammation and oxidative stress pathway molecules and gliomas. The elucidation of specific effects and interactions of these factors may provide the opportunity for the identification of new target molecules leading to improved diagnosis and treatment.

Role of Inflammation and Oxidative Stress Mediators in Gliomas

International Nuclear Information System (INIS)

Conti, Alfredo; Gulì, Carlo; La Torre, Domenico; Tomasello, Chiara; Angileri, Filippo F.; Aguennouz, M’Hammed

2010-01-01

Gliomas are the most common primary brain tumors of the central nervous system. Despite relevant progress in conventional treatments, the prognosis of such tumors remains almost invariably dismal. The genesis of gliomas is a complex, multistep process that includes cellular neoplastic transformation, resistance to apoptosis, loss of control of the cell cycle, angiogenesis, and the acquisition of invasive properties. Among a number of different biomolecular events, the existence of molecular connections between inflammation and oxidative stress pathways and the development of this cancer has been demonstrated. In particular, the tumor microenvironment, which is largely orchestrated by inflammatory molecules, is an indispensable participant in the neoplastic process, promoting proliferation, survival and migration of such tumors. Proinflammatory cytokines, such as tumor necrosis factor-alpha, interleukin-1beta, and interferon-gamma, as well as chemokines and prostaglandins, are synthesized by resident brain cells and lymphocytes invading the affected brain tissue. Key mediators of cancer progression include nuclear factor-kappaB, reactive oxygen and nitrogen species, and specific microRNAs. The collective activity of these mediators is largely responsible for a pro-tumorigenic response through changes in cell proliferation, cell death, cellular senescence, DNA mutation rates, DNA methylation and angiogenesis. We provide a general overview of the connection between specific inflammation and oxidative stress pathway molecules and gliomas. The elucidation of specific effects and interactions of these factors may provide the opportunity for the identification of new target molecules leading to improved diagnosis and treatment

Control channels in the brain and their influence on brain executive functions

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Meng, Qinglei; Choa, Fow-Sen; Hong, Elliot; Wang, Zhiguang; Islam, Mohammad

2014-05-01

In a computer network there are distinct data channels and control channels where massive amount of visual information are transported through data channels but the information streams are routed and controlled by intelligent algorithm through "control channels". Recent studies on cognition and consciousness have shown that the brain control channels are closely related to the brainwave beta (14-40 Hz) and alpha (7-13 Hz) oscillations. The high-beta wave is used by brain to synchronize local neural activities and the alpha oscillation is for desynchronization. When two sensory inputs are simultaneously presented to a person, the high-beta is used to select one of the inputs and the alpha is used to deselect the other so that only one input will get the attention. In this work we demonstrated that we can scan a person's brain using binaural beats technique and identify the individual's preferred control channels. The identified control channels can then be used to influence the subject's brain executive functions. In the experiment, an EEG measurement system was used to record and identify a subject's control channels. After these channels were identified, the subject was asked to do Stroop tests. Binaural beats was again used to produce these control-channel frequencies on the subject's brain when we recorded the completion time of each test. We found that the high-beta signal indeed speeded up the subject's executive function performance and reduced the time to complete incongruent tests, while the alpha signal didn't seem to be able to slow down the executive function performance.

Role of pattern recognition receptors of the neurovascular unit in inflamm-aging.

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Wilhelm, Imola; Nyúl-Tóth, Ádám; Kozma, Mihály; Farkas, Attila E; Krizbai, István A

2017-11-01

Aging is associated with chronic inflammation partly mediated by increased levels of damage-associated molecular patterns, which activate pattern recognition receptors (PRRs) of the innate immune system. Furthermore, many aging-related disorders are associated with inflammation. PRRs, such as Toll-like receptors (TLRs) and nucleotide-binding oligomerization domain-like receptors (NLRs), are expressed not only in cells of the innate immune system but also in other cells, including cells of the neurovascular unit and cerebral vasculature forming the blood-brain barrier. In this review, we summarize our present knowledge about the relationship between activation of PRRs expressed by cells of the neurovascular unit-blood-brain barrier, chronic inflammation, and aging-related pathologies of the brain. The most important damage-associated molecular pattern-sensing PRRs in the brain are TLR2, TLR4, and NLR family pyrin domain-containing protein-1 and pyrin domain-containing protein-3, which are activated during physiological and pathological aging in microglia, neurons, astrocytes, and possibly endothelial cells and pericytes. Copyright © 2017 the American Physiological Society.

Peripheral lipopolysaccharide administration transiently affects expression of brain-derived neurotrophic factor, corticotropin and proopiomelanocortin in mouse brain.

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Schnydrig, Sabine; Korner, Lukas; Landweer, Svenja; Ernst, Beat; Walker, Gaby; Otten, Uwe; Kunz, Dieter

2007-12-11

Peripheral inflammation induced by intraperitoneal (i.p.) injection of Lipopolysaccharide (LPS) is known to cause functional impairments in the brain affecting memory and learning. One of mechanisms may be the interference with neurotrophin (NT) expression and function. In the current study we administered a single, high dose of LPS (3mg/kg, i.p.) into mice and investigated changes in brain-derived neurotrophic factor (BDNF) gene expression within 1-6 days after LPS injection. Crude synaptosomes were isolated from brain tissue and subjected to Western-blot analyses. We found transient reductions in synaptosomal proBDNF- and BDNF protein expression, with a maximal decrease at day 3 as compared to saline injected controls. The time course of reduction of BDNF mRNA in whole brain extracts parallels the decrease in protein levels in synaptosomes. LPS effects in the central nervous system (CNS) are known to crucially involve the activation of the hypothalamic-pituitary-adrenal (HPA) axis. We analysed the time course of corticotropin releasing hormone (CRH)- and proopiomelanocortin (POMC) mRNA expression. As observed for BDNF-, CRH- and POMC mRNA levels are also significantly reduced on day 3 indicating a comparable time course. These results suggest that peripheral inflammation causes a reduction of trophic supply in the brain, including BDNF at synaptic sites. The mechanisms involved could be a negative feedback of the activated HPA axis.

Role of Perinatal Inflammation in Neonatal Arterial Ischemic Stroke

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Antoine Giraud

2017-11-01

Full Text Available Based on the review of the literature, perinatal inflammation often induced by infection is the only consistent independent risk factor of neonatal arterial ischemic stroke (NAIS. Preclinical studies show that acute inflammatory processes take place in placenta, cerebral arterial wall of NAIS-susceptible arteries and neonatal brain. A top research priority in NAIS is to further characterize the nature and spatiotemporal features of the inflammatory processes involved in multiple levels of the pathophysiology of NAIS, to adequately design randomized control trials using targeted anti-inflammatory vasculo- and neuroprotective agents.

Odor Signals of Immune Activation and CNS Inflammation

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2014-12-01

inflammation results in detectable alteration of body odor and that traumatic brain injury (TBI) might similarly produce volatile metabolites specific to...Because both LPS and TBI elicit inflammatory processes and LPS-induced inflammation induces body odor changes, we hypothesized that (1) TBI would...induce a distinct change in body odor and (2) this change would resemble the change induced by LPS. Mice receiving surgery and lateral fluid percussion

Methamphetamine abuse affects gene expression in brain-derived microglia of SIV-infected macaques to enhance inflammation and promote virus targets

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Najera, Julia A.

2016-04-23

Background Methamphetamine (Meth) abuse is a major health problem linked to the aggravation of HIV- associated complications, especially within the Central Nervous System (CNS). Within the CNS, Meth has the ability to modify the activity/function of innate immune cells and increase brain viral loads. Here, we examined changes in the gene expression profile of neuron-free microglial cell preparations isolated from the brain of macaques infected with the Simian Immunodeficiency Virus (SIV), a model of neuroAIDS, and exposed to Meth. We aimed to identify molecular patterns triggered by Meth that could explain the detection of higher brain viral loads and the development of a pro-inflammatory CNS environment in the brain of infected drug abusers. Results We found that Meth alone has a strong effect on the transcription of genes associated with immune pathways, particularly inflammation and chemotaxis. Systems analysis led to a strong correlation between Meth exposure and enhancement of molecules associated with chemokines and chemokine receptors, especially CXCR4 and CCR5, which function as co-receptors for viral entry. The increase in CCR5 expression was confirmed in the brain in correlation with increased brain viral load. Conclusions Meth enhances the availability of CCR5-expressing cells for SIV in the brain, in correlation with increased viral load. This suggests that Meth is an important factor in the susceptibility to the infection and to the aggravated CNS inflammatory pathology associated with SIV in macaques and HIV in humans.

Change in brain magnetic resonance spectroscopy after treatment during acute HIV infection.

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Sailasuta, Napapon; Ross, William; Ananworanich, Jintanat; Chalermchai, Thep; DeGruttola, Victor; Lerdlum, Sukalaya; Pothisri, Mantana; Busovaca, Edgar; Ratto-Kim, Silvia; Jagodzinski, Linda; Spudich, Serena; Michael, Nelson; Kim, Jerome H; Valcour, Victor

2012-01-01

Single voxel proton magnetic resonance spectroscopy (MRS) can be used to monitor changes in brain inflammation and neuronal integrity associated with HIV infection and its treatments. We used MRS to measure brain changes during the first weeks following HIV infection and in response to antiretroviral therapy (ART). Brain metabolite levels of N-acetyl aspartate (NAA), choline (tCHO), creatine (CR), myoinositol (MI), and glutamate and glutamine (GLX) were measured in acute HIV subjects (n = 31) and compared to chronic HIV+individuals (n = 26) and HIV negative control subjects (n = 10) from Bangkok, Thailand. Metabolites were measured in frontal gray matter (FGM), frontal white matter (FWM), occipital gray matter (OGM), and basal ganglia (BG). Repeat measures were obtained in 17 acute subjects 1, 3 and 6 months following initiation of ART. After adjustment for age we identified elevated BG tCHO/CR in acute HIV cases at baseline (median 14 days after HIV infection) compared to control (p = 0.0014), as well as chronic subjects (p = 0.0023). A similar tCHO/CR elevation was noted in OGM; no other metabolite abnormalities were seen between acute and control subjects. Mixed longitudinal models revealed resolution of BG tCHO/CR elevation after ART (p = 0.022) with tCHO/CR similar to control subjects at 6 months. We detected cellular inflammation in the absence of measurable neuronal injury within the first month of HIV infection, and normalization of this inflammation following acutely administered ART. Our findings suggest that early ART may be neuroprotective in HIV infection by mitigating processes leading to CNS injury.

Wireless brain-machine interface using EEG and EOG: brain wave classification and robot control

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Oh, Sechang; Kumar, Prashanth S.; Kwon, Hyeokjun; Varadan, Vijay K.

2012-04-01

A brain-machine interface (BMI) links a user's brain activity directly to an external device. It enables a person to control devices using only thought. Hence, it has gained significant interest in the design of assistive devices and systems for people with disabilities. In addition, BMI has also been proposed to replace humans with robots in the performance of dangerous tasks like explosives handling/diffusing, hazardous materials handling, fire fighting etc. There are mainly two types of BMI based on the measurement method of brain activity; invasive and non-invasive. Invasive BMI can provide pristine signals but it is expensive and surgery may lead to undesirable side effects. Recent advances in non-invasive BMI have opened the possibility of generating robust control signals from noisy brain activity signals like EEG and EOG. A practical implementation of a non-invasive BMI such as robot control requires: acquisition of brain signals with a robust wearable unit, noise filtering and signal processing, identification and extraction of relevant brain wave features and finally, an algorithm to determine control signals based on the wave features. In this work, we developed a wireless brain-machine interface with a small platform and established a BMI that can be used to control the movement of a robot by using the extracted features of the EEG and EOG signals. The system records and classifies EEG as alpha, beta, delta, and theta waves. The classified brain waves are then used to define the level of attention. The acceleration and deceleration or stopping of the robot is controlled based on the attention level of the wearer. In addition, the left and right movements of eye ball control the direction of the robot.

Brain Computer Interface-Controlling Devices Utilizing The Alpha Brain Waves

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Rohan Hundia

2015-01-01

Full Text Available Abstract This paper describes the development and testing of an interface system whereby one can control external devices by voluntarily controlling alpha waves that is through eye movement. Such a system may be used for the control of prosthetics robotic arms and external devices like wheelchairs using the alpha brain waves and the Mu rhythm. The response generated through the movement of the eye detecting and controlling the amplitude of the alpha brain waves is interfaced and processed to control Robotic systems and smart home control. In order to measure the response of alpha waves over different lobes of the brain initially I measured these signals over 32 regions using silver chloride plated electrodes. By the opening and the closure of the eyes and the movement in the up-down left-right directions and processing these movements measuring them over the occipital region I was able to differentiate the amplitude of the alpha waves generated due to these several movements. In the First session testing period subjects were asked to close and open their eyes and they were able to control limited movements of a Robot and a prosthetic arm. In the Second 2session the movement of the eyes was also considered left-right up-down along with the opening and closure during this time span they were able to control more dimensions of the robot several devices at the same time using different eye movements.

Brain-controlled body movement assistance devices and methods

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Leuthardt, Eric C.; Love, Lonnie J.; Coker, Rob; Moran, Daniel W.

2017-01-10

Methods, devices, systems, and apparatus, including computer programs encoded on a computer storage medium, for brain-controlled body movement assistance devices. In one aspect, a device includes a brain-controlled body movement assistance device with a brain-computer interface (BCI) component adapted to be mounted to a user, a body movement assistance component operably connected to the BCI component and adapted to be worn by the user, and a feedback mechanism provided in connection with at least one of the BCI component and the body movement assistance component, the feedback mechanism being configured to output information relating to a usage session of the brain-controlled body movement assistance device.

G-CSF maintains controlled neutrophil mobilization during acute inflammation by negatively regulating CXCR2 signaling

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Bajrami, Besnik; Zhu, Haiyan; Zhang, Yu C.

2016-01-01

Cytokine-induced neutrophil mobilization from the bone marrow to circulation is a critical event in acute inflammation, but how it is accurately controlled remains poorly understood. In this study, we report that CXCR2 ligands are responsible for rapid neutrophil mobilization during early-stage acute inflammation. Nevertheless, although serum CXCR2 ligand concentrations increased during inflammation, neutrophil mobilization slowed after an initial acute fast phase, suggesting a suppression of neutrophil response to CXCR2 ligands after the acute phase. We demonstrate that granulocyte colony-stimulating factor (G-CSF), usually considered a prototypical neutrophil-mobilizing cytokine, was expressed later in the acute inflammatory response and unexpectedly impeded CXCR2-induced neutrophil mobilization by negatively regulating CXCR2-mediated intracellular signaling. Blocking G-CSF in vivo paradoxically elevated peripheral blood neutrophil counts in mice injected intraperitoneally with Escherichia coli and sequestered large numbers of neutrophils in the lungs, leading to sterile pulmonary inflammation. In a lipopolysaccharide-induced acute lung injury model, the homeostatic imbalance caused by G-CSF blockade enhanced neutrophil accumulation, edema, and inflammation in the lungs and ultimately led to significant lung damage. Thus, physiologically produced G-CSF not only acts as a neutrophil mobilizer at the relatively late stage of acute inflammation, but also prevents exaggerated neutrophil mobilization and the associated inflammation-induced tissue damage during early-phase infection and inflammation. PMID:27551153

Addictive genes and the relationship to obesity and inflammation.

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Heber, David; Carpenter, Catherine L

2011-10-01

There is increasing evidence that the same brain reward circuits involved in perpetuating drug abuse are involved in the hedonic urges and food cravings observed clinically in overweight and obese subjects. A polymorphism of the D2 dopamine receptor which renders it less sensitive to dopamine stimulation has been proposed to promote self-stimulatory behavior such as consuming alcohol, abusing drugs, or binging on foods. It is important to determine how this polymorphism may interact with other well-known candidate genes for obesity including polymorphisms of the leptin receptor gene and the opiomelanocortin gene. Leptin is a proinflammatory cytokine as well as a long-term signal maintaining body fat. Upper-body obesity stimulates systemic inflammation through the action of multiple cytokines including leptin throughout many organs including the brain. The association of numerous diseases including diabetes mellitus, heart disease, as well as depression with chronic low-grade inflammation due to abdominal obesity has raised the possibility that obesity-associated inflammation affecting the brain may promote addictive behaviors leading to a self-perpetuating cycle that may affect not only foods but addictions to drugs, alcohol, and gambling. This new area of interdisciplinary research holds the promise of developing new approaches to treating drug abuse and obesity.

Brain-derived neurotrophic factor: a bridge between inflammation and neuroplasticity

Directory of Open Access Journals (Sweden)

Francesca eCalabrese

2014-12-01

Full Text Available Cytokines are key regulatory mediators involved in the host response to immunological challenges, but also play a critical role in the communication between the immune and the central nervous system. For this, their expression in both systems is under a tight regulatory control. However, pathological conditions may lead to an overproduction of pro-inflammatory cytokines that may have a detrimental impact on central nervous system. In particular, they may damage neuronal structure and function leading to deficits of neuroplasticity, the ability of nervous system to perceive, respond and adapt to external or internal stimuli.In search of the mechanisms by which pro-inflammatory cytokines may affect this crucial brain capability, we will discuss one of the most interesting hypotheses: the involvement of the neurotrophin brain-derived neurotrophic factor, which represents one of the major mediators of neuroplasticity.

DMPD: Protein kinase C epsilon: a new target to control inflammation andimmune-mediated disorders. [Dynamic Macrophage Pathway CSML Database

Lifescience Database Archive (English)

Full Text Available 14643884 Protein kinase C epsilon: a new target to control inflammation andimmune-m...g) (.html) (.csml) Show Protein kinase C epsilon: a new target to control inflammation andimmune-mediated di...sorders. PubmedID 14643884 Title Protein kinase C epsilon: a new target to contro

Mitochondria: An Organelle of Bacterial Origin Controlling Inflammation

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Alain Meyer

2018-04-01

Full Text Available Inflammation is a cellular and molecular response to infection and/or tissues injury. While a suited inflammatory response in intensity and time allows for killing pathogens, clearing necrotic tissue, and healing injury; an excessive inflammatory response drives various diseases in which inflammation and tissues damages/stress self-sustain each other. Microbes have been poorly implied in non-resolving inflammation, emphasizing the importance of endogenous regulation of inflammation. Mitochondria have been historically identified as the main source of cellular energy, by coupling the oxidation of fatty acids and pyruvate with the production of high amount of adenosine triphosphate by the electron transport chain. Mitochondria are also the main source of reactive oxygen species. Interestingly, research in the last decade has highlighted that since its integration in eukaryote cells, this organelle of bacterial origin has not only been tolerated by immunity, but has also been placed as a central regulator of cell defense. In intact cells, mitochondria regulate cell responses to critical innate immune receptors engagement. Downstream intracellular signaling pathways interact with mitochondrial proteins and are tuned by mitochondrial functioning. Moreover, upon cell stress or damages, mitochondrial components are released into the cytoplasm or the extra cellular milieu, where they act as danger signals when recognized by innate immune receptors. Finally, by regulating the energetic state of immunological synapse between dendritic cells and lymphocytes, mitochondria regulate the inflammation fate toward immunotolerance or immunogenicity. As dysregulations of these processes have been recently involved in various diseases, the identification of the underlying mechanisms might open new avenues to modulate inflammation.

Brain-lung crosstalk in critical care: how protective mechanical ventilation can affect the brain homeostasis.

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Mazzeo, A T; Fanelli, V; Mascia, L

2013-03-01

The maintenance of brain homeostasis against multiple internal and external challenges occurring during the acute phase of acute brain injury may be influenced by critical care management, especially in its respiratory, hemodynamic and metabolic components. The occurrence of acute lung injury represents the most frequent extracranial complication after brain injury and deserves special attention in daily practice as optimal ventilatory strategy for patients with acute brain and lung injury are potentially in conflict. Protecting the lung while protecting the brain is thus a new target in the modern neurointensive care. This article discusses the essentials of brain-lung crosstalk and focuses on how mechanical ventilation may exert an active role in the process of maintaining or treatening brain homeostasis after acute brain injury, highlighting the following points: 1) the role of inflammation as common pathomechanism of both acute lung and brain injury; 2) the recognition of ventilatory induced lung injury as determinant of systemic inflammation affecting distal organs, included the brain; 3) the possible implication of protective mechanical ventilation strategy on the patient with an acute brain injury as an undiscovered area of research in both experimental and clinical settings.

[Menstruation, inflammation and comorbidities: implications for woman health].

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Graziottin, A; Zanello, P P

2015-02-01

Menstruation is the genital sign of systemic endocrine events. Heterogeneity of perimenstrual symptoms is associated with levels of inflammation, triggered by the fall of estrogens at genital and systemic level. Aim of the review is to concisely analyze the evidence on: 1) genital and systemic endocrine and inflammatory events associated with periods and perimenstrual symptoms; 2) rationale of intervention to reduce their intensity and impact on women's lives. This review of the literature, selected with a clinical perspective, supports the inflammatory basis of the menstrual event, triggered by the estrogens' and progesterone' fall. Moreover, the review analyzes the endocrine and inflammatory basis of perimenstrual pelvic and extrapelvic symptoms such as: menstrual pain, menstrual irregularities, premenstrual syndrome, gastrointestinal symptoms, catamenial headache, depression, perimenstrual myalgia, joint pain, allergies and asthma, heavy menstrual bleeding, associated ironless anemia, brain and behavioral consequences. Inflammation, with increase of cytokines and other markers, is modulated by the degranulation of mast cells at the basal level of the endometrium, in the blood, in all the organs where mast-cell are already activated from local pathologies and within the brain. The shift of inflammation from physiological to a pathologic intensity increases the severity of perimenstrual symptoms. Symptoms persist, moderately attenuated, also during the hormone free interval (HFI) in contraception. The HFI reduction from seven to two days significantly reduces menstrual inflammation and associated symptoms.

Brain inflammation accompanies amyloid in the majority of mild cognitive impairment cases due to Alzheimer's disease.

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Parbo, Peter; Ismail, Rola; Hansen, Kim V; Amidi, Ali; Mårup, Frederik H; Gottrup, Hanne; Brændgaard, Hans; Eriksson, Bengt O; Eskildsen, Simon F; Lund, Torben E; Tietze, Anna; Edison, Paul; Pavese, Nicola; Stokholm, Morten G; Borghammer, Per; Hinz, Rainer; Aanerud, Joel; Brooks, David J

2017-07-01

See Kreisl (doi:10.1093/awx151) for a scientific commentary on this article.Subjects with mild cognitive impairment associated with cortical amyloid-β have a greatly increased risk of progressing to Alzheimer's disease. We hypothesized that neuroinflammation occurs early in Alzheimer's disease and would be present in most amyloid-positive mild cognitive impairment cases. 11C-Pittsburgh compound B and 11C-(R)-PK11195 positron emission tomography was used to determine the amyloid load and detect the extent of neuroinflammation (microglial activation) in 42 mild cognitive impairment cases. Twelve age-matched healthy control subjects had 11C-Pittsburgh compound B and 10 healthy control subjects had 11C-(R)-PK11195 positron emission tomography for comparison. Amyloid-positivity was defined as 11C-Pittsburgh compound B target-to-cerebellar ratio above 1.5 within a composite cortical volume of interest. Supervised cluster analysis was used to generate parametric maps of 11C-(R)-PK11195 binding potential. Levels of 11C-(R)-PK11195 binding potential were measured in a selection of cortical volumes of interest and at a voxel level. Twenty-six (62%) of 42 mild cognitive impairment cases showed a raised cortical amyloid load compared to healthy controls. Twenty-two (85%) of the 26 amyloid-positive mild cognitive impairment cases showed clusters of increased cortical microglial activation accompanying the amyloid. There was a positive correlation between levels of amyloid load and 11C-(R)-PK11195 binding potentials at a voxel level within subregions of frontal, parietal and temporal cortices. 11C-(R)-PK11195 positron emission tomography reveals increased inflammation in a majority of amyloid positive mild cognitive impairment cases, its cortical distribution overlapping that of amyloid deposition. © The Author (2017). Published by Oxford University Press on behalf of the Guarantors of Brain. All rights reserved. For Permissions, please email: journals.permissions@oup.com.

Effect of Insulin Therapy using Hyper-insulinemic Normoglycemic Clamp on Inflammatory Response in Brain Dead Organ Donors.

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Aljiffry, M; Hassanain, M; Schricker, T; Shaheen, M; Nouh, T; Lattermann, R; Salman, A; Wykes, L; Metrakos, P

2016-05-01

Brain death is a major stress that is associated with a massive inflammatory response and systemic hyperglycemia. Severe inflammation leads to increased graft immunogenicity and risk of graft dysfunction; while acute hyperglycemia aggravates the inflammatory response and increases the risk of morbidity and mortality. Insulin therapy not only controls hyperglycemia but also suppresses inflammation. The present study is to investigate the anti-inflammatory properties and the normoglycemia maintenance of high dose insulin on brain dead organ donors. 15 brain dead organ donors were divided into 2 groups, insulin treated (n=6) and controls (n=9). Insulin was provided for a minimum of 6 h using the hyperinsulinemic normoglycemic clamp technique. The changes of serum cytokines, including IL-6, IL-10, IL-1β, IL-8, TNFα, TGFα and MCP-1, were measured by suspension bead array immunoassay and glucose by a glucose monitor. Compared to controls, insulin treated donors had a significant lower blood glucose 4.8 (4-6.9) vs. 9 (5.6-11.7) mmol/L, pinsulin treated donors compared with those in controls. High dose insulin therapy decreases the concentrations of inflammatory cytokines in brain dead donors and preserves normoglycemia. High dose of insulin may have anti-inflammatory effects in brain dead organ donors and therefore, improve the quality of donor organs and potentially improve outcomes. © Georg Thieme Verlag KG Stuttgart · New York.

DMPD: The involvement of the interleukin-1 receptor-associated kinases (IRAKs) incellular signaling networks controlling inflammation. [Dynamic Macrophage Pathway CSML Database

Lifescience Database Archive (English)

Full Text Available ncellular signaling networks controlling inflammation. Ringwood L, Li L. Cytokine. 2008 Apr;42(1):1-7. Epub ...ases (IRAKs) incellular signaling networks controlling inflammation. PubmedID 182...49132 Title The involvement of the interleukin-1 receptor-associated kinases (IRAKs) incellular signaling networks controlling

Maternal obesity increases inflammation and exacerbates damage following neonatal hypoxic-ischaemic brain injury in rats.

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Teo, Jonathan D; Morris, Margaret J; Jones, Nicole M

2017-07-01

In humans, maternal obesity is associated with an increase in the incidence of birth related difficulties. However, the impact of maternal obesity on the severity of brain injury in offspring is not known. Recent studies have found evidence of increased glial response and inflammatory mediators in the brains as a result of obesity in humans and rodents. We hypothesised that hypoxic-ischaemic (HI) brain injury is greater in neonatal offspring from obese rat mothers compared to lean controls. Female Sprague Dawley rats were randomly allocated to high fat (HFD, n=8) or chow (n=4) diet and mated with lean male rats. On postnatal day 7 (P7), male and female pups were randomly assigned to HI injury or control (C) groups. HI injury was induced by occlusion of the right carotid artery followed by 3h exposure to 8% oxygen, at 37°C. Control pups were removed from the mother for the same duration under ambient conditions. Righting behaviour was measured on day 1 and 7 following HI. The extent of brain injury was quantified in brain sections from P14 pups using cresyl violet staining and the difference in volume between brain hemispheres was measured. Before mating, HFD mothers were 11% heavier than Chow mothers (pmaternal weight. Similar observations were made with neuronal staining showing a greater loss of neurons in the brain of offspring from HFD-mothers following HI compared to Chow. Astrocytes appeared to more hypertrophic and a greater number of microglia were present in the injured hemisphere in offspring from mothers on HFD. HI caused an increase in the proportion of amoeboid microglia and exposure to maternal HFD exacerbated this response. In the contralateral hemisphere, offspring exposed to maternal HFD displayed a reduced proportion of ramified microglia. Our data clearly demonstrate that maternal obesity can exacerbate the severity of brain damage caused by HI in neonatal offspring. Given that previous studies have shown enhanced inflammatory responses in

Mdivi-1 ameliorates early brain injury after subarachnoid hemorrhage via the suppression of inflammation-related blood-brain barrier disruption and endoplasmic reticulum stress-based apoptosis.

Science.gov (United States)

Fan, Lin-Feng; He, Ping-You; Peng, Yu-Cong; Du, Qing-Hua; Ma, Yi-Jun; Jin, Jian-Xiang; Xu, Hang-Zhe; Li, Jian-Ru; Wang, Zhi-Jiang; Cao, Sheng-Long; Li, Tao; Yan, Feng; Gu, Chi; Wang, Lin; Chen, Gao

2017-11-01

of inflammation-related blood-brain barrier disruption and endoplasmic reticulum stress-based apoptosis. Copyright © 2017 Elsevier Inc. All rights reserved.

Antioxidant and signal modulation properties of plant polyphenols in controlling vascular inflammation.

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Kostyuk, Vladimir A; Potapovich, Alla I; Suhan, Tatyana O; de Luca, Chiara; Korkina, Liudmila G

2011-05-11

Oxidized low-density lipoproteins (oxLDL) play a critical role in the initiation of atherosclerosis through activation of inflammatory signaling. In the present work we investigated the role of antioxidant and signal modulation properties of plant polyphenols in controlling vascular inflammation. Significant decrease in intracellular NO level and superoxide overproduction was found in human umbilical vein endothelial cells (HUVEC) treated with oxLDL, but not with LDL. The redox imbalance was prevented by the addition of quercetin or resveratrol. Expression analysis of 14 genes associated with oxidative stress and inflammation revealed oxLDL-mediated up-regulation of genes specifically involved in leukocyte recruitment and adhesion. This up-regulation could be partially avoided by the addition of verbascoside or resveratrol, while treatment with quercetin resulted in a further increase in the expression of these genes. Lipopolysaccharide (LPS)-treated HUVEC were also used for the evaluation of anti-inflammatory potency of plant polyphenols. Significant differences between HUVEC treaded with oxLDL and LPS were found in both the expression pattern of inflammation-related genes and the effects of plant polyphenols on cellular responses. The present data indicate that plant polyphenols may affect vascular inflammation not only as antioxidants but also as modulators of inflammatory redox signaling pathways. Crown Copyright © 2011. Published by Elsevier B.V. All rights reserved.

Cerebral amyloid angiopathy-related inflammation: imaging findings and clinical outcome

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Martucci, Matia [Vall d' Hebron University Hospital, Neuroradiology Unit, Radiology Department (IDI), Barcelona (Spain); Catholic University of Sacred Heart, ' ' A. Gemelli' ' University Hospital, Department of Radiological Sciences, Rome (Italy); Sarria, Silvana; Coscojuela, Pilar; Vert, Carla; Siurana, Sahyly; Auger, Cristina; Rovira, Alex [Vall d' Hebron University Hospital, Neuroradiology Unit, Radiology Department (IDI), Barcelona (Spain); Toledo, Manuel [Vall d' Hebron University Hospital, Epilepsy Unit, Neurology Department, Barcelona (Spain)

2014-04-15

We aim to investigate the clinical onset, computed tomography (CT) and magnetic resonance (MR) imaging findings, and follow-up of patients with cerebral amyloid angiopathy (CAA)-related inflammation, an uncommon but clinically striking presentation of CAA. We retrospectively reviewed the clinical manifestations, CT/MR imaging findings, and outcome of ten consecutive patients with CAA-related inflammation. In each patient, a brain CT study was performed at hospital admission, and brain MR imaging was carried out 2 to 4 days later. Clinical and radiologic follow-up findings were evaluated in all patients. The most common clinical onset was rapidly progressive cognitive decline, followed by focal neurological signs. Brain CT/MR showed unenhanced expansive subcortical lesions, corresponding to areas of vasogenic edema, associated with chronic lobar, cortical, or cortical-subcortical micro/macrohemorrhages. Clinical symptoms recovered in a few weeks under treatment in eight patients and spontaneously in the remaining two. MRI follow-up at 2 to 12 months after treatment showed resolution of the lesions. Three patients experienced symptomatic disease recurrence, with new lesions on CT/MR. In the absence of histological data, early recognition of the clinical symptoms and typical radiologic features of CAA-related inflammation is essential to enable timely establishment of proper treatment. (orig.)

Cerebral amyloid angiopathy-related inflammation: imaging findings and clinical outcome

International Nuclear Information System (INIS)

Martucci, Matia; Sarria, Silvana; Coscojuela, Pilar; Vert, Carla; Siurana, Sahyly; Auger, Cristina; Rovira, Alex; Toledo, Manuel

2014-01-01

We aim to investigate the clinical onset, computed tomography (CT) and magnetic resonance (MR) imaging findings, and follow-up of patients with cerebral amyloid angiopathy (CAA)-related inflammation, an uncommon but clinically striking presentation of CAA. We retrospectively reviewed the clinical manifestations, CT/MR imaging findings, and outcome of ten consecutive patients with CAA-related inflammation. In each patient, a brain CT study was performed at hospital admission, and brain MR imaging was carried out 2 to 4 days later. Clinical and radiologic follow-up findings were evaluated in all patients. The most common clinical onset was rapidly progressive cognitive decline, followed by focal neurological signs. Brain CT/MR showed unenhanced expansive subcortical lesions, corresponding to areas of vasogenic edema, associated with chronic lobar, cortical, or cortical-subcortical micro/macrohemorrhages. Clinical symptoms recovered in a few weeks under treatment in eight patients and spontaneously in the remaining two. MRI follow-up at 2 to 12 months after treatment showed resolution of the lesions. Three patients experienced symptomatic disease recurrence, with new lesions on CT/MR. In the absence of histological data, early recognition of the clinical symptoms and typical radiologic features of CAA-related inflammation is essential to enable timely establishment of proper treatment. (orig.)

Impact of lipopolysaccharide-induced acute inflammation on baroreflex-controlled sympathetic arterial pressure regulation.

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Takeshi Tohyama

Full Text Available Lipopolysaccharide (LPS induces acute inflammation, activates sympathetic nerve activity (SNA and alters hemodynamics. Since the arterial baroreflex is a negative feedback system to stabilize arterial pressure (AP, examining the arterial baroreflex function is a prerequisite to understanding complex hemodynamics under LPS challenge. We investigated the impact of LPS-induced acute inflammation on SNA and AP regulation by performing baroreflex open-loop analysis.Ten anesthetized Sprague-Dawley rats were used. Acute inflammation was induced by an intravenous injection of LPS (60 μg/kg. We isolated the carotid sinuses from the systemic circulation and controlled carotid sinus pressure (CSP by a servo-controlled piston pump. We matched CSP to AP to establish the baroreflex closed-loop condition, whereas we decoupled CSP from AP to establish the baroreflex open-loop condition and changed CSP stepwise to evaluate the baroreflex open-loop function. We recorded splanchnic SNA and hemodynamic parameters under baroreflex open- and closed-loop conditions at baseline and at 60 and 120 min after LPS injection.In the baroreflex closed-loop condition, SNA continued to increase after LPS injection, reaching three-fold the baseline value at 120 min (baseline: 94.7 ± 3.6 vs. 120 min: 283.9 ± 31.9 a.u.. In contrast, AP increased initially (until 75 min, then declined to the baseline level. In the baroreflex open-loop condition, LPS reset the neural arc (CSP-SNA relationship upward to higher SNA, while shifted the peripheral arc (SNA-AP relationship downward at 120 min after the injection. As a result, the operating point determined by the intersection between function curves of neural arc and peripheral arc showed marked sympatho-excitation without substantial changes in AP.LPS-induced acute inflammation markedly increased SNA via resetting of the baroreflex neural arc, and suppressed the peripheral arc. The balance between the augmented neural arc and

Impact of lipopolysaccharide-induced acute inflammation on baroreflex-controlled sympathetic arterial pressure regulation.

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Tohyama, Takeshi; Saku, Keita; Kawada, Toru; Kishi, Takuya; Yoshida, Keimei; Nishikawa, Takuya; Mannoji, Hiroshi; Kamada, Kazuhiro; Sunagawa, Kenji; Tsutsui, Hiroyuki

2018-01-01

Lipopolysaccharide (LPS) induces acute inflammation, activates sympathetic nerve activity (SNA) and alters hemodynamics. Since the arterial baroreflex is a negative feedback system to stabilize arterial pressure (AP), examining the arterial baroreflex function is a prerequisite to understanding complex hemodynamics under LPS challenge. We investigated the impact of LPS-induced acute inflammation on SNA and AP regulation by performing baroreflex open-loop analysis. Ten anesthetized Sprague-Dawley rats were used. Acute inflammation was induced by an intravenous injection of LPS (60 μg/kg). We isolated the carotid sinuses from the systemic circulation and controlled carotid sinus pressure (CSP) by a servo-controlled piston pump. We matched CSP to AP to establish the baroreflex closed-loop condition, whereas we decoupled CSP from AP to establish the baroreflex open-loop condition and changed CSP stepwise to evaluate the baroreflex open-loop function. We recorded splanchnic SNA and hemodynamic parameters under baroreflex open- and closed-loop conditions at baseline and at 60 and 120 min after LPS injection. In the baroreflex closed-loop condition, SNA continued to increase after LPS injection, reaching three-fold the baseline value at 120 min (baseline: 94.7 ± 3.6 vs. 120 min: 283.9 ± 31.9 a.u.). In contrast, AP increased initially (until 75 min), then declined to the baseline level. In the baroreflex open-loop condition, LPS reset the neural arc (CSP-SNA relationship) upward to higher SNA, while shifted the peripheral arc (SNA-AP relationship) downward at 120 min after the injection. As a result, the operating point determined by the intersection between function curves of neural arc and peripheral arc showed marked sympatho-excitation without substantial changes in AP. LPS-induced acute inflammation markedly increased SNA via resetting of the baroreflex neural arc, and suppressed the peripheral arc. The balance between the augmented neural arc and suppressed

Low-grade inflammation decreases emotion recognition - Evidence from the vaccination model of inflammation.

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Balter, Leonie J T; Hulsken, Sasha; Aldred, Sarah; Drayson, Mark T; Higgs, Suzanne; Veldhuijzen van Zanten, Jet J C S; Raymond, Jane E; Bosch, Jos A

2018-05-06

The ability to adequately interpret the mental state of another person is key to complex human social interaction. Recent evidence suggests that this ability, considered a hallmark of 'theory of mind' (ToM), becomes impaired by inflammation. However, extant supportive empirical evidence is based on experiments that induce not only inflammation but also induce discomfort and sickness, factors that could also account for temporary social impairment. Hence, an experimental inflammation manipulation was applied that avoided this confound, isolating effects of inflammation and social interaction. Forty healthy male participants (mean age = 25, SD = 5 years) participated in this double-blind placebo-controlled crossover trial. Inflammation was induced using Salmonella Typhi vaccination (0.025 mg; Typhim Vi, Sanofi Pasteur, UK); saline-injection was used as a control. About 6 h 30 m after injection in each condition, participants completed the Reading the Mind in the Eyes Test (RMET), a validated test for assessing how well the mental states of others can be inferred through observation of the eyes region of the face. Vaccination induced systemic inflammation, elevating IL-6 by +419% (p  .21). Importantly, compared to placebo, vaccination significantly reduced RMET accuracy (p valence (positive, negative, neutral) provided no evidence of a selective impact of treatment. By utilizing an inflammation-induction procedure that avoided concurrent sicknesses or symptoms in a double-blinded design, the present study provides further support for the hypothesis that immune activation impairs ToM. Such impairment may provide a mechanistic link explaining social-cognitive deficits in psychopathologies that exhibit low-grade inflammation, such as major depression. Copyright © 2018 Elsevier Inc. All rights reserved.

Impact of Cocoa Consumption on Inflammation Processes—A Critical Review of Randomized Controlled Trials

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Ellinger, Sabine; Stehle, Peter

2016-01-01

Background: Cocoa flavanols have strong anti-inflammatory properties in vitro. If these also occur in vivo, cocoa consumption may contribute to the prevention or treatment of diseases mediated by chronic inflammation. This critical review judged the evidence for such effects occurring after cocoa consumption. Methods: A literature search in Medline was performed for randomized controlled trials (RCTs) that investigated the effects of cocoa consumption on inflammatory biomarkers. Results: Thirty-three RCTs were included, along with 9 bolus and 24 regular consumption studies. Acute cocoa consumption decreased adhesion molecules and 4-series leukotrienes in serum, nuclear factor κB activation in leukocytes, and the expression of CD62P and CD11b on monocytes and neutrophils. In healthy subjects and in patients with cardiovascular diseases, most regular consumption trials did not find any changes except for a decreased number of endothelial microparticles, but several cellular and humoral inflammation markers decreased in patients suffering from type 2 diabetes and impaired fasting glucose. Conclusions: Little evidence exists that consumption of cocoa-rich food may reduce inflammation, probably by lowering the activation of monocytes and neutrophils. The efficacy seems to depend on the extent of the basal inflammatory burden. Further well-designed RCTs with inflammation as the primary outcome are needed, focusing on specific markers of leukocyte activation and considering endothelial microparticles as marker of vascular inflammation. PMID:27240397

Impact of Cocoa Consumption on Inflammation Processes—A Critical Review of Randomized Controlled Trials

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Sabine Ellinger

2016-05-01

Full Text Available Background: Cocoa flavanols have strong anti-inflammatory properties in vitro. If these also occur in vivo, cocoa consumption may contribute to the prevention or treatment of diseases mediated by chronic inflammation. This critical review judged the evidence for such effects occurring after cocoa consumption. Methods: A literature search in Medline was performed for randomized controlled trials (RCTs that investigated the effects of cocoa consumption on inflammatory biomarkers. Results: Thirty-three RCTs were included, along with 9 bolus and 24 regular consumption studies. Acute cocoa consumption decreased adhesion molecules and 4-series leukotrienes in serum, nuclear factor κB activation in leukocytes, and the expression of CD62P and CD11b on monocytes and neutrophils. In healthy subjects and in patients with cardiovascular diseases, most regular consumption trials did not find any changes except for a decreased number of endothelial microparticles, but several cellular and humoral inflammation markers decreased in patients suffering from type 2 diabetes and impaired fasting glucose. Conclusions: Little evidence exists that consumption of cocoa-rich food may reduce inflammation, probably by lowering the activation of monocytes and neutrophils. The efficacy seems to depend on the extent of the basal inflammatory burden. Further well-designed RCTs with inflammation as the primary outcome are needed, focusing on specific markers of leukocyte activation and considering endothelial microparticles as marker of vascular inflammation.

Impact of Cocoa Consumption on Inflammation Processes-A Critical Review of Randomized Controlled Trials.

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Ellinger, Sabine; Stehle, Peter

2016-05-26

Cocoa flavanols have strong anti-inflammatory properties in vitro. If these also occur in vivo, cocoa consumption may contribute to the prevention or treatment of diseases mediated by chronic inflammation. This critical review judged the evidence for such effects occurring after cocoa consumption. A literature search in Medline was performed for randomized controlled trials (RCTs) that investigated the effects of cocoa consumption on inflammatory biomarkers. Thirty-three RCTs were included, along with 9 bolus and 24 regular consumption studies. Acute cocoa consumption decreased adhesion molecules and 4-series leukotrienes in serum, nuclear factor κB activation in leukocytes, and the expression of CD62P and CD11b on monocytes and neutrophils. In healthy subjects and in patients with cardiovascular diseases, most regular consumption trials did not find any changes except for a decreased number of endothelial microparticles, but several cellular and humoral inflammation markers decreased in patients suffering from type 2 diabetes and impaired fasting glucose. Little evidence exists that consumption of cocoa-rich food may reduce inflammation, probably by lowering the activation of monocytes and neutrophils. The efficacy seems to depend on the extent of the basal inflammatory burden. Further well-designed RCTs with inflammation as the primary outcome are needed, focusing on specific markers of leukocyte activation and considering endothelial microparticles as marker of vascular inflammation.

The bilingual brain: Flexibility and control in the human cortex

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Buchweitz, Augusto; Prat, Chantel

2013-12-01

The goal of the present review is to discuss recent cognitive neuroscientific findings concerning bilingualism. Three interrelated questions about the bilingual brain are addressed: How are multiple languages represented in the brain? how are languages controlled in the brain? and what are the real-world implications of experience with multiple languages? The review is based on neuroimaging research findings about the nature of bilingual processing, namely, how the brain adapts to accommodate multiple languages in the bilingual brain and to control which language should be used, and when. We also address how this adaptation results in differences observed in the general cognition of bilingual individuals. General implications for models of human learning, plasticity, and cognitive control are discussed.

Chronic gastrointestinal inflammation induces anxiety-like behavior and alters central nervous system biochemistry in mice.

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Bercik, Premysl; Verdu, Elena F; Foster, Jane A; Macri, Joseph; Potter, Murray; Huang, Xiaxing; Malinowski, Paul; Jackson, Wendy; Blennerhassett, Patricia; Neufeld, Karen A; Lu, Jun; Khan, Waliul I; Corthesy-Theulaz, Irene; Cherbut, Christine; Bergonzelli, Gabriela E; Collins, Stephen M

2010-12-01

Clinical and preclinical studies have associated gastrointestinal inflammation and infection with altered behavior. We investigated whether chronic gut inflammation alters behavior and brain biochemistry and examined underlying mechanisms. AKR mice were infected with the noninvasive parasite Trichuris muris and given etanercept, budesonide, or specific probiotics. Subdiaphragmatic vagotomy was performed in a subgroup of mice before infection. Gastrointestinal inflammation was assessed by histology and quantification of myeloperoxidase activity. Serum proteins were measured by proteomic analysis, circulating cytokines were measured by fluorescence activated cell sorting array, and serum tryptophan and kynurenine were measured by liquid chromatography. Behavior was assessed using light/dark preference and step-down tests. In situ hybridization was used to assess brain-derived neurotrophic factor (BDNF) expression in the brain. T muris caused mild to moderate colonic inflammation and anxiety-like behavior that was associated with decreased hippocampal BDNF messenger RNA (mRNA). Circulating tumor necrosis factor-α and interferon-γ, as well as the kynurenine and kynurenine/tryptophan ratio, were increased. Proteomic analysis showed altered levels of several proteins related to inflammation and neural function. Administration of etanercept, and to a lesser degree of budesonide, normalized behavior, reduced cytokine and kynurenine levels, but did not influence BDNF expression. The probiotic Bifidobacterium longum normalized behavior and BDNF mRNA but did not affect cytokine or kynurenine levels. Anxiety-like behavior was present in infected mice after vagotomy. Chronic gastrointestinal inflammation induces anxiety-like behavior and alters central nervous system biochemistry, which can be normalized by inflammation-dependent and -independent mechanisms, neither of which requires the integrity of the vagus nerve. Copyright © 2010 AGA Institute. Published by Elsevier Inc

Milk Fat Globule-Epidermal Growth Factor-8 Pretreatment Attenuates Apoptosis and Inflammation via the Integrin-β3 Pathway after Surgical Brain Injury in Rats

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Yicai Xiao

2018-02-01

Full Text Available Iatrogenic brain injury inevitably occurs in neurosurgical operations, leading to brain edema, ischemia, intracranial hematoma, and other postoperative complications, eventually worsening neurological outcomes of patients. If apoptotic cells are not rapidly eliminated by phagocytic engulfment, they may communicate with surrounding cells to undergo secondary necrosis and releasing toxic signals. Recent studies have shown that milk fat globule-epidermal growth factor-8 (MFGE8, which promotes phagocytosis and inhibits inflammation, is an endogenous protective factor in response to brain infarction, Alzheimer’s disease, subarachnoid hemorrhage, and prion disease. In the present study, we sought to investigate the different effects of both pretreated and posttreated recombinant milk fat globule-epidermal growth factor-8 (rhMFGE8 for the surgical brain injury (SBI rat model and potential involvement of its receptor integrin β3 for apoptosis and neuroinflammation after SBI. One hundred and sixty-seven male rats were employed in the preset study. Experiment 1 was performed to evaluate neurological scores and MFGE8, cleaved caspase-3 (CC3, and interleukine-1 beta (IL-1β levels at 3, 24, and 120 h after SBI. Experiment 2 was performed to evaluate the effects of rhMFGE8 pretreatment (10 min before SBI and rhMFGE8 posttreatment (6 h after SBI on brain edema at 24 and 72 h after SBI. Experiment 3 was performed to evaluate the potential anti-apoptotic and anti-inflammatory effects of rhMFGE8 pretreatment and posttreatment. Experiment 4 sought to investigate the involvement of the integrin-β3 signal in the effects of MFGE8 pretreatment. Our data showed rhMFGE8 pretreatment alleviated neurological deficits and decreased brain water content and apoptotic cells in the SBI model, which exhibited neurological dysfunction, apoptosis, and inflammation. Meanwhile, MFGE8 siRNA, which inhibited endogenous MFGE8 expression, significantly increased IL-1�

Glial and neuronal control of brain blood flow

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Attwell, David; Buchan, Alastair M; Charpak, Serge

2010-01-01

Blood flow in the brain is regulated by neurons and astrocytes. Knowledge of how these cells control blood flow is crucial for understanding how neural computation is powered, for interpreting functional imaging scans of brains, and for developing treatments for neurological disorders. It is now...... in our understanding of cerebral blood flow control have important implications for the development of new therapeutic approaches....

Endogenous Receptor Agonists: Resolving Inflammation

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Gerhard Bannenberg

2007-01-01

Full Text Available Controlled resolution or the physiologic resolution of a well-orchestrated inflammatory response at the tissue level is essential to return to homeostasis. A comprehensive understanding of the cellular and molecular events that control the termination of acute inflammation is needed in molecular terms given the widely held view that aberrant inflammation underlies many common diseases. This review focuses on recent advances in the understanding of the role of arachidonic acid and ω-3 polyunsaturated fatty acids (PUFA–derived lipid mediators in regulating the resolution of inflammation. Using a functional lipidomic approach employing LC-MS-MS–based informatics, recent studies, reviewed herein, uncovered new families of local-acting chemical mediators actively biosynthesized during the resolution phase from the essential fatty acids eicosapentaenoic acid (EPA and docosahexaenoic acid (DHA. These new families of local chemical mediators are generated endogenously in exudates collected during the resolution phase, and were coined resolvins and protectins because specific members of these novel chemical families control both the duration and magnitude of inflammation in animal models of complex diseases. Recent advances on the biosynthesis, receptors, and actions of these novel anti-inflammatory and proresolving lipid mediators are reviewed with the aim to bring to attention the important role of specific lipid mediators as endogenous agonists in inflammation resolution.

Supplementary Material for: Methamphetamine abuse affects gene expression in brain-derived microglia of SIV-infected macaques to enhance inflammation and promote virus targets

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Najera, Julia

2016-01-01

Abstract Background Methamphetamine (Meth) abuse is a major health problem linked to the aggravation of HIV- associated complications, especially within the Central Nervous System (CNS). Within the CNS, Meth has the ability to modify the activity/function of innate immune cells and increase brain viral loads. Here, we examined changes in the gene expression profile of neuron-free microglial cell preparations isolated from the brain of macaques infected with the Simian Immunodeficiency Virus (SIV), a model of neuroAIDS, and exposed to Meth. We aimed to identify molecular patterns triggered by Meth that could explain the detection of higher brain viral loads and the development of a pro-inflammatory CNS environment in the brain of infected drug abusers. Results We found that Meth alone has a strong effect on the transcription of genes associated with immune pathways, particularly inflammation and chemotaxis. Systems analysis led to a strong correlation between Meth exposure and enhancement of molecules associated with chemokines and chemokine receptors, especially CXCR4 and CCR5, which function as co-receptors for viral entry. The increase in CCR5 expression was confirmed in the brain in correlation with increased brain viral load. Conclusions Meth enhances the availability of CCR5-expressing cells for SIV in the brain, in correlation with increased viral load. This suggests that Meth is an important factor in the susceptibility to the infection and to the aggravated CNS inflammatory pathology associated with SIV in macaques and HIV in humans.

TRPA1 controls inflammation and pruritogen responses in allergic contact dermatitis

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Liu, Boyi; Escalera, Jasmine; Balakrishna, Shrilatha; Fan, Lu; Caceres, Ana I.; Robinson, Eve; Sui, Aiwei; McKay, M. Craig; McAlexander, M. Allen; Herrick, Christina A.; Jordt, Sven E.

2013-01-01

Allergic contact dermatitis is a common skin disease associated with inflammation and persistent pruritus. Transient receptor potential (TRP) ion channels in skin-innervating sensory neurons mediate acute inflammatory and pruritic responses following exogenous stimulation and may contribute to allergic responses. Genetic ablation or pharmacological inhibition of TRPA1, but not TRPV1, inhibited skin edema, keratinocyte hyperplasia, nerve growth, leukocyte infiltration, and antihistamine-resistant scratching behavior in mice exposed to the haptens, oxazolone and urushiol, the contact allergen of poison ivy. Hapten-challenged skin of TRPA1-deficient mice contained diminished levels of inflammatory cytokines, nerve growth factor, and endogenous pruritogens, such as substance P (SP) and serotonin. TRPA1-deficient sensory neurons were defective in SP signaling, and SP-induced scratching behavior was abolished in Trpa1−/− mice. SP receptor antagonists, such as aprepitant inhibited both hapten-induced cutaneous inflammation and scratching behavior. These findings support a central role for TRPA1 and SP in the integration of immune and neuronal mechanisms leading to chronic inflammatory responses and pruritus associated with contact dermatitis.—Liu, B., Escalera, J., Balakrishna, S., Fan, L., Caceres, A. I., Robinson, E., Sui, A., McKay, M. C., McAlexander, M. A., Herrick, C. A., Jordt, S. E. TRPA1 controls inflammation and pruritogen responses in allergic contact dermatitis. PMID:23722916

Fetal uptake of intra-amniotically delivered dendrimers in a mouse model of intrauterine inflammation and preterm birth.

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Burd, Irina; Zhang, Fan; Dada, Tahani; Mishra, Manoj K; Borbiev, Talaibek; Lesniak, Wojciech G; Baghlaf, Haitham; Kannan, Sujatha; Kannan, Rangaramanujam M

2014-08-01

Intrauterine inflammation is associated with preterm birth and can lead to fetal neuroinflammation and neurobehavioral disorders in newborns. Dendrimers can intrinsically target and deliver drugs for the treatment of neuroinflammation. We explore whether hydroxyl polyamidoamine (PAMAM) dendrimer (G4-OH)-based nanomedicines can be delivered to the fetus by intra-amniotic administration, in a mouse model of intrauterine inflammation. The time-dependent accumulation of G4-OH-fluorophore conjugate was quantified by fluorescence. These studies suggest that, after intra-amniotic administration, there is significant accumulation of dendrimer in the fetus gut and brain. In addition, there is some fetal-maternal transport of the dendrimer. Confocal microscopy confirmed the presence of G4-OH in the fetal brain, with a large accumulation in the brain blood vessels and the brain parenchyma, and some microglial uptake. We believe that intra-amniotic administration of G4-OH-drug nanomedicines may enable the treatment of diseases related to intrauterine inflammation and fetal neuroinflammation. Using a mouse model of intrauterin inflammation leading to neuroinflammation in the fetus, these investigators demonstrate that intra-amniotic delivery of hydroxyl polyamidoamine (PAMAM) dendrimer (G4-OH)-based nanomedicines may provide an effective method in preventing this complication. Copyright © 2014 Elsevier Inc. All rights reserved.

Presenilin/γ-secretase and inflammation

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Carlos A Saura

2010-05-01

Full Text Available Presenilins (PS are the catalytic components of γ-secretase, an aspartyl protease that regulates through proteolytic processing the function of multiple signaling proteins. Specially relevant is the γ-secretase-dependent cleavage of the β-amyloid precursor protein (APP since generates the β-amyloid (Aβ peptides that aggregate and accumulate in the brain of Alzheimer´s disease (AD patients. Abnormal processing and/or accumulation of Aβ disrupt synaptic and metabolic processes leading to neuron dysfunction and neurodegeneration. Studies in presenilin conditional knockout mice have revealed that presenilin-1 is essential for age-dependent Aβ accumulation and inflammation. By contrast, mutations in the presenilin genes reponsible for early onset familial AD cause rapid disease progression and accentuate clinical and pathological features including inflammation. In addition, a number of loss of function mutations in presenilin-1 have been recently associated to non-Alzheimer's dementias including frontotemporal dementia and dementia with Lewy bodies. In agreement, total loss of presenilin function in the brain results in striking neurodegeneration and inflammation, which includes activation of glial cells and induction of proinflammatory genes, besides altered inflammatory responses in the periphery. Interestingly, some non-steroidal anti-inflammatory drugs (NSAIDs that slow cognitive decline and reduce the risk of AD, decrease amyloidogenic Aβ42 levels by modulating allosterically PS/γ-secretase. In this review, I present current evidence supporting a role of presenilin/γ-secretase signaling on gliogenesis and gliosis in normal and pathological conditions. Understanding the cellular mechanisms regulated by presenilin/γ-secretase during chronic inflammatory processes may provide new approaches for the development of effective therapeutic strategies for AD.

Whole grains, bran, and germ in relation to homocysteine and markers of glycemic control, lipids, and inflammation 1

DEFF Research Database (Denmark)

Jensen, Majken K; Koh-Banerjee, Pauline; Franz, Mary

2006-01-01

BACKGROUND: Intake of whole grains is inversely associated with risk of diabetes and ischemic heart disease in observational studies. The lower risk associated with high whole-grain intakes may be mediated through improvements in glycemic control, lipid profiles, or reduced inflammation. OBJECTIV...... in this population. CONCLUSION: The results suggest a lower risk of diabetes and heart disease in persons who consume diets high in whole grains.......BACKGROUND: Intake of whole grains is inversely associated with risk of diabetes and ischemic heart disease in observational studies. The lower risk associated with high whole-grain intakes may be mediated through improvements in glycemic control, lipid profiles, or reduced inflammation. OBJECTIVE......-reactive protein, fibrinogen, and interleukin 6). DESIGN: This was a cross-sectional study of the relations of whole grains, bran, and germ intakes with homocysteine and markers of glycemic control, lipids, and inflammation in 938 healthy men and women. RESULTS: Whole-grain intake was inversely associated...

β-Adrenoceptor activation depresses brain inflammation and is neuroprotective in lipopolysaccharide-induced sensitization to oxygen-glucose deprivation in organotypic hippocampal slices

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Cilio Corrado

2010-12-01

Full Text Available Abstract Background Inflammation acting in synergy with brain ischemia aggravates perinatal ischemic brain damage. The sensitizing effect of pro-inflammatory exposure prior to hypoxia is dependent on signaling by TNF-α through TNF receptor (TNFR 1. Adrenoceptor (AR activation is known to modulate the immune response and synaptic transmission. The possible protective effect of α˜ and β˜AR activation against neuronal damage caused by tissue ischemia and inflammation, acting in concert, was evaluated in murine hippocampal organotypic slices treated with lipopolysaccharide (LPS and subsequently subjected to oxygen-glucose deprivation (OGD. Method Hippocampal slices from mice were obtained at P6, and were grown in vitro for 9 days on nitrocellulose membranes. Slices were treated with β1(dobutamine-, β2(terbutaline-, α1(phenylephrine- and α2(clonidine-AR agonists (5 and 50 μM, respectively during LPS (1 μg/mL, 24 h -exposure followed by exposure to OGD (15 min in a hypoxic chamber. Cell death in the slice CA1 region was assessed by propidium iodide staining of dead cells. Results Exposure to LPS + OGD caused extensive cell death from 4 up to 48 h after reoxygenation. Co-incubation with β1-agonist (50 μM during LPS exposure before OGD conferred complete protection from cell death (P -/- and TNFR2-/- slices exposed to LPS followed by OGD. Conclusions Our data demonstrate that activation of both β1- and β2-receptors is neuroprotective and may offer mechanistic insights valuable for development of neuro-protective strategies in neonates.

Protective properties of 6-gingerol-rich fraction from Zingiber officinale (Ginger) on chlorpyrifos-induced oxidative damage and inflammation in the brain, ovary and uterus of rats.

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Abolaji, Amos O; Ojo, Mercy; Afolabi, Tosin T; Arowoogun, Mary D; Nwawolor, Darlinton; Farombi, Ebenezer O

2017-05-25

Chlorpyrifos (CPF) is an organophosphorus pesticide widely used in agricultural applications and household environments. 6-Gingerol-rich fraction from Zingiber officinale (Ginger, 6-GRF) has been reported to possess potent anti-oxidative, anti-inflammatory and anti-apoptotic properties. Here, we investigated the protective properties of 6-GRF on CPF-induced oxidative damage and inflammation in the brain, ovary and uterus of rats. Five groups of rats containing 14 rats/group received corn oil (control), CPF (5 mg/kg), 6-GRF (100 mg/kg), CPF (5 mg/kg) + 6-GRF (50 mg/kg) and CPF (5 mg/kg) + 6-GRF (100 mg/kg) through gavage once per day for 35 days respectively. The results showed that 6-GRF protected against CPF-induced increases in oxidative stress ((hydrogen peroxide (H 2 O 2 ) and malondialdehyde (MDA)), inflammatory (myeloperoxidase (MPO), nitric oxide (NO) and tumour necrosis factor-α (TNF- α)), and apoptotic (caspase-3) markers. Also, 6-GRF improved the activities of antioxidant enzymes catalase, superoxide dismutase (SOD), glutathione peroxidase (GPx), and glutathione S-transferase (GST) as well as glutathione (GSH) level in the brain, ovary and uterus of rats exposed to CPF (p < 0.05). Overall, the protective effects of 6-GRF on CPF-induced toxicity in the brain and reproductive organs of rats may be due to its potent antioxidative, anti-inflammatory and antiapoptotic properties. Copyright © 2017 Elsevier B.V. All rights reserved.

Inflammation in Patients with Schizophrenia: the Therapeutic Benefits of Risperidone Plus Add-On Dextromethorphan

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Chen, Shiou-Lan; Lee, Sheng-Yu; Chang, Yun-Hsuan; Chen, Shih-Heng; Chu, Chun-Hsieh; Tzeng, Nian-Sheng; Lee, I-Hui; Chen, Po-See; Yeh, Tzung Lieh; Huang, San-Yuan; Yang, Yen-Kuang; Lu, Ru-Band; Hong, Jau-Shyong

2013-01-01

Objectives Increasing evidence suggests that inflammation contributes to the etiology and progression of schizophrenia. Molecules that initiate inflammation, such as virus- and toxin-induced cytokines, are implicated in neuronal degeneration and schizophrenia-like behavior. Using therapeutic agents with anti-inflammatory or neurotrophic effects may be beneficial for treating schizophrenia. Methods One hundred healthy controls and 95 Han Chinese patients with schizophrenia were tested in this double-blind study. Their PANSS scores, plasma interleukin (IL)-1β, TNF-α and brain-derived neurotrophic factor (BDNF) levels were measured before and after pharmacological treatment. Results Pretreatment, plasma levels of IL-1β and TNF-α were significantly higher in patients with schizophrenia than in controls, but plasma BDNF levels were significantly lower. Patients were treated with the atypical antipsychotic risperidone (Risp) only or with Risp+add-on dextromethorphan (DM). PANSS scores and plasma IL-1β levels significantly decreased, but plasma TNF-α and BDNF levels significantly increased after 11 weeks of Risp treatment. Patients in the Risp+DM group showed a greater and earlier reduction of symptoms than did those in the Risp-only group. Moreover, Risp+DM treatment attenuated Risp-induced plasma increases in TNF-α. Conclusion Patients with schizophrenia had a high level of peripheral inflammation and a low level of peripheral BDNF. Long-term Risp treatment attenuated inflammation and potentiated the neurotrophic function but also produced a certain degree of toxicity. Risp+DM was more beneficial and less toxic than Risp-only treatment. PMID:22730040

When "altering brain function" becomes "mind control".

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Koivuniemi, Andrew; Otto, Kevin

2014-01-01

Functional neurosurgery has seen a resurgence of interest in surgical treatments for psychiatric illness. Deep brain stimulation (DBS) technology is the preferred tool in the current wave of clinical experiments because it allows clinicians to directly alter the functions of targeted brain regions, in a reversible manner, with the intent of correcting diseases of the mind, such as depression, addiction, anorexia nervosa, dementia, and obsessive compulsive disorder. These promising treatments raise a critical philosophical and humanitarian question. "Under what conditions does 'altering brain function' qualify as 'mind control'?" In order to answer this question one needs a definition of mind control. To this end, we reviewed the relevant philosophical, ethical, and neurosurgical literature in order to create a set of criteria for what constitutes mind control in the context of DBS. We also outline clinical implications of these criteria. Finally, we demonstrate the relevance of the proposed criteria by focusing especially on serendipitous treatments involving DBS, i.e., cases in which an unintended therapeutic benefit occurred. These cases highlight the importance of gaining the consent of the subject for the new therapy in order to avoid committing an act of mind control.

Xanomeline suppresses excessive pro-inflammatory cytokine responses through neural signal-mediated pathways and improves survival in lethal inflammation

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Rosas-Ballina, Mauricio; Ferrer, Sergio Valdés; Dancho, Meghan; Ochani, Mahendar; Katz, David; Cheng, Kai Fan; Olofsson, Peder S.; Chavan, Sangeeta S.; Al-Abed, Yousef; Tracey, Kevin J.; Pavlov, Valentin A.

2014-01-01

Inflammatory conditions characterized by excessive immune cell activation and cytokine release, are associated with bidirectional immune system-brain communication, underlying sickness behavior and other physiological responses. The vagus nerve has an important role in this communication by conveying sensory information to the brain, and brain-derived immunoregulatory signals that suppress peripheral cytokine levels and inflammation. Brain muscarinic acetylcholine receptor (mAChR)-mediated cholinergic signaling has been implicated in this regulation. However, the possibility of controlling inflammation by peripheral administration of centrally-acting mAChR agonists is unexplored. To provide insight we used the centrally-acting M1 mAChR agonist xanomeline, previously developed in the context of Alzheimer’s disease and schizophrenia. Intraperitoneal administration of xanomeline significantly suppressed serum and splenic TNF levels, alleviated sickness behavior, and increased survival during lethal murine endotoxemia. The anti-inflammatory effects of xanomeline were brain mAChR-mediated and required intact vagus nerve and splenic nerve signaling. The anti-inflammatory efficacy of xanomeline was retained for at least 20h, associated with alterations in splenic lymphocyte, and dendritic cell proportions, and decreased splenocyte responsiveness to endotoxin. These results highlight an important role of the M1 mAChR in a neural circuitry to spleen in which brain cholinergic activation lowers peripheral pro-inflammatory cytokines to levels favoring survival. The therapeutic efficacy of xanomeline was also manifested by significantly improved survival in preclinical settings of severe sepsis. These findings are of interest for strategizing novel therapeutic approaches in inflammatory diseases. PMID:25063706

Evaluation of [{sup 11}C]rofecoxib as PET tracer for cyclooxygenase 2 overexpression in rat models of inflammation

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Vries, Erik F.J. de [Department of Nuclear Medicine and Molecular Imaging, University Medical Center Groningen, University of Groningen, P.O. Box 30.001, 9700 RB Groningen (Netherlands)], E-mail: e.f.j.de.vries@ngmb.umcg.nl; Doorduin, Janine; Dierckx, Rudi A.; Waarde, Aren van [Department of Nuclear Medicine and Molecular Imaging, University Medical Center Groningen, University of Groningen, P.O. Box 30.001, 9700 RB Groningen (Netherlands)

2008-01-15

Background: Overexpression of cyclooxygenase type 2 (COX-2) is triggered by inflammatory stimuli, but it also plays a prominent role in the initiation and progression of various diseases. This study aims to investigate [{sup 11}C]rofecoxib as a positron emission tomography (PET) tracer for COX-2 expression. Methods: [{sup 11}C]Rofecoxib was prepared by methylation of its sulphinate precursor. Regional brain distribution and specific binding of [{sup 11}C]rofecoxib in healthy rats was studied by ex vivo biodistribution and autoradiography. Regional brain distribution and PET imaging studies were also performed on rats with severe encephalitis, caused by nasal infection with herpes simplex virus (HSV). Finally, ex vivo biodistribution and blocking studies were carried in rats with a sterile inflammation, induced by intramuscular turpentine injection. Results: [{sup 11}C]rofecoxib brain uptake in control animals corresponded with the known distribution of COX-2. Pretreatment with NS398 significantly reduced tracer uptake in the cingulate/frontopolar cortex, whereas the reduction in hippocampus approached significance. Ex vivo autoradiography also revealed preferential tracer uptake in hippocampus and cortical areas that could be blocked by NS398. In HSV-infected animals, [{sup 11}C]rofecoxib uptake was moderately increased in all brain regions, but it could not be blocked with indomethacin. Yet, some PET images revealed increased tracer uptake in brain areas with microglia activation. In turpentine-injected animals, [{sup 11}C]rofecoxib uptake in inflamed muscle was not higher than in control muscle and could not be blocked with NS398. Indomethacin caused a slight reduction in muscle uptake. Conclusions: Despite the apparent correlation between [{sup 11}C]rofecoxib uptake and COX-2 distribution in healthy rats, [{sup 11}C]rofecoxib could not unambiguously detect COX-2 overexpression in two rat models of inflammation.

Brain and Peripheral Atypical Inflammatory Mediators Potentiate Neuroinflammation and Neurodegeneration.

Science.gov (United States)

Kempuraj, Duraisamy; Thangavel, Ramasamy; Selvakumar, Govindhasamy P; Zaheer, Smita; Ahmed, Mohammad E; Raikwar, Sudhanshu P; Zahoor, Haris; Saeed, Daniyal; Natteru, Prashant A; Iyer, Shankar; Zaheer, Asgar

2017-01-01

Neuroinflammatory response is primarily a protective mechanism in the brain. However, excessive and chronic inflammatory responses can lead to deleterious effects involving immune cells, brain cells and signaling molecules. Neuroinflammation induces and accelerates pathogenesis of Parkinson's disease (PD), Alzheimer's disease (AD) and Multiple sclerosis (MS). Neuroinflammatory pathways are indicated as novel therapeutic targets for these diseases. Mast cells are immune cells of hematopoietic origin that regulate inflammation and upon activation release many proinflammatory mediators in systemic and central nervous system (CNS) inflammatory conditions. In addition, inflammatory mediators released from activated glial cells induce neurodegeneration in the brain. Systemic inflammation-derived proinflammatory cytokines/chemokines and other factors cause a breach in the blood brain-barrier (BBB) thereby allowing for the entry of immune/inflammatory cells including mast cell progenitors, mast cells and proinflammatory cytokines and chemokines into the brain. These peripheral-derived factors and intrinsically generated cytokines/chemokines, α-synuclein, corticotropin-releasing hormone (CRH), substance P (SP), beta amyloid 1-42 (Aβ1-42) peptide and amyloid precursor proteins can activate glial cells, T-cells and mast cells in the brain can induce additional release of inflammatory and neurotoxic molecules contributing to chronic neuroinflammation and neuronal death. The glia maturation factor (GMF), a proinflammatory protein discovered in our laboratory released from glia, activates mast cells to release inflammatory cytokines and chemokines. Chronic increase in the proinflammatory mediators induces neurotoxic Aβ and plaque formation in AD brains and neurodegeneration in PD brains. Glial cells, mast cells and T-cells can reactivate each other in neuroinflammatory conditions in the brain and augment neuroinflammation. Further, inflammatory mediators from the brain can

Glial and neuronal control of brain blood flow

DEFF Research Database (Denmark)

Attwell, David; Buchan, Alastair M; Charpak, Serge

2010-01-01

Blood flow in the brain is regulated by neurons and astrocytes. Knowledge of how these cells control blood flow is crucial for understanding how neural computation is powered, for interpreting functional imaging scans of brains, and for developing treatments for neurological disorders. It is now...... recognized that neurotransmitter-mediated signalling has a key role in regulating cerebral blood flow, that much of this control is mediated by astrocytes, that oxygen modulates blood flow regulation, and that blood flow may be controlled by capillaries as well as by arterioles. These conceptual shifts...

Interleukin-1 and acute brain injury

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Katie N Murray

2015-02-01

Full Text Available Inflammation is the key host-defense response to infection and injury, yet also a major contributor to a diverse range of diseases, both peripheral and central in origin. Brain injury as a result of stroke or trauma is a leading cause of death and disability worldwide, yet there are no effective treatments, resulting in enormous social and economic costs. Increasing evidence, both preclinical and clinical, highlights inflammation as an important factor in stroke, both in determining outcome and as a contributor to risk. A number of inflammatory mediators have been proposed as key targets for intervention to reduce the burden of stroke, several reaching clinical trial, but as yet yielding no success. Many factors could explain these failures, including the lack of robust preclinical evidence and poorly designed clinical trials, in addition to the complex nature of the clinical condition. Lack of consideration in preclinical studies of associated co-morbidities prevalent in the clinical stroke population is now seen as an important omission in previous work. These co-morbidities (atherosclerosis, hypertension, diabetes, infection have a strong inflammatory component, supporting the need for greater understanding of how inflammation contributes to acute brain injury. Interleukin (IL-1 is the prototypical pro-inflammatory cytokine, first identified many years ago as the endogenous pyrogen. Research over the last 20 years or so reveals that IL-1 is an important mediator of neuronal injury and blocking the actions of IL-1 is beneficial in a number of experimental models of brain damage. Mechanisms underlying the actions of IL-1 in brain injury remain unclear, though increasing evidence indicates the cerebrovasculature as a key target. Recent literature supporting this and other aspects of how IL-1 and systemic inflammation in general contribute to acute brain injury are discussed in this review.

Electroacupuncture therapy in inflammation regulation: current perspectives

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Park JY

2018-05-01

Full Text Available Ji-Yeun Park, Uk Namgung Department of Oriental Medicine, Daejeon University, Daejeon, South Korea Abstract: Although acupuncture therapy is increasingly used to treat diverse symptoms and disorders in humans, its underlying mechanism is not known well. Only recently have experimental studies begun to provide insights into how acupuncture stimulation generates and relates to pathophysiological responsiveness. Acupuncture intervention is frequently used to control pathologic symptoms in several visceral organs, and a growing number of studies using experimental animal models suggest that acupuncture stimulation may be involved in inducing anti-inflammatory responses. The vagus nerve, a principal parasympathetic nerve connecting neurons in the central nervous system to cardiovascular systems and a majority of visceral organs, is known to modulate neuroimmune communication and anti-inflammatory responses in target organs. Here, we review a broad range of experimental studies demonstrating anti-inflammatory effects of electroacupuncture in pathologic animal models of cardiovascular and visceral organs and also ischemic brains. Then, we provide recent progress on the role of autonomic nerve activity in anti-inflammation mediated by electroacupuncture. We also discuss a perspective on the role of sensory signals generated by acupuncture stimulation, which may induce a neural code unique to acupuncture in the central nervous system. Keywords: electroacupuncture, anti-inflammation, vagus nerve, animal model, acupuncture mechanism

Antidiabetic Effect of Brain-Derived Neurotrophic Factor and Its Association with Inflammation in Type 2 Diabetes Mellitus

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Ceren Eyileten

2017-01-01

Full Text Available Brain-derived neurotrophic factor (BDNF is a neurotrophin, which plays an important role in the central nervous system, and systemic or peripheral inflammatory conditions, such as acute coronary syndrome and type 2 diabetes mellitus (T2DM. BDNF is also expressed in several nonneuronal tissues, and platelets are the major source of peripheral BDNF. Here, we reviewed the potential role of BDNF in platelet reactivity in T2DM and its association with selected inflammatory and platelet activation mediators. Besides that, we focused on adipocytokines such as leptin, resistin, and adiponectin which are considered to take part in inflammation and both lipid and glucose metabolism in diabetic patients as previous studies showed the relation between adipocytokines and BDNF. We also reviewed the evidences of the antidiabetic effect of BDNF and the association with circulating inflammatory cytokines in T2DM.

Clearing the corpses: regulatory mechanisms, novel tools, and therapeutic potential of harnessing microglial phagocytosis in the diseased brain

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Irune Diaz-Aparicio

2016-01-01

Full Text Available Apoptosis is a widespread phenomenon that occurs in the brain in both physiological and pathological conditions. Dead cells must be quickly removed to avoid the further toxic effects they exert in the parenchyma, a process executed by microglia, the brain professional phagocytes. Although phagocytosis is critical to maintain tissue homeostasis, it has long been either overlooked or indirectly assessed based on microglial morphology, expression of classical activation markers, or engulfment of artificial phagocytic targets in vitro. Nevertheless, these indirect methods present several limitations and, thus, direct observation and quantification of microglial phagocytosis is still necessary to fully grasp its relevance in the diseased brain. To overcome these caveats and obtain a comprehensive, quantitative picture of microglial phagocytosis we have developed a novel set of parameters. These parameters have allowed us to identify the different strategies utilized by microglia to cope with apoptotic challenges induced by excitotoxicity or inflammation. In contrast, we discovered that in mouse and human epilepsy microglia failed to find and engulf apoptotic cells, resulting in accumulation of debris and inflammation. Herein, we advocate that the efficiency of microglial phagocytosis should be routinely tested in neurodegenerative and neurological disorders, in order to determine the extent to which it contributes to apoptosis and inflammation found in these conditions. Finally, our findings point towards enhancing microglial phagocytosis as a novel therapeutic strategy to control tissue damage and inflammation, and accelerate recovery in brain diseases.

Rosiglitazone attenuates inflammation and CA3 neuronal loss following traumatic brain injury in rats

International Nuclear Information System (INIS)

Liu, Hao; Rose, Marie E.; Culver, Sherman; Ma, Xiecheng; Dixon, C. Edward; Graham, Steven H.

2016-01-01

Rosiglitazone, a potent peroxisome proliferator-activated receptor (PPAR)-γ agonist, has been shown to confer neuroprotective effects in stroke and spinal cord injury, but its role in the traumatic brain injury (TBI) is still controversial. Using a controlled cortical impact model in rats, the current study was designed to determine the effects of rosiglitazone treatment (6 mg/kg at 5 min, 6 h and 24 h post injury) upon inflammation and histological outcome at 21 d after TBI. In addition, the effects of rosiglitazone upon inflammatory cytokine transcription, vestibulomotor behavior and spatial memory function were determined at earlier time points (24 h, 1–5 d, 14–20 d post injury, respectively). Compared with the vehicle-treated group, rosiglitazone treatment suppressed production of TNFα at 24 h after TBI, attenuated activation of microglia/macrophages and increased survival of CA3 neurons but had no effect on lesion volume at 21 d after TBI. Rosiglitazone-treated animals had improved performance on beam balance testing, but there was no difference in spatial memory function as determined by Morris water maze. In summary, this study indicates that rosiglitazone treatment in the first 24 h after TBI has limited anti-inflammatory and neuroprotective effects in rat traumatic injury. Further study using an alternative dosage paradigm and more sensitive behavioral testing may be warranted. - Highlights: • Effects of rosiglitazone after CCI were evaluated using a rat TBI model. • Rosiglitazone suppressed production of TNFα at 24 h after CCI. • Rosiglitazone inhibited microglial activation at 21 d after CCI. • Rosiglitazone increased survival of CA3 neurons at 21 d after CCI. • Rosiglitazone-treated animals had improved performance in beam balance testing.

Rosiglitazone attenuates inflammation and CA3 neuronal loss following traumatic brain injury in rats

Energy Technology Data Exchange (ETDEWEB)

Liu, Hao; Rose, Marie E. [Geriatric Research Educational and Clinical Center, V.A. Pittsburgh Healthcare System, PA (United States); Department of Neurology, University of Pittsburgh School of Medicine, PA (United States); Culver, Sherman; Ma, Xiecheng; Dixon, C. Edward [Geriatric Research Educational and Clinical Center, V.A. Pittsburgh Healthcare System, PA (United States); Department of Neurosurgery, University of Pittsburgh, PA 15216 (United States); Department of Critical Care Medicine, University of Pittsburgh, PA 15216 (United States); Graham, Steven H., E-mail: Steven.Graham@va.gov [Geriatric Research Educational and Clinical Center, V.A. Pittsburgh Healthcare System, PA (United States); Department of Neurology, University of Pittsburgh School of Medicine, PA (United States)

2016-04-15

Rosiglitazone, a potent peroxisome proliferator-activated receptor (PPAR)-γ agonist, has been shown to confer neuroprotective effects in stroke and spinal cord injury, but its role in the traumatic brain injury (TBI) is still controversial. Using a controlled cortical impact model in rats, the current study was designed to determine the effects of rosiglitazone treatment (6 mg/kg at 5 min, 6 h and 24 h post injury) upon inflammation and histological outcome at 21 d after TBI. In addition, the effects of rosiglitazone upon inflammatory cytokine transcription, vestibulomotor behavior and spatial memory function were determined at earlier time points (24 h, 1–5 d, 14–20 d post injury, respectively). Compared with the vehicle-treated group, rosiglitazone treatment suppressed production of TNFα at 24 h after TBI, attenuated activation of microglia/macrophages and increased survival of CA3 neurons but had no effect on lesion volume at 21 d after TBI. Rosiglitazone-treated animals had improved performance on beam balance testing, but there was no difference in spatial memory function as determined by Morris water maze. In summary, this study indicates that rosiglitazone treatment in the first 24 h after TBI has limited anti-inflammatory and neuroprotective effects in rat traumatic injury. Further study using an alternative dosage paradigm and more sensitive behavioral testing may be warranted. - Highlights: • Effects of rosiglitazone after CCI were evaluated using a rat TBI model. • Rosiglitazone suppressed production of TNFα at 24 h after CCI. • Rosiglitazone inhibited microglial activation at 21 d after CCI. • Rosiglitazone increased survival of CA3 neurons at 21 d after CCI. • Rosiglitazone-treated animals had improved performance in beam balance testing.

Air pollution and brain damage.

Science.gov (United States)

Calderón-Garcidueñas, Lilian; Azzarelli, Biagio; Acuna, Hilda; Garcia, Raquel; Gambling, Todd M; Osnaya, Norma; Monroy, Sylvia; DEL Tizapantzi, Maria Rosario; Carson, Johnny L; Villarreal-Calderon, Anna; Rewcastle, Barry

2002-01-01

Exposure to complex mixtures of air pollutants produces inflammation in the upper and lower respiratory tract. Because the nasal cavity is a common portal of entry, respiratory and olfactory epithelia are vulnerable targets for toxicological damage. This study has evaluated, by light and electron microscopy and immunohistochemical expression of nuclear factor-kappa beta (NF-kappaB) and inducible nitric oxide synthase (iNOS), the olfactory and respiratory nasal mucosae, olfactory bulb, and cortical and subcortical structures from 32 healthy mongrel canine residents in Southwest Metropolitan Mexico City (SWMMC), a highly polluted urban region. Findings were compared to those in 8 dogs from Tlaxcala, a less polluted, control city. In SWMMC dogs, expression of nuclear neuronal NF-kappaB and iNOS in cortical endothelial cells occurred at ages 2 and 4 weeks; subsequent damage included alterations of the blood-brain barrier (BBB), degenerating cortical neurons, apoptotic glial white matter cells, deposition of apolipoprotein E (apoE)-positive lipid droplets in smooth muscle cells and pericytes, nonneuritic plaques, and neurofibrillary tangles. Persistent pulmonary inflammation and deteriorating olfactory and respiratory barriers may play a role in the neuropathology observed in the brains of these highly exposed canines. Neurodegenerative disorders such as Alzheimer's may begin early in life with air pollutants playing a crucial role.

Brain Transcriptional and Epigenetic Associations with Autism

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Ginsberg, Matthew R.; Rubin, Robert A.; Falcone, Tatiana; Ting, Angela H.; Natowicz, Marvin R.

2012-01-01

Background Autism is a common neurodevelopmental syndrome. Numerous rare genetic etiologies are reported; most cases are idiopathic. Methodology/Principal Findings To uncover important gene dysregulation in autism we analyzed carefully selected idiopathic autistic and control cerebellar and BA19 (occipital) brain tissues using high resolution whole genome gene expression and whole genome DNA methylation microarrays. No changes in DNA methylation were identified in autistic brain but gene expression abnormalities in two areas of metabolism were apparent: down-regulation of genes of mitochondrial oxidative phosphorylation and of protein translation. We also found associations between specific behavioral domains of autism and specific brain gene expression modules related to myelin/myelination, inflammation/immune response and purinergic signaling. Conclusions/Significance This work highlights two largely unrecognized molecular pathophysiological themes in autism and suggests differing molecular bases for autism behavioral endophenotypes. PMID:22984548

Time Course of Brain Network Reconfiguration Supporting Inhibitory Control.

Science.gov (United States)

Popov, Tzvetan; Westner, Britta U; Silton, Rebecca L; Sass, Sarah M; Spielberg, Jeffrey M; Rockstroh, Brigitte; Heller, Wendy; Miller, Gregory A

2018-05-02

Hemodynamic research has recently clarified key nodes and links in brain networks implementing inhibitory control. Although fMRI methods are optimized for identifying the structure of brain networks, the relatively slow temporal course of fMRI limits the ability to characterize network operation. The latter is crucial for developing a mechanistic understanding of how brain networks shift dynamically to support inhibitory control. To address this critical gap, we applied spectrally resolved Granger causality (GC) and random forest machine learning tools to human EEG data in two large samples of adults (test sample n = 96, replication sample n = 237, total N = 333, both sexes) who performed a color-word Stroop task. Time-frequency analysis confirmed that recruitment of inhibitory control accompanied by slower behavioral responses was related to changes in theta and alpha/beta power. GC analyses revealed directionally asymmetric exchanges within frontal and between frontal and parietal brain areas: top-down influence of superior frontal gyrus (SFG) over both dorsal ACC (dACC) and inferior frontal gyrus (IFG), dACC control over middle frontal gyrus (MFG), and frontal-parietal exchanges (IFG, precuneus, MFG). Predictive analytics confirmed a combination of behavioral and brain-derived variables as the best set of predictors of inhibitory control demands, with SFG theta bearing higher classification importance than dACC theta and posterior beta tracking the onset of behavioral response. The present results provide mechanistic insight into the biological implementation of a psychological phenomenon: inhibitory control is implemented by dynamic routing processes during which the target response is upregulated via theta-mediated effective connectivity within key PFC nodes and via beta-mediated motor preparation. SIGNIFICANCE STATEMENT Hemodynamic neuroimaging research has recently clarified regional structures in brain networks supporting inhibitory control. However, due to

Aerobic Activity in the Healthy Elderly Is Associated with Larger Plasticity in Memory Related Brain Structures and Lower Systemic Inflammation

Science.gov (United States)

Thielen, Jan-Willem; Kärgel, Christian; Müller, Bernhard W.; Rasche, Ina; Genius, Just; Bus, Boudewijn; Maderwald, Stefan; Norris, David G.; Wiltfang, Jens; Tendolkar, Indira

2016-01-01

Cognitive abilities decline over the time course of our life, a process, which may be mediated by brain atrophy and enhanced inflammatory processes. Lifestyle factors, such as regular physical activities have been shown to counteract those noxious processes and are assumed to delay or possibly even prevent pathological states, such as dementing disorders. Whereas the impact of lifestyle and immunological factors and their interactions on cognitive aging have been frequently studied, their effects on neural parameters as brain activation and functional connectivity are less well studied. Therefore, we investigated 32 healthy elderly individuals (60.4 ± 5.0 SD; range 52–71 years) with low or high level of self-reported aerobic physical activity at the time of testing. A higher compared to a lower level in aerobic physical activity was associated with an increased encoding related functional connectivity in an episodic memory network comprising mPFC, thalamus, hippocampus precuneus, and insula. Moreover, encoding related functional connectivity of this network was associated with decreased systemic inflammation, as measured by systemic levels of interleukin 6. PMID:28082894

Pediatric respiratory and systemic effects of chronic air pollution exposure: nose, lung, heart, and brain pathology.

Science.gov (United States)

Calderón-Garcidueñas, Lilian; Franco-Lira, Maricela; Torres-Jardón, Ricardo; Henriquez-Roldán, Carlos; Barragán-Mejía, Gerardo; Valencia-Salazar, Gildardo; González-Maciel, Angelica; Reynoso-Robles, Rafael; Villarreal-Calderón, Rafael; Reed, William

2007-01-01

Exposures to particulate matter and gaseous air pollutants have been associated with respiratory tract inflammation, disruption of the nasal respiratory and olfactory barriers, systemic inflammation, production of mediators of inflammation capable of reaching the brain and systemic circulation of particulate matter. Mexico City (MC) residents are exposed to significant amounts of ozone, particulate matter and associated lipopolysaccharides. MC dogs exhibit brain inflammation and an acceleration of Alzheimer's-like pathology, suggesting that the brain is adversely affected by air pollutants. MC children, adolescents and adults have a significant upregulation of cyclooxygenase-2 (COX2) and interleukin-1beta (IL-1beta) in olfactory bulb and frontal cortex, as well as neuronal and astrocytic accumulation of the 42 amino acid form of beta -amyloid peptide (Abeta 42), including diffuse amyloid plaques in frontal cortex. The pathogenesis of Alzheimer's disease (AD) is characterized by brain inflammation and the accumulation of Abeta 42, which precede the appearance of neuritic plaques and neurofibrillary tangles, the pathological hallmarks of AD. Our findings of nasal barrier disruption, systemic inflammation, and the upregulation of COX2 and IL-1beta expression and Abeta 42 accumulation in brain suggests that sustained exposures to significant concentrations of air pollutants such as particulate matter could be a risk factor for AD and other neurodegenerative diseases.

Intra-amniotic Ureaplasma parvum-Induced Maternal and Fetal Inflammation and Immune Responses in Rhesus Macaques.

Science.gov (United States)

Senthamaraikannan, Paranthaman; Presicce, Pietro; Rueda, Cesar M; Maneenil, Gunlawadee; Schmidt, Augusto F; Miller, Lisa A; Waites, Ken B; Jobe, Alan H; Kallapur, Suhas G; Chougnet, Claire A

2016-11-15

 Although Ureaplasma species are the most common organisms associated with prematurity, their effects on the maternal and fetal immune system remain poorly characterized.  Rhesus macaque dams at approximately 80% gestation were injected intra-amniotically with 10 7 colony-forming units of Ureaplasma parvum or saline (control). Fetuses were delivered surgically 3 or 7 days later. We performed comprehensive assessments of inflammation and immune effects in multiple fetal and maternal tissues.  Although U. parvum grew well in amniotic fluid, there was minimal chorioamnionitis. U. parvum colonized the fetal lung, but fetal systemic microbial invasion was limited. Fetal lung inflammation was mild, with elevations in CXCL8, tumor necrosis factor (TNF) α, and CCL2 levels in alveolar washes at day 7. Inflammation was not detected in the fetal brain. Significantly, U. parvum decreased regulatory T cells (Tregs) and activated interferon γ production in these Tregs in the fetus. It was detected in uterine tissue by day 7 and induced mild inflammation and increased expression of connexin 43, a gap junction protein involved with labor.  U. parvum colonized the amniotic fluid and caused uterine inflammation, but without overt chorioamnionitis. It caused mild fetal lung inflammation but had a more profound effect on the fetal immune system, decreasing Tregs and polarizing them toward a T-helper 1 phenotype. © The Author 2016. Published by Oxford University Press for the Infectious Diseases Society of America. All rights reserved. For permissions, e-mail journals.permissions@oup.com.

Pathogenic inflammation and its therapeutic targeting in systemic lupus erythematosus

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Timothy Andrew Gottschalk

2015-10-01

Full Text Available Systemic Lupus Erythematosus (SLE, lupus is a highly complex and heterogeneous autoimmune disease that most often afflicts women in their child-bearing years. It is characterized by circulating self-reactive antibodies that deposit in tissues including skin, kidneys and brain, and the ensuing inflammatory response can lead to irreparable tissue damage. Over many years, clinical trials in SLE have focused on agents that control B and T lymphocyte activation, and, with the single exception of an agent known as Belimumab which targets the B cell survival factor BAFF, they have been disappointing. At present, standard therapy for SLE with mild disease is the agent hydroxychloroquine. During disease flares, steroids are often used, while the more severe manifestations with major organ involvement warrant potent, broad-spectrum immuno-suppression with cyclophosphamide or mycophenolate. Current treatments have severe and dose-limiting toxicities and thus a more specific therapy targeting a causative factor or signaling pathway would be greatly beneficial in SLE treatment. Moreover, the ability to control inflammation alongside B cell activation may be a superior approach for disease control. There has been a recent focus on the innate immune system and associated inflammation, which has uncovered key players in driving the pathogenesis of SLE. Delineating some of these intricate inflammatory mechanisms has been possible with studies using spontaneous mouse mutants and genetically engineered mice. These strains, to varying degrees, exhibit hallmarks of the human disease and therefore have been utilized to model human SLE and to test new drugs. Developing a better understanding of the initiation and perpetuation of disease in SLE may uncover suitable novel targets for therapeutic intervention. Here we discuss the involvement of inflammation in SLE disease pathogenesis, with a focus on several key proinflammatory cytokines and myeloid growth factors, and

Pathogenic Inflammation and Its Therapeutic Targeting in Systemic Lupus Erythematosus

Science.gov (United States)

Gottschalk, Timothy A.; Tsantikos, Evelyn; Hibbs, Margaret L.

2015-01-01

Systemic lupus erythematosus (SLE, lupus) is a highly complex and heterogeneous autoimmune disease that most often afflicts women in their child-bearing years. It is characterized by circulating self-reactive antibodies that deposit in tissues, including skin, kidneys, and brain, and the ensuing inflammatory response can lead to irreparable tissue damage. Over many years, clinical trials in SLE have focused on agents that control B- and T-lymphocyte activation, and, with the single exception of an agent known as belimumab which targets the B-cell survival factor BAFF, they have been disappointing. At present, standard therapy for SLE with mild disease is the agent hydroxychloroquine. During disease flares, steroids are often used, while the more severe manifestations with major organ involvement warrant potent, broad-spectrum immunosuppression with cyclophosphamide or mycophenolate. Current treatments have severe and dose-limiting toxicities and thus a more specific therapy targeting a causative factor or signaling pathway would be greatly beneficial in SLE treatment. Moreover, the ability to control inflammation alongside B-cell activation may be a superior approach for disease control. There has been a recent focus on the innate immune system and associated inflammation, which has uncovered key players in driving the pathogenesis of SLE. Delineating some of these intricate inflammatory mechanisms has been possible with studies using spontaneous mouse mutants and genetically engineered mice. These strains, to varying degrees, exhibit hallmarks of the human disease and therefore have been utilized to model human SLE and to test new drugs. Developing a better understanding of the initiation and perpetuation of disease in SLE may uncover suitable novel targets for therapeutic intervention. Here, we discuss the involvement of inflammation in SLE disease pathogenesis, with a focus on several key proinflammatory cytokines and myeloid growth factors, and review the known

Aging-related renal injury and inflammation are associated with downregulation of Klotho and induction of RIG-I/NF-κB signaling pathway in senescence-accelerated mice.

Science.gov (United States)

Zeng, Yi; Wang, Ping-Han; Zhang, Mao; Du, Jun-Rong

2016-02-01

The predominant distribution of the antiaging Klotho protein in both the kidneys and brain may point to its essential role in protecting against dysfunction of the kidney-brain axis during the aging process. Our previous study showed that the downregulation of Klotho was involved in aging-related cognitive impairment in aged senescence-accelerated mouse prone-8 (SAMP8) mice. The present study investigated the potential role of Klotho in aging-associated inflammation and renal injury. Age- and gender-matched groups of SAMP8 mice and their corresponding normal control senescence-accelerated mouse resistant-1 (SAMR1) were used to investigate the potential role of Klotho in aging-associated inflammation and renal injury. Compared with aged SAMR1 controls, early-stage chronic kidney disease (CKD), which is associated with an increase in the urinary albumin-to-creatinine ratio, inflammatory cell infiltration, glomerulosclerosis, and tubulointerstitial fibrosis, was observed in aged SAMP8 mice. Furthermore, the aging-related loss of Klotho-induced activation of the retinoic acid-inducible gene 1/nuclear factor-κB (RIG-I/NF-κB) signaling pathway and subsequent production of the proinflammatory mediators tumor necrosis factor α, interleukin-6, and inducible nitric oxide synthase in the kidneys of aged SAMP8 mice compared with SAMR1 controls. The present results suggest that aging-related inflammation and the development of early-stage CKD are likely associated with the downregulation of Klotho and induction of the RIG-I/NF-κB signaling pathway in 12-month-old SAMP8 mice. Moreover, aged SAMP8 mice with cognitive deficits and renal damage may be a potential mouse model for investigating the kidney-brain axis in the aging process.

Antecedent control in the treatment of brain-injured clients.

Science.gov (United States)

Zencius, A H; Wesolowski, M D; Burke, W H; McQuade, P

1989-01-01

Three brain-injured clients failed to respond significantly to consequence management programmes designed to increase attendance, use of a cane, and to reduce unauthorized breaks. When antecedent stimulus control procedures were applied, attendance and use of a cane increased and unauthorized breaks decreased. The study shows that antecedent control may be the treatment of choice when treating brain-injured clients with memory loss.

α7 Nicotinic acetylcholine receptor-specific antibody induces inflammation and amyloid β42 accumulation in the mouse brain to impair memory.

Directory of Open Access Journals (Sweden)

Olena Lykhmus

Full Text Available Nicotinic acetylcholine receptors (nAChRs expressed in the brain are involved in regulating cognitive functions, as well as inflammatory reactions. Their density is decreased upon Alzheimer disease accompanied by accumulation of β-amyloid (Aβ42, memory deficit and neuroinflammation. Previously we found that α7 nAChR-specific antibody induced pro-inflammatory interleukin-6 production in U373 glioblastoma cells and that such antibodies were present in the blood of humans. We raised a hypothesis that α7 nAChR-specific antibody can cause neuroinflammation when penetrating the brain. To test this, C57Bl/6 mice were either immunized with extracellular domain of α7 nAChR subunit α7(1-208 or injected with bacterial lipopolysaccharide (LPS for 5 months. We studied their behavior and the presence of α3, α4, α7, β2 and β4 nAChR subunits, Aβ40 and Aβ42 and activated astrocytes in the brain by sandwich ELISA and confocal microscopy. It was found that either LPS injections or immunizations with α7(1-208 resulted in region-specific decrease of α7 and α4β2 and increase of α3β4 nAChRs, accumulation of Aβ42 and activated astrocytes in the brain of mice and worsening of their episodic memory. Intravenously transferred α7 nAChR-specific-antibodies penetrated the brain parenchyma of mice pre-injected with LPS. Our data demonstrate that (1 neuroinflammation is sufficient to provoke the decrease of α7 and α4β2 nAChRs, Aβ42 accumulation and memory impairment in mice and (2 α7(1-208 nAChR-specific antibodies can cause inflammation within the brain resulting in the symptoms typical for Alzheimer disease.

Brain control and information transfer.

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Tehovnik, Edward J; Chen, Lewis L

2015-12-01

In this review, we examine the importance of having a body as essential for the brain to transfer information about the outside world to generate appropriate motor responses. We discuss the context-dependent conditioning of the motor control neural circuits and its dependence on the completion of feedback loops, which is in close agreement with the insights of Hebb and colleagues, who have stressed that for learning to occur the body must be intact and able to interact with the outside world. Finally, we apply information theory to data from published studies to evaluate the robustness of the neuronal signals obtained by bypassing the body (as used for brain-machine interfaces) versus via the body to move in the world. We show that recording from a group of neurons that bypasses the body exhibits a vastly degraded level of transfer of information as compared to that of an entire brain using the body to engage in the normal execution of behaviour. We conclude that body sensations provide more than just feedback for movements; they sustain the necessary transfer of information as animals explore their environment, thereby creating associations through learning. This work has implications for the development of brain-machine interfaces used to move external devices.

Systematic Review of Human and Animal Studies Examining the Efficacy and Safety of N-Acetylcysteine (NAC) and N-Acetylcysteine Amide (NACA) in Traumatic Brain Injury: Impact on Neurofunctional Outcome and Biomarkers of Oxidative Stress and Inflammation.

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Bhatti, Junaid; Nascimento, Barto; Akhtar, Umbreen; Rhind, Shawn G; Tien, Homer; Nathens, Avery; da Luz, Luis Teodoro

2017-01-01

No new therapies for traumatic brain injury (TBI) have been officially translated into current practice. At the tissue and cellular level, both inflammatory and oxidative processes may be exacerbated post-injury and contribute to further brain damage. N- acetylcysteine (NAC) has the potential to downregulate both processes. This review focuses on the potential neuroprotective utility of NAC and N -acetylcysteine amide (NACA) post-TBI. Medline, Embase, Cochrane Library, and ClinicalTrials.gov were searched up to July 2017. Studies that examined clinical and laboratory effects of NAC and NACA post-TBI in human and animal studies were included. Risk of bias was assessed in human and animal studies according to the design of each study (randomized or not). The primary outcome assessed was the effect of NAC/NACA treatment on functional outcome, while secondary outcomes included the impact on biomarkers of inflammation and oxidation. Due to the clinical and methodological heterogeneity observed across studies, no meta-analyses were conducted. Our analyses revealed only three human trials, including two randomized controlled trials (RCTs) and 20 animal studies conducted using standardized animal models of brain injury. The two RCTs reported improvement in the functional outcome post-NAC/NACA administration. Overall, the evidence from animal studies is more robust and demonstrated substantial improvement of cognition and psychomotor performance following NAC/NACA use. Animal studies also reported significantly more cortical sparing, reduced apoptosis, and lower levels of biomarkers of inflammation and oxidative stress. No safety concerns were reported in any of the studies included in this analysis. Evidence from the animal literature demonstrates a robust association for the prophylactic application of NAC and NACA post-TBI with improved neurofunctional outcomes and downregulation of inflammatory and oxidative stress markers at the tissue level. While a growing body of

Systematic Review of Human and Animal Studies Examining the Efficacy and Safety of N-Acetylcysteine (NAC and N-Acetylcysteine Amide (NACA in Traumatic Brain Injury: Impact on Neurofunctional Outcome and Biomarkers of Oxidative Stress and Inflammation

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Junaid Bhatti

2018-01-01

Full Text Available BackgroundNo new therapies for traumatic brain injury (TBI have been officially translated into current practice. At the tissue and cellular level, both inflammatory and oxidative processes may be exacerbated post-injury and contribute to further brain damage. N-acetylcysteine (NAC has the potential to downregulate both processes. This review focuses on the potential neuroprotective utility of NAC and N-acetylcysteine amide (NACA post-TBI.MethodsMedline, Embase, Cochrane Library, and ClinicalTrials.gov were searched up to July 2017. Studies that examined clinical and laboratory effects of NAC and NACA post-TBI in human and animal studies were included. Risk of bias was assessed in human and animal studies according to the design of each study (randomized or not. The primary outcome assessed was the effect of NAC/NACA treatment on functional outcome, while secondary outcomes included the impact on biomarkers of inflammation and oxidation. Due to the clinical and methodological heterogeneity observed across studies, no meta-analyses were conducted.ResultsOur analyses revealed only three human trials, including two randomized controlled trials (RCTs and 20 animal studies conducted using standardized animal models of brain injury. The two RCTs reported improvement in the functional outcome post-NAC/NACA administration. Overall, the evidence from animal studies is more robust and demonstrated substantial improvement of cognition and psychomotor performance following NAC/NACA use. Animal studies also reported significantly more cortical sparing, reduced apoptosis, and lower levels of biomarkers of inflammation and oxidative stress. No safety concerns were reported in any of the studies included in this analysis.ConclusionEvidence from the animal literature demonstrates a robust association for the prophylactic application of NAC and NACA post-TBI with improved neurofunctional outcomes and downregulation of inflammatory and oxidative stress markers at

Inflammation and post-operative recovery in patients undergoing total knee arthroplasty-secondary analysis of a randomized controlled trial

DEFF Research Database (Denmark)

Langkilde, A; Jakobsen, T L; Bandholm, T Q

2017-01-01

OBJECTIVE: Reduced function persists for many patients after total knee arthroplasty (TKA). Inflammation is part of osteoarthritis' pathophysiology, and surgery induces a marked inflammatory response. We therefore wanted to explore the role of inflammation in long-term recovery after TKA, and thus...... conducted this secondary analysis of our randomized controlled trial (RCT) of physical rehabilitation ± progressive strength training (PST). We aimed to investigate whether (1) inflammation is associated with functional performance, knee-extension strength, and knee pain before TKA; (2) PST affects...... factor (TNF)-α at baseline; day 1, week 4, 8, and 26 after TKA. RESULTS: At baseline, suPAR (P = 006) was negatively associated with 6MWT. Neither baseline nor surgery-induced inflammation modified the response to rehabilitation ± PST. Only surgery-induced IL-10 was associated with Δ6MWT26 weeks...

Automatic Incubator-type Temperature Control System for Brain Hypothermia Treatment

Science.gov (United States)

Gaohua, Lu; Wakamatsu, Hidetoshi

An automatic air-cooling incubator is proposed to replace the manual water-cooling blanket to control the brain tissue temperature for brain hypothermia treatment. Its feasibility is theoretically discussed as follows: First, an adult patient with the cooling incubator is modeled as a linear dynamical patient-incubator biothermal system. The patient is represented by an 18-compartment structure and described by its state equations. The air-cooling incubator provides almost same cooling effect as the water-cooling blanket, if a light breeze of speed around 3 m/s is circulated in the incubator. Then, in order to control the brain temperature automatically, an adaptive-optimal control algorithm is adopted, while the patient-blanket therapeutic system is considered as a reference model. Finally, the brain temperature of the patient-incubator biothermal system is controlled to follow up the given reference temperature course, in which an adaptive algorithm is confirmed useful for unknown environmental change and/or metabolic rate change of the patient in the incubating system. Thus, the present work ensures the development of the automatic air-cooling incubator for a better temperature regulation of the brain hypothermia treatment in ICU.

[Control of asthma symptoms and cellular markers of inflammation in induced sputum in children and adolescents with chronic asthma].

Science.gov (United States)

Ciółkowski, Janusz; Stasiowska, Barbara; Mazurek, Henryk

2009-03-01

After the GINA 2006 publication, asthma therapy is based on control of symptoms. However there are suggestions of monitoring of airway inflammation. Aim of the study was to compare clinical criteria of asthma control with cellular markers of lower airway inflammation in induced sputum in a group of young asthmatics. To assess relationship between sputum eosinophilia, asthma severity and spirometry. A group of 154 young patients with chronic asthma (8-21 years) underwent sputum induction by inhalation of 4,5% saline solution. Sputum induction was effective in 121 patients (78%), and in this group control of clinical symptoms was assessed according to GINA 2006 criteria. Asthma was controlled in 82 subjects (67.8%) and uncontrolled in 39 (32.2%). Patients with controlled asthma had higher FEV1/FVC (79.8 +/- 7.1% vs 74.2 +/- 9.9%; p = 0.004) and MMEF (80.7 +/- 23.0% vs 65.3 +/- 21.8%; p 3%) was observed in 24.4% of patients with controlled asthma and in 61.5% with uncontrolled asthma (p astma than in patients with moderate-severe disease (3.1 +/- 5.7% vs 7.1% +/- 8.8; p = 0.006). Patients with high sputum eosinophil count had lower FEV1 (89.4 +/- 14.9% vs 94.9 +/- 13.9%; p = 0.047), FEV1/FVC (74.5 +/- 10.1% vs 79.2 +/- 9.3%; p = 0.01) and MMEF (68.7 +/- 23.3% vs 81.7 +/- 23.1%; p = 0.004). In this study of young asthmatics, control of asthma symptoms was observed in 67.8% of patients. However, cellular markers of lower airway inflammation were present in 1/4 of patients with controlled asthma and in 3/4 with uncontrolled disease. Sputum eosinophilia was related to asthma severity. FEV1/FVC and MMEF were more important that FEV1 for estimating control of asthma. Improvement of asthma control scoring is needed as well as availability of simple methods of inflammation monitoring.

Post-treatment vascular leakage and inflammatory responses around brain cysts in porcine neurocysticercosis.

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Siddhartha Mahanty

2015-03-01

Full Text Available Cysticidal treatment of neurocysticercosis, an infection of humans and pig brains with Taenia solium, results in an early inflammatory response directed to cysts causing seizures and focal neurological manifestations. Treatment-induced pericystic inflammation and its association with blood brain barrier (BBB dysfunction, as determined by Evans blue (EB extravasation, was studied in infected untreated and anthelmintic-treated pigs. We compared the magnitude and extent of the pericystic inflammation, presence of EB-stained capsules, the level of damage to the parasite, expression of genes for proinflammatory and regulatory cytokines, chemokines, and tissue remodeling by quantitative PCR assays between treated and untreated infected pigs and between EB-stained (blue and non stained (clear cysts. Inflammatory scores were higher in pericystic tissues from EB-stained cysts compared to clear cysts from untreated pigs and also from anthelmintic-treated pigs 48 hr and 120 hr after treatment. The degree of inflammation correlated with the severity of cyst wall damage and both increased significantly at 120 hours. Expression levels of the proinflammatory genes for IL-6, IFN-γ, TNF-α were higher in EB-stained cysts compared to clear cysts and unaffected brain tissues, and were generally highest at 120 hr. Additionally, expression of some markers of immunoregulatory activity (IL-10, IL-2Rα were decreased in EB-stained capsules. An increase in other markers for regulatory T cells (CTLA4, FoxP3 was found, as well as significant increases in expression of two metalloproteases, MMP1 and MMP2 at 48 hr and 120 hr post-treatment. We conclude that the increase in severity of the inflammation caused by treatment is accompanied by both a proinflammatory and a complex regulatory response, largely limited to pericystic tissues with compromised vascular integrity. Because treatment induced inflammation occurs in porcine NCC similar to that in human cases, this model

Reduced pain and inflammation in juvenile and adult rats fed a ketogenic diet.

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David N Ruskin

2009-12-01

Full Text Available The ketogenic diet is a high-fat, low-carbohydrate regimen that forces ketone-based rather than glucose-based cellular metabolism. Clinically, maintenance on a ketogenic diet has been proven effective in treating pediatric epilepsy and type II diabetes, and recent basic research provides evidence that ketogenic strategies offer promise in reducing brain injury. Cellular mechanisms hypothesized to be mobilized by ketone metabolism and underlying the success of ketogenic diet therapy, such as reduced reactive oxygen species and increased central adenosine, suggest that the ketolytic metabolism induced by the diet could reduce pain and inflammation. To test the effects of a ketone-based metabolism on pain and inflammation directly, we fed juvenile and adult rats a control diet (standard rodent chow or ketogenic diet (79% fat ad libitum for 3-4 weeks. We then quantified hindpaw thermal nociception as a pain measure and complete Freund's adjuvant-induced local hindpaw swelling and plasma extravasation (fluid movement from the vasculature as inflammation measures. Independent of age, maintenance on a ketogenic diet reduced the peripheral inflammatory response significantly as measured by paw swelling and plasma extravasation. The ketogenic diet also induced significant thermal hypoalgesia independent of age, shown by increased hindpaw withdrawal latency in the hotplate nociception test. Anti-inflammatory and hypoalgesic diet effects were generally more robust in juveniles. The ketogenic diet elevated plasma ketones similarly in both age groups, but caused slowed body growth only in juveniles. These data suggest that applying a ketogenic diet or exploiting cellular mechanisms associated with ketone-based metabolism offers new therapeutic opportunities for controlling pain and peripheral inflammation, and that such a metabolic strategy may offer significant benefits for children and adults.

Electroencephalography(EEG)-based instinctive brain-control of a quadruped locomotion robot.

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Jia, Wenchuan; Huang, Dandan; Luo, Xin; Pu, Huayan; Chen, Xuedong; Bai, Ou

2012-01-01

Artificial intelligence and bionic control have been applied in electroencephalography (EEG)-based robot system, to execute complex brain-control task. Nevertheless, due to technical limitations of the EEG decoding, the brain-computer interface (BCI) protocol is often complex, and the mapping between the EEG signal and the practical instructions lack of logic associated, which restrict the user's actual use. This paper presents a strategy that can be used to control a quadruped locomotion robot by user's instinctive action, based on five kinds of movement related neurophysiological signal. In actual use, the user drives or imagines the limbs/wrists action to generate EEG signal to adjust the real movement of the robot according to his/her own motor reflex of the robot locomotion. This method is easy for real use, as the user generates the brain-control signal through the instinctive reaction. By adopting the behavioral control of learning and evolution based on the proposed strategy, complex movement task may be realized by instinctive brain-control.

Brain-Computer Interface Controlled Cyborg: Establishing a Functional Information Transfer Pathway from Human Brain to Cockroach Brain.

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Li, Guangye; Zhang, Dingguo

2016-01-01

An all-chain-wireless brain-to-brain system (BTBS), which enabled motion control of a cyborg cockroach via human brain, was developed in this work. Steady-state visual evoked potential (SSVEP) based brain-computer interface (BCI) was used in this system for recognizing human motion intention and an optimization algorithm was proposed in SSVEP to improve online performance of the BCI. The cyborg cockroach was developed by surgically integrating a portable microstimulator that could generate invasive electrical nerve stimulation. Through Bluetooth communication, specific electrical pulse trains could be triggered from the microstimulator by BCI commands and were sent through the antenna nerve to stimulate the brain of cockroach. Serial experiments were designed and conducted to test overall performance of the BTBS with six human subjects and three cockroaches. The experimental results showed that the online classification accuracy of three-mode BCI increased from 72.86% to 78.56% by 5.70% using the optimization algorithm and the mean response accuracy of the cyborgs using this system reached 89.5%. Moreover, the results also showed that the cyborg could be navigated by the human brain to complete walking along an S-shape track with the success rate of about 20%, suggesting the proposed BTBS established a feasible functional information transfer pathway from the human brain to the cockroach brain.

Perinatal programming of depressive-like behavior by inflammation in adult offspring mice whose mothers were fed polluted eels: Gender selective effects.

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Soualeh, Nidhal; Dridi, Imen; Eppe, Gauthier; Némos, Christophe; Soulimani, Rachid; Bouayed, Jaouad

2017-07-01

Several lines of evidence indicate that early-life inflammation may predispose to mental illness, including depression, in later-life. We investigated the impact of perinatal exposure to polluted eels on neonatal, postnatal, and adult brain inflammation, and on the resignation behavior of male and female adult offspring mice. The effects of maternal standard diet (laboratory food) were compared to the same diet enriched with low, intermediate, or highly polluted eels. Brain inflammatory markers including cytokines were assessed in offspring mice on the day of birth (i.e., on the postnatal day-PND 1), upon weaning (PND 21) and at adulthood (PND 100). Plasma myeloperoxidase and corticosterone levels were evaluated at PND 100. Immobility behavior of offspring was assessed in adulthood (i.e., at PNDs 95-100), using the tail suspension and forced swimming tests. Chronic brain inflammation was found in male and female offspring mice compared to controls, as assessed at PNDs 1, 21, and 100. The level of myeloperoxidase was found to be significantly higher in both adult males and females vs. control offspring. However, high corticosterone levels were only found in male offspring mice that were perinatally exposed to eels, suggesting a gender-selective dysregulation of the adult hypothalamic-pituitaryadrenal (HPA) axis. Gender-specific differences were also detected in adulthood in regard to offspring resignation behavior. Thus, compared to controls, males, but not females, whose mothers were fed eels during pregnancy and lactation exhibited a depressive-like behavior in adult age in both behavioral models of depression. Depressive symptoms were more pronounced in male mice perinatally exposed to either intermediate or highly polluted eels than those exposed to only lowly polluted eels. Our results indicate that early-life inflammatory insult is a plausible causative factor that induces the depressive phenotype exhibited by male adult offspring mice, most likely through a

Oxidant-Antioxidant Balance in Severe Brain Injury

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N. N. Yepifantseva

2010-01-01

Full Text Available Objective: to study the time course of changes in oxidative status parameters and their relationship with inflammation mediators in the acute period of severe brain injury (SBI. Subjects and methods. One hundred and thirteen patients aged 17—67 years were examined. The injury was closed and open in 54 (47.8% and 59 (52.2% patients, respectively. Severe brain contusions were observed in 47 patients, diffuse axonal lesions were seen in 2, and intracranial hematomas were present in 64 patients. The Glasgow coma scores for admission consciousness loss were 6.8±0.25. A control group comprised 23 healthy individuals. The significance of differences was estimated by Student’s test, Wilcoxon-Mann-Whitney, test, Spearman’s correlation test. Venous blood samples were used to study total oxidative activity (TOA and total antioxidative activity (TAA, diene conjugates, lactic acid, albumin, transferrin (TF, ceruloplasmin, C-reactive protein, and lactoferrin (LF were measured in venous blood on disease days 1, 4, 7, 10, 14, and 21. The profile of plasma cytokines (IL-1j8, IL-2, IL-4, IL-5, IL-6, IL-8, IL-10, IL-12p70, TNF-а, and IFN-y was studied by flow fluorometry on a Cytomics FC 500 cytofluorometer (Beckman Counlter, USA (reagents were from Bender Medsystems, Austria. Results. In SBI, there was an increase in oxidants, a reduction in antioxidant activity, and lipid peroxidation activation, which were closely related. The oxidation coefficient (TOA/TAA was 40 times greater than the normal values on days 7 to 10. The oxidation parameters were found to be associated with inflammation and cytokine-mediated immunological reactions. The time course of changes in the study proteins was characteristic for systemic inflammation and there was an association with oxidative processes only for ceruloplasm. TF was found to have an association with IL-5 and IL-10, which reflects its involvement in immunological reactions. The association with hypoxia was

KINETIC CHARACTERISTICS OF EUFLAMMATION: THE INDUCTION OF CONTROLLED INFLAMMATION WITHOUT OVERT SICKNESS BEHAVIOR

OpenAIRE

Tarr, Andrew J.; Liu, Xiaoyu; Reed, Nathaniel S.; Quan, Ning

2014-01-01

We found recently that controlled progressive challenge with subthreshold levels of E.coli can confer progressively stronger resistance to future reinfection-induced sickness behavior to the host. We have termed this type of inflammation “euflammation”. In this study, we further characterized the kinetic changes in the behavior, immunological, and neuroendocrine aspects of euflammation. Results show euflammatory animals only display transient and subtle sickness behaviors of...

Dietary inflammation potential and postmenopausal breast cancer risk in a German case-control study.

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Ge, Isabell; Rudolph, Anja; Shivappa, Nitin; Flesch-Janys, Dieter; Hébert, James R; Chang-Claude, Jenny

2015-08-01

Unhealthy dietary habits can increase the risk for serious medical conditions, such as cancer, yet the association between diet and breast cancer remains unclear. We investigated whether individual diets based on their inflammatory potential are associated with postmenopausal breast cancer risk by employing an energy-adjusted dietary inflammation index. In a German population-based case-control study, 2887 postmenopausal breast cancer patients (aged 50-74 years, first diagnosed between 2002 and 2005) and 5512 healthy age-matched controls provided information on dietary habits for the year prior to diagnosis (cases) or recruitment (controls) using a 176-items food frequency questionnaire. Associations between the energy-adjusted dietary inflammation index (E-DII) score (both as continuous variable and in quintiles) and risk for breast cancer were assessed using conditional logistic regression adjusted for potential confounders. No significant associations between the E-DII score and postmenopausal breast cancer risk were observed (adjusted OR Q5 vs Q1: 1.01, 95% CI: 0.86-1.17). Associations did not differ by estrogen receptor/progesterone receptor status (ER + PR+: adjusted OR Q5 vs Q1: 1.06, 95% CI: 0.88-1.27; ER + or PR+: OR Q5 vs Q1: 1,07, 95% CI: 0.79-1.45; ER-PR-: OR Q5 vs Q1: 0.87 95% CI: 0.63-1.20). Our results regarding E-DII are consistent with previous studies reporting a lack of association between C-reactive protein, a marker of systemic inflammation, and postmenopausal breast cancer risk. The findings may reflect a real absence of association between dietary inflammatory potential and postmenopausal cancer risk or an underestimation of association due to recall bias. Further investigation is warranted in cohort studies. Copyright © 2015 Elsevier Ltd. All rights reserved.

Neuroprotective Effects of Platonin, a Therapeutic Immunomodulating Medicine, on Traumatic Brain Injury in Mice after Controlled Cortical Impact

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Ting-Lin Yen

2018-04-01

Full Text Available Traumatic brain injury (TBI is one of the leading causes of mortality worldwide and leads to persistent cognitive, sensory, motor dysfunction, and emotional disorders. TBI-caused primary injury results in structural damage to brain tissues. Following the primary injury, secondary injuries which are accompanied by neuroinflammation, microglial activation, and additional cell death subsequently occur. Platonin, a cyanine photosensitizing dye, has been used to treat trauma, ulcers, and some types of acute inflammation. In the present study, the neuroprotective effects of platonin against TBI were explored in a controlled cortical impact (CCI injury model in mice. Treatment with platonin (200 µg/kg significantly reduced the neurological severity score, general locomotor activity, and anxiety-related behavior, and improved the rotarod performance of CCI-injured mice. In addition, platonin reduced lesion volumes, the expression of cleaved caspase-3, and microglial activation in TBI-insulted brains. Platonin also suppressed messenger (mRNA levels of caspase-3, caspase-1, cyclooxygenase-2, tumor necrosis factor-α, interleukin-6, and interleukin-1β. On the other hand, free radical production after TBI was obviously attenuated in platonin-treated mice. Treatment with platonin exhibited prominent neuroprotective properties against TBI in a CCI mouse model through its anti-inflammatory, anti-apoptotic, and anti-free radical capabilities. This evidence collectively indicates that platonin may be a potential therapeutic medicine for use with TBIs.

Studi Histopatologi Limpa Anjing Penderita Distemper Dikaitkan Dengan Sebaran Sel-Sel Radang Pada Otak Dan Paru (HISTOPHATOLOGICAL STUDY OF SPLEEN ON DOGS INFECTED WITH DISTEMPER ASSOCIATED TO INFLAMATION IN THE BRAIN AND LUNGS

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Muhamad Furkam Fadilah

2015-08-01

Full Text Available This study aim was to determine the distribution of inflammatory cells in canine distemper in terms of the level of inflammation in the spleen, brain and lungs. The sample used 20 infected dogs wihich from the spleens, brains, and lungs of the dogs were collected. These organs were processed for histophatological observation using harris hematoxilyn-eosyn stain. The inflammation of the organs examined by using binocular microscope with 200X magnification. the results showed that inflammation was observed in the spleens: 9 samples (45% showed the presence of lymphoidcells that experienced a mild inflammation 7 (35% moderate inflammation, and 4 (20% severe inflammation in brain, 3 samples (15% did not show observe inflammation, 12 (60% mild, 5(25% moderate inflammation, and not observed any severe inflammation in brain, pulmonary: 6(30% mild inflammation, 11 (55% moderate inflammation, and 3 (15% severe inflammation. It can be concluded that the inflammation was observed microscopically in the spleen, brain and lungin the dog that infected with canine distemper virus

[ENT inflammation and importance of fenspiride].

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Jankowski, R

2002-09-01

PERSISTENT INFLAMMATION: Inflammation may persist despite the eviction of the aggressive agent because of the disruption of the regulator mechanisms. In such patients, drugs such as fenspiride can be effective at several levels, from onset of inflammation, in an attempt to control its progression. INHIBITION OF NEUROPHIL MIGRATION: Could be a very interesting propriety for controlling inflammation of the human respiratory mucosa. CONTROL OF FREE RADICALS: In certain cases, clearance of free oxygen radicals by cells implicated in the inflammatory process may be overrun. Fenespiride can limit the production of free radicals, probably at the level of the producing cells. ACTION ON THE ARACHIDONIC ACID CASCADE: The mechanism and site of action of fenspiride remains to be clarified. It does not act like conventional antiinflammatory drugs by inhibiting cyclo-oxygenase. ANTIHISTAMINE ACTIVITY: Fenspiride has a certain antihistamine activity, basically by blocking H1 receptors. This action should be tested in subjects with nonspecific nasal hyperreactivity. OTHER PROPERTIES: Fenspiride also has an alpha-1-adrenolytic activity and an inhibitor effect on cyclic AMP, two properties which could have an impact on inflammatory diseases of the upper airways.

RIP3-dependent necrosis induced inflammation exacerbates atherosclerosis

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Meng, Lingjun, E-mail: menglingjun@nibs.ac.cn [College of Biological Sciences, China Agricultural University, Beijing 100094 (China); National Institute of Biological Sciences, Beijing 102206 (China); Jin, Wei [Institute for Immunology, Tsinghua University, Beijing 100084 (China); Wang, Yuhui [Institute of Cardiovascular Sciences, Health Science Center, Peking University, Beijing 100191 (China); Huang, Huanwei; Li, Jia; Zhang, Cai [National Institute of Biological Sciences, Beijing 102206 (China)

2016-04-29

Atherothrombotic vascular disease is already the leading cause of mortality worldwide. Atherosclerosis shares features with diseases caused by chronic inflammation. More attention should concentrates on the innate immunity effect atherosclerosis progress. RIP3 (receptor-interacting protein kinase 3) act through the transcription factor named Nr4a3 (Nuclear orphan receptors) to regulate cytokine production. Deletion RIP3 decreases IL-1α production. Injection of anti-IL-1α antibody protects against the progress of atherosclerosis in ApoE −/− mice. RIP3 as a molecular switch in necrosis, controls macrophage necrotic death caused inflammation. Inhibiting necrosis will certainly reduce atherosclerosis through limit inflammation. Necrotic cell death caused systemic inflammation exacerbated cardiovascular disease. Inhibition of necrosis may yield novel therapeutic targets for treatment in years to come. - Highlights: • RIP3 regulate the Nr4a3 to control cytokine production. • Deletion RIP3 decreases IL-1a production. • Injection anti-IL-1a antibody protects against the progress of atherosclerosis. • RIP3 controls macrophage necrotic dead caused inflammation.

RIP3-dependent necrosis induced inflammation exacerbates atherosclerosis

International Nuclear Information System (INIS)

Meng, Lingjun; Jin, Wei; Wang, Yuhui; Huang, Huanwei; Li, Jia; Zhang, Cai

2016-01-01

Atherothrombotic vascular disease is already the leading cause of mortality worldwide. Atherosclerosis shares features with diseases caused by chronic inflammation. More attention should concentrates on the innate immunity effect atherosclerosis progress. RIP3 (receptor-interacting protein kinase 3) act through the transcription factor named Nr4a3 (Nuclear orphan receptors) to regulate cytokine production. Deletion RIP3 decreases IL-1α production. Injection of anti-IL-1α antibody protects against the progress of atherosclerosis in ApoE −/− mice. RIP3 as a molecular switch in necrosis, controls macrophage necrotic death caused inflammation. Inhibiting necrosis will certainly reduce atherosclerosis through limit inflammation. Necrotic cell death caused systemic inflammation exacerbated cardiovascular disease. Inhibition of necrosis may yield novel therapeutic targets for treatment in years to come. - Highlights: • RIP3 regulate the Nr4a3 to control cytokine production. • Deletion RIP3 decreases IL-1a production. • Injection anti-IL-1a antibody protects against the progress of atherosclerosis. • RIP3 controls macrophage necrotic dead caused inflammation.

TNF-α blockade suppresses pericystic inflammation following anthelmintic treatment in porcine neurocysticercosis.

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Siddhartha Mahanty

2017-11-01

Full Text Available Neurocysticercosis (NCC is an infection of the brain with the larval cyst of the tapeworm, Taenia solium. Cysticidal treatment induces parasite killing resulting in a post inflammatory response and seizures, which generally requires corticosteroid treatment to control inflammation. The nature of this response and how to best control it is unclear. We investigated the anti-inflammatory effects of pretreatment with etanercept (ETN, an anti-tumor necrosis factor agent, or dexamethasone (DEX, a high potency corticosteroid, on the post treatment inflammatory response in naturally infected pigs with neurocysticercosis after a single dose of the cysticidal drug praziquantel (PZQ.We followed the methods from a previously developed treatment model of NCC in naturally infected swine. The four study groups of infected pigs included 3 groups treated with PZQ on day 0: PZQ-treated alone (100 mg/kg PO; n = 9, pretreated with dexamethasone (DEX, 0.2 mg/kg IM administered on days -1, +1 and +3; n = 6, and pretreated with etanercept (ETN, 25 mg IM per animal on days -7 and 0; n = 6. The fourth group remained untreated (n = 3. As measured by quantitative RT-PCR, ETN pretreatment depressed transcription of a wide range of proinflammatory, regulatory and matrix protease encoding genes at 120 hr post PZQ treatment in capsules of cysts that demonstrated extravasated Evans Blue (EB (a measure of blood brain barrier dysfunction compared to animals not receiving ETN. Transcription was significantly depressed for the proinflammatory genes tumor necrosis factor (TNF-α, and interferon (IFN-γ; the inflammation regulating genes cytotoxic T-lymphocyte-associated protein (CTLA4, interleukin (IL-13 and transforming growth factor (TGF-β; the tissue remodeling genes matrix metalloprotease (MMP1 and 9, tissue inhibitors of metalloproteases (TIMP1 and 2, and the genes regulating endothelial function vascular endothelial growth factor (VEGF1, angiopoietin (Ang1, Ang 2, and

Efficient foot motor control by Neymar’s brain

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Eiichi eNaito

2014-08-01

Full Text Available How very long-term (over many years motor skill training shapes internal motor representation remains poorly understood. We provide valuable evidence that the football brain of Neymar da Silva Santos Júnior (the Brasilian footballer recruits very limited neural resources in the motor-cortical foot regions during foot movements. We scanned his brain activity with a 3-tesla functional magnetic resonance imaging (fMRI while he rotated his right ankle at 1Hz. We also scanned brain activity when three other age-controlled professional footballers, two top-athlete swimmers and one amateur footballer performed the identical task. A comparison was made between Neymar’s brain activity with that obtained from the others. We found activations in the left medial-wall foot motor regions during the foot movements consistently across all participants. However, the size and intensity of medial-wall activity was smaller in the four professional footballers than in the three other participants, despite no difference in amount of foot movement. Surprisingly, the reduced recruitment of medial-wall foot motor regions became apparent in Neymar. His medial-wall activity was smallest among all participants with absolutely no difference in amount of foot movement. Neymar may efficiently control given foot movements probably by largely conserving motor-cortical neural resources. We discuss this possibility in terms of over-years motor skill training effect, use-dependent plasticity, and efficient motor control.

Indoleamine 2,3-dioxygenase-dependent neurotoxic kynurenine metabolism mediates inflammation-induced deficit in recognition memory.

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Heisler, Jillian M; O'Connor, Jason C

2015-11-01

Cognitive dysfunction in depression is a prevalent and debilitating symptom that is poorly treated by the currently available pharmacotherapies. Research over the past decade has provided evidence for proinflammatory involvement in the neurobiology of depressive disorders and symptoms associated with these disorders, including aspects of memory dysfunction. Recent clinical studies implicate inflammation-related changes in kynurenine metabolism as a potential pathogenic factor in the development of a range of depressive symptoms, including deficits in cognition and memory. Additionally, preclinical work has demonstrated a number of mood-related depressive-like behaviors to be dependent on indoleamine 2,3-dioxygenase-1 (IDO1), the inflammation-induced rate-limiting enzyme of the kynurenine pathway. Here, we demonstrate in a mouse model, that peripheral administration of endotoxin induced a deficit in recognition memory. Mice deficient in IDO were protected from cognitive impairment. Furthermore, endotoxin-induced inflammation increased kynurenine metabolism within the perirhinal/entorhinal cortices, brain regions which have been implicated in recognition memory. A single peripheral injection of kynurenine, the metabolic product of IDO1, was sufficient to induce a deficit in recognition memory in both control and IDO null mice. Finally, kynurenine monooxygenase (KMO) deficient mice were also protected from inflammation-induced deficits on novel object recognition. These data implicate IDO-dependent neurotoxic kynurenine metabolism as a pathogenic factor for cognitive dysfunction in inflammation-induced depressive disorders and a potential novel target for the treatment of these disorders. Published by Elsevier Inc.

Indoleamine 2,3-dioxygenase-dependent neurotoxic kynurenine metabolism mediates inflammation-induced deficit in recognition memory

Science.gov (United States)

Heisler, Jillian M.; O’Connor, Jason C.

2015-01-01

Cognitive dysfunction in depression is a prevalent and debilitating symptom that is poorly treated by the currently available pharmacotherapies. Research over the past decade has provided evidence for proinflammatory involvement in the neurobiology of depressive disorders and symptoms associated with these disorders, including aspects of memory dysfunction. Recent clinical studies implicate inflammation-related changes in kynurenine metabolism as a potential pathogenic factor in the development of a range of depressive symptoms, including deficits in cognition and memory. Additionally, preclinical work has demonstrated a number of mood-related depressive-like behaviors to be dependent on indoleamine 2,3-dioxygenase-1 (IDO1), the inflammation-induced rate-limiting enzyme of the kynurenine pathway. Here, we demonstrate in a mouse model, that peripheral administration of endotoxin induced a deficit in recognition memory. Mice deficient in IDO were protected from cognitive impairment. Furthermore, endotoxin-induced inflammation increased kynurenine metabolism within the perirhinal/entorhinal cortices, brain regions which have been implicated in recognition memory. A single peripheral injection of kynurenine, the metabolic product of IDO1, was sufficient to induce a deficit in recognition memory in both control and IDO null mice. Finally, kynurenine monooxygenase (KMO) deficient mice were also protected from inflammation-induced deficits on novel object recognition. These data implicate IDO-dependent neurotoxic kynurenine metabolism as a pathogenic factor for cognitive dysfunction in inflammation-induced depressive disorders and a potential novel target for the treatment of these disorders. PMID:26130057

Observability and Controllability of Networks: Symmetry in Representations of Brains and Controllers for Epidemics

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Schiff, Steven

Observability and controllability are essential concepts to the design of predictive observer models and feedback controllers of networked systems. We present a numerical and group representational framework, to quantify the observability and controllability of nonlinear networks with explicit symmetries that shows the connection between symmetries and nonlinear measures of observability and controllability. In addition to the topology of brain networks, we have advanced our ability to represent network nodes within the brain using conservation principles and more accurate biophysics that unifies the dynamics of spikes, seizures, and spreading depression. Lastly, we show how symmetries in controller design can be applied to infectious disease epidemics. NIH Grants 1R01EB014641, 1DP1HD086071.

Effects of dissolucytotic gold ions on recovering brain lesions.

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Danscher, Gorm; Larsen, Agnete

2010-04-01

Recent experimental research has shown that metallic gold releases charged gold atoms when placed intracerebrally and that the liberated gold ions affect inflammation in the brain. The observations suggest that metallic gold can be used as a safe suppressor of inflammation in the central nervous system.

Causes of CNS inflammation and potential targets for anticonvulsants.

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Falip, Mercé; Salas-Puig, Xavier; Cara, Carlos

2013-08-01

Inflammation is one of the most important endogenous defence mechanisms in an organism. It has been suggested that inflammation plays an important role in the pathophysiology of a number of human epilepsies and convulsive disorders, and there is clinical and experimental evidence to suggest that inflammatory processes within the CNS may either contribute to or be a consequence of epileptogenesis. This review discusses evidence from human studies on the role of inflammation in epilepsy and highlights potential new targets in the inflammatory cascade for antiepileptic drugs. A number of mechanisms have been shown to be involved in CNS inflammatory reactions. These include an inflammatory response at the level of the blood-brain barrier (BBB), immune-mediated damage to the CNS, stress-induced release of inflammatory mediators and direct neuronal dysfunction or damage as a result of inflammatory reactions. Mediators of inflammation in the CNS include interleukin (IL)-1β, tumour necrosis factor-α, nuclear factor-κB and toll-like receptor-4 (TLR4). IL-1β, BBB and high-mobility group box-1-TLR4 signalling appear to be the most promising targets for anticonvulsant agents directed at inflammation. Such agents may provide effective therapy for drug-resistant epilepsies in the future.

Reward-based hypertension control by a synthetic brain-dopamine interface.

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Rössger, Katrin; Charpin-El Hamri, Ghislaine; Fussenegger, Martin

2013-11-05

Synthetic biology has significantly advanced the design of synthetic trigger-controlled devices that can reprogram mammalian cells to interface with complex metabolic activities. In the brain, the neurotransmitter dopamine coordinates communication with target neurons via a set of dopamine receptors that control behavior associated with reward-driven learning. This dopamine transmission has recently been suggested to increase central sympathetic outflow, resulting in plasma dopamine levels that correlate with corresponding brain activities. By functionally rewiring the human dopamine receptor D1 (DRD1) via the second messenger cyclic adenosine monophosphate (cAMP) to synthetic promoters containing cAMP response element-binding protein 1(CREB1)-specific cAMP-responsive operator modules, we have designed a synthetic dopamine-sensitive transcription controller that reversibly fine-tunes specific target gene expression at physiologically relevant brain-derived plasma dopamine levels. Following implantation of circuit-transgenic human cell lines insulated by semipermeable immunoprotective microcontainers into mice, the designer device interfaced with dopamine-specific brain activities and produced a systemic expression response when the animal's reward system was stimulated by food, sexual arousal, or addictive drugs. Reward-triggered brain activities were able to remotely program peripheral therapeutic implants to produce sufficient amounts of the atrial natriuretic peptide, which reduced the blood pressure of hypertensive mice to the normal physiologic range. Seamless control of therapeutic transgenes by subconscious behavior may provide opportunities for treatment strategies of the future.

Theory of feedback controlled brain stimulations for Parkinson's disease

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Sanzeni, A.; Celani, A.; Tiana, G.; Vergassola, M.

2016-01-01

Limb tremor and other debilitating symptoms caused by the neurodegenerative Parkinson's disease are currently treated by administering drugs and by fixed-frequency deep brain stimulation. The latter interferes directly with the brain dynamics by delivering electrical impulses to neurons in the subthalamic nucleus. While deep brain stimulation has shown therapeutic benefits in many instances, its mechanism is still unclear. Since its understanding could lead to improved protocols of stimulation and feedback control, we have studied a mathematical model of the many-body neural network dynamics controlling the dynamics of the basal ganglia. On the basis of the results obtained from the model, we propose a new procedure of active stimulation, that depends on the feedback of the network and that respects the constraints imposed by existing technology. We show by numerical simulations that the new protocol outperforms the standard ones for deep brain stimulation and we suggest future experiments that could further improve the feedback procedure.

inflammation and iron metabolism

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A Dzedzej

2016-08-01

Full Text Available Following acute physical activity, blood hepcidin concentration appears to increase in response to exercise-induced inflammation, but the long-term impact of exercise on hepcidin remains unclear. Here we investigated changes in hepcidin and the inflammation marker interleukin-6 to evaluate professional basketball players’ response to a season of training and games. The analysis also included vitamin D (25(OHD3 assessment, owing to its anti-inflammatory effects. Blood samples were collected for 14 players and 10 control non-athletes prior to and after the 8-month competitive season. Athletes’ performance was assessed with the NBA efficiency score. At the baseline hepcidin correlated with blood ferritin (r=0.61; 90% CL ±0.31, but at the end of the season this correlation was absent. Compared with the control subjects, athletes experienced clear large increases in hepcidin (50%; 90% CI 15-96% and interleukin-6 (77%; 90% CI 35-131% and a clear small decrease in vitamin D (-12%; 90% CI -20 to -3% at the season completion. Correlations between change scores of these variables were unclear (r = -0.21 to 0.24, 90% CL ±0.5, but their uncertainty generally excluded strong relationships. Athletes were hence concluded to have experienced acute inflammation at the beginning but chronic inflammation at the end of the competitive season. At the same time, the moderate correlation between changes in vitamin D and players’ performance (r=0.43 was suggestive of its beneficial influence. Maintaining the appropriative concentration of vitamin D is thus necessary for basketball players’ performance and efficiency. The assessment of hepcidin has proven to be useful in diagnosing inflammation in response to chronic exercise.

Flexible brain network reconfiguration supporting inhibitory control.

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Spielberg, Jeffrey M; Miller, Gregory A; Heller, Wendy; Banich, Marie T

2015-08-11

The ability to inhibit distracting stimuli from interfering with goal-directed behavior is crucial for success in most spheres of life. Despite an abundance of studies examining regional brain activation, knowledge of the brain networks involved in inhibitory control remains quite limited. To address this critical gap, we applied graph theory tools to functional magnetic resonance imaging data collected while a large sample of adults (n = 101) performed a color-word Stroop task. Higher demand for inhibitory control was associated with restructuring of the global network into a configuration that was more optimized for specialized processing (functional segregation), more efficient at communicating the output of such processing across the network (functional integration), and more resilient to potential interruption (resilience). In addition, there were regional changes with right inferior frontal sulcus and right anterior insula occupying more central positions as network hubs, and dorsal anterior cingulate cortex becoming more tightly coupled with its regional subnetwork. Given the crucial role of inhibitory control in goal-directed behavior, present findings identifying functional network organization supporting inhibitory control have the potential to provide additional insights into how inhibitory control may break down in a wide variety of individuals with neurological or psychiatric difficulties.

Multidimensional control using a mobile-phone based brain-muscle-computer interface.

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Vernon, Scott; Joshi, Sanjay S

2011-01-01

Many well-known brain-computer interfaces measure signals at the brain, and then rely on the brain's ability to learn via operant conditioning in order to control objects in the environment. In our lab, we have been developing brain-muscle-computer interfaces, which measure signals at a single muscle and then rely on the brain's ability to learn neuromuscular skills via operant conditioning. Here, we report a new mobile-phone based brain-muscle-computer interface prototype for severely paralyzed persons, based on previous results from our group showing that humans may actively create specified power levels in two separate frequency bands of a single sEMG signal. Electromyographic activity on the surface of a single face muscle (Auricularis superior) is recorded with a standard electrode. This analog electrical signal is imported into an Android-based mobile phone. User-modulated power in two separate frequency band serves as two separate and simultaneous control channels for machine control. After signal processing, the Android phone sends commands to external devices via Bluetooth. Users are trained to use the device via biofeedback, with simple cursor-to-target activities on the phone screen.

Myeloid-Related Protein 14 Promotes Inflammation and Injury in Meningitis

DEFF Research Database (Denmark)

Wache, Christina; Klein, Matthias; Andersen, Christian Østergaard

2015-01-01

BACKGROUND:  Neutrophilic inflammation often persists for days despite effective antibiotic treatment and contributes to brain damage in bacterial meningitis. We propose here that myeloid-related protein 14 (MRP14), an abundant cytosolic protein in myeloid cells, acts as an endogenous danger signal......, driving inflammation and aggravating tissue injury. METHODS:  The release pattern of MRP14 was analyzed in human and murine cerebrospinal fluid (CSF), as well as in isolated neutrophils. Its functional role was assessed in a mouse meningitis model, using MRP14-deficient mice. RESULTS:  We detected large...... quantities of MRP14 in CSF specimens from patients and mice with pneumococcal meningitis. Immunohistochemical analyses and a cell-depletion approach indicated neutrophils as the major source of MRP14. In a meningitis model, MRP14-deficient mice showed a better resolution of inflammation during antibiotic...

An optical brain computer interface for environmental control.

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Ayaz, Hasan; Shewokis, Patricia A; Bunce, Scott; Onaral, Banu

2011-01-01

A brain computer interface (BCI) is a system that translates neurophysiological signals detected from the brain to supply input to a computer or to control a device. Volitional control of neural activity and its real-time detection through neuroimaging modalities are key constituents of BCI systems. The purpose of this study was to develop and test a new BCI design that utilizes intention-related cognitive activity within the dorsolateral prefrontal cortex using functional near infrared (fNIR) spectroscopy. fNIR is a noninvasive, safe, portable and affordable optical technique with which to monitor hemodynamic changes, in the brain's cerebral cortex. Because of its portability and ease of use, fNIR is amenable to deployment in ecologically valid natural working environments. We integrated a control paradigm in a computerized 3D virtual environment to augment interactivity. Ten healthy participants volunteered for a two day study in which they navigated a virtual environment with keyboard inputs, but were required to use the fNIR-BCI for interaction with virtual objects. Results showed that participants consistently utilized the fNIR-BCI with an overall success rate of 84% and volitionally increased their cerebral oxygenation level to trigger actions within the virtual environment.

Energy metabolism and inflammation in brain aging and Alzheimer's disease.

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Yin, Fei; Sancheti, Harsh; Patil, Ishan; Cadenas, Enrique

2016-11-01

The high energy demand of the brain renders it sensitive to changes in energy fuel supply and mitochondrial function. Deficits in glucose availability and mitochondrial function are well-known hallmarks of brain aging and are particularly accentuated in neurodegenerative disorders such as Alzheimer's disease. As important cellular sources of H 2 O 2 , mitochondrial dysfunction is usually associated with altered redox status. Bioenergetic deficits and chronic oxidative stress are both major contributors to cognitive decline associated with brain aging and Alzheimer's disease. Neuroinflammatory changes, including microglial activation and production of inflammatory cytokines, are observed in neurodegenerative diseases and normal aging. The bioenergetic hypothesis advocates for sequential events from metabolic deficits to propagation of neuronal dysfunction, to aging, and to neurodegeneration, while the inflammatory hypothesis supports microglia activation as the driving force for neuroinflammation. Nevertheless, growing evidence suggests that these diverse mechanisms have redox dysregulation as a common denominator and connector. An independent view of the mechanisms underlying brain aging and neurodegeneration is being replaced by one that entails multiple mechanisms coordinating and interacting with each other. This review focuses on the alterations in energy metabolism and inflammatory responses and their connection via redox regulation in normal brain aging and Alzheimer's disease. Interaction of these systems is reviewed based on basic research and clinical studies. Copyright © 2016 Elsevier Inc. All rights reserved.

Research progress of immune tolerance in the treatment of brain injury

Directory of Open Access Journals (Sweden)

Hua YAN

2014-08-01

Full Text Available Due to its special anatomical structures and immune pathophysiological mechanisms, brain damage repair is greatly different from damage repair of other systems. Secondary brain injury and inflammation are closely related. As a "double-edged sword", inflammation scavenges hazardous substances on the early stage of injury, but has side effects on normal brain tissue. The use of immunosuppressive therapy or hypothermia can inhibit immune injury, but the presence of reduced immunity may result in infection and tumorigenesis in the long term. Only reducing the autoimmune attack against brain tissue without affecting other immune capacity of the body will be optimized solution, and this paper will make a review on the research of immune tolerance in the treatment of brain injury with optimized program. doi: 10.3969/j.issn.1672-6731.2014.08.017

[Orbital inflammation].

Science.gov (United States)

Mouriaux, F; Coffin-Pichonnet, S; Robert, P-Y; Abad, S; Martin-Silva, N

2014-12-01

Orbital inflammation is a generic term encompassing inflammatory pathologies affecting all structures within the orbit : anterior (involvement up to the posterior aspect of the globe), diffuse (involvement of intra- and/or extraconal fat), apical (involvement of the posterior orbit), myositis (involvement of only the extraocular muscles), dacryoadenitis (involvement of the lacrimal gland). We distinguish between specific inflammation and non-specific inflammation, commonly referred to as idiopathic inflammation. Specific orbital inflammation corresponds to a secondary localization of a "generalized" disease (systemic or auto-immune). Idiopathic orbital inflammation corresponds to uniquely orbital inflammation without generalized disease, and thus an unknown etiology. At the top of the differential diagnosis for specific or idiopathic orbital inflammation are malignant tumors, represented most commonly in the adult by lympho-proliferative syndromes and metastases. Treatment of specific orbital inflammation begins with treatment of the underlying disease. For idiopathic orbital inflammation, treatment (most often corticosteroids) is indicated above all in cases of visual loss due to optic neuropathy, in the presence of pain or oculomotor palsy. Copyright © 2014 Elsevier Masson SAS. All rights reserved.

Control of a mobile robot through brain computer interface

Directory of Open Access Journals (Sweden)

Robinson Jimenez Moreno

2015-07-01

Full Text Available This paper poses a control interface to command the movement of a mobile robot according to signals captured from the user's brain. These signals are acquired and interpreted by Emotiv EPOC device, a 14-electrode type sensor which captures electroencephalographic (EEG signals with high resolution, which, in turn, are sent to a computer for processing. One brain-computer interface (BCI was developed based on the Emotiv software and SDK in order to command the mobile robot from a distance. Functionality tests are performed with the sensor to discriminate shift intentions of a user group, as well as with a fuzzy controller to hold the direction in case of concentration loss. As conclusion, it was possible to obtain an efficient system for robot movements by brain commands.

A combined marker of inflammation in individuals with mania.

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Faith Dickerson

Full Text Available BACKGROUND: Markers of immune activation have been associated with mania but have not been examined in combination. We studied the association between mania and an inflammation score based on four immune markers. METHODS: A total of 57 individuals with mania were assessed at up to three time points: the day of hospital admission, evaluation several days later, and six-month follow-up. Also assessed were 207 non-psychiatric controls and 330 individuals with recent onset psychosis, multi-episode schizophrenia, or bipolar disorder depression. A combined inflammation score was calculated by factor analysis of the levels of class-specific antibodies to the NR peptide of the NMDA receptor; gliadin; Mason-Pfizer monkey virus protein 24; and Toxoplasma gondii. Inflammation scores among groups were compared by multivariate analyses. The inflammation score of the mania group at evaluation was studied as a predictor of re-hospitalization in the follow-up period. RESULTS: The combined inflammation score of the mania group at hospital admission and at evaluation differed significantly from that of the non-psychiatric controls (t=3.95, 4.10, p<.001. The inflammation score was significantly decreased at six month follow-up (F=5.85, p=0.004. There were not any significant differences in the inflammation scores of any of the other psychiatric groups and that of the controls. Within the mania group, an elevated inflammation score at evaluation predicted re-hospitalization (Hazard ratio=7.12, p=.005. CONCLUSIONS: Hospitalization for mania is associated with immune activation. The level of this activation is predictive of subsequent re-hospitalization. Interventions for the modulation of inflammation should be evaluated for the therapy of individuals with mania.

Innate Immunity and Inflammation Post-Stroke: An α7-Nicotinic Agonist Perspective

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Silke Neumann

2015-12-01

Full Text Available Stroke is one of the leading causes of death and long-term disability, with limited treatment options available. Inflammation contributes to damage tissue in the central nervous system across a broad range of neuropathologies, including Alzheimer’s disease, pain, Schizophrenia, and stroke. While the immune system plays an important role in contributing to brain damage produced by ischemia, the damaged brain, in turn, can exert a powerful immune-suppressive effect that promotes infections and threatens the survival of stroke patients. Recently the cholinergic anti-inflammatory pathway, in particular its modulation using α7-nicotinic acetylcholine receptor (α7-nAChR ligands, has shown potential as a strategy to dampen the inflammatory response and facilitate functional recovery in stroke patients. Here we discuss the current literature on stroke-induced inflammation and the effects of α7-nAChR modulators on innate immune cells.

Speaking and cognitive distractions during EEG-based brain control of a virtual neuroprosthesis-arm

OpenAIRE

Foldes, Stephen T; Taylor, Dawn M

2013-01-01

Background Brain-computer interface (BCI) systems have been developed to provide paralyzed individuals the ability to command the movements of an assistive device using only their brain activity. BCI systems are typically tested in a controlled laboratory environment were the user is focused solely on the brain-control task. However, for practical use in everyday life people must be able to use their brain-controlled device while mentally engaged with the cognitive responsibilities of daily a...

VEGF controls lung Th2 inflammation via the miR-1-Mpl (myeloproliferative leukemia virus oncogene)-P-selectin axis.

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Takyar, Seyedtaghi; Vasavada, Hema; Zhang, Jian-ge; Ahangari, Farida; Niu, Naiqian; Liu, Qing; Lee, Chun Geun; Cohn, Lauren; Elias, Jack A

2013-09-23

Asthma, the prototypic Th2-mediated inflammatory disorder of the lung, is an emergent disease worldwide. Vascular endothelial growth factor (VEGF) is a critical regulator of pulmonary Th2 inflammation, but the underlying mechanism and the roles of microRNAs (miRNAs) in this process have not been defined. Here we show that lung-specific overexpression of VEGF decreases miR-1 expression in the lung, most prominently in the endothelium, and a similar down-regulation occurs in lung endothelium in Th2 inflammation models. Intranasal delivery of miR-1 inhibited inflammatory responses to ovalbumin, house dust mite, and IL-13 overexpression. Blocking VEGF inhibited Th2-mediated lung inflammation, and this was restored by antagonizing miR-1. Using mRNA arrays, Argonaute pull-down assays, luciferase expression assays, and mutational analysis, we identified Mpl as a direct target of miR-1 and showed that VEGF controls the expression of endothelial Mpl during Th2 inflammation via the regulation of miR-1. In vivo knockdown of Mpl inhibited Th2 inflammation and indirectly inhibited the expression of P-selectin in lung endothelium. These experiments define a novel VEGF-miR-1-Mpl-P-selectin effector pathway in lung Th2 inflammation and herald the utility of miR-1 and Mpl as potential therapeutic targets for asthma.

Effect of probiotics (Saccharomyces boulardii) on microbial translocation and inflammation in HIV-treated patients: a double-blind, randomized, placebo-controlled trial.

Science.gov (United States)

Villar-García, Judit; Hernández, Juan J; Güerri-Fernández, Robert; González, Alicia; Lerma, Elisabet; Guelar, Ana; Saenz, David; Sorlí, Lluisa; Montero, Milagro; Horcajada, Juan P; Knobel Freud, Hernando

2015-03-01

Microbial translocation has been associated with an increase in immune activation and inflammation in HIV infection despite effective highly active antiretroviral therapy. It has been shown that some probiotics have a beneficial effect by reducing intestinal permeability and, consequently, microbial translocation. To assess changes in microbial translocation and inflammation after treatment with probiotics (Saccharomyces boulardii) in HIV-1-infected patients with virologic suppression. A double-blind, randomized, placebo-controlled trial was conducted in 44 nonconsecutive HIV-1-infected patients with viral load of boulardii decreases microbial translocation (LBP) and inflammation parameters (IL-6) in HIV-1-infected patients with long-term virologic suppression.

Control of Hepatic Glucose Metabolism by Islet and Brain

Science.gov (United States)

Rojas, Jennifer M.; Schwartz, Michael W.

2014-01-01

Dysregulation of hepatic glucose uptake (HGU) and inability of insulin to suppress hepatic glucose production (HGP), both contribute to hyperglycemia in patients with type 2 diabetes (T2D). Growing evidence suggests that insulin can inhibit HGP not only through a direct effect on the liver, but also via a mechanism involving the brain. Yet the notion that insulin action in the brain plays a physiological role in the control of HGP continues to be controversial. Although studies in dogs suggest that the direct hepatic effect of insulin is sufficient to explain day-to-day control of HGP, a surprising outcome has been revealed by recent studies in mice investigating whether the direct hepatic action of insulin is necessary for normal HGP: when hepatic insulin signaling pathway was genetically disrupted, HGP was maintained normally even in the absence of direct input from insulin. Here we present evidence that points to a potentially important role of the brain in the physiological control of both HGU and HGP in response to input from insulin as well as other hormones and nutrients. PMID:25200294

Development of a cerebral circulation model for the automatic control of brain physiology.

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Utsuki, T

2015-01-01

In various clinical guidelines of brain injury, intracranial pressure (ICP), cerebral blood flow (CBF) and brain temperature (BT) are essential targets for precise management for brain resuscitation. In addition, the integrated automatic control of BT, ICP, and CBF is required for improving therapeutic effects and reducing medical costs and staff burden. Thus, a new model of cerebral circulation was developed in this study for integrative automatic control. With this model, the CBF and cerebral perfusion pressure of a normal adult male were regionally calculated according to cerebrovascular structure, blood viscosity, blood distribution, CBF autoregulation, and ICP. The analysis results were consistent with physiological knowledge already obtained with conventional studies. Therefore, the developed model is potentially available for the integrative control of the physiological state of the brain as a reference model of an automatic control system, or as a controlled object in various control simulations.

Brain antibodies in the cortex and blood of people with schizophrenia and controls.

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Glass, L J; Sinclair, D; Boerrigter, D; Naude, K; Fung, S J; Brown, D; Catts, V S; Tooney, P; O'Donnell, M; Lenroot, R; Galletly, C; Liu, D; Weickert, T W; Shannon Weickert, C

2017-08-08

The immune system is implicated in the pathogenesis of schizophrenia, with elevated proinflammatory cytokine mRNAs found in the brains of ~40% of individuals with the disorder. However, it is not clear if antibodies (specifically immunoglobulin-γ (IgG)) can be found in the brain of people with schizophrenia and if their abundance relates to brain inflammatory cytokine mRNA levels. Therefore, we investigated the localization and abundance of IgG in the frontal cortex of people with schizophrenia and controls, and the impact of proinflammatory cytokine status on IgG abundance in these groups. Brain IgGs were detected surrounding blood vessels in the human and non-human primate frontal cortex by immunohistochemistry. IgG levels did not differ significantly between schizophrenia cases and controls, or between schizophrenia cases in 'high' and 'low' proinflammatory cytokine subgroups. Consistent with the existence of IgG in the parenchyma of human brain, mRNA and protein of the IgG transporter (FcGRT) were present in the brain, and did not differ according to diagnosis or inflammatory status. Finally, brain-reactive antibody presence and abundance was investigated in the blood of living people. The plasma of living schizophrenia patients and healthy controls contained antibodies that displayed positive binding to Rhesus macaque cerebellar tissue, and the abundance of these antibodies was significantly lower in patients than controls. These findings suggest that antibodies in the brain and brain-reactive antibodies in the blood are present under normal circumstances.

Neural control of finger movement via intracortical brain-machine interface

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Irwin, Z. T.; Schroeder, K. E.; Vu, P. P.; Bullard, A. J.; Tat, D. M.; Nu, C. S.; Vaskov, A.; Nason, S. R.; Thompson, D. E.; Bentley, J. N.; Patil, P. G.; Chestek, C. A.

2017-12-01

Objective. Intracortical brain-machine interfaces (BMIs) are a promising source of prosthesis control signals for individuals with severe motor disabilities. Previous BMI studies have primarily focused on predicting and controlling whole-arm movements; precise control of hand kinematics, however, has not been fully demonstrated. Here, we investigate the continuous decoding of precise finger movements in rhesus macaques. Approach. In order to elicit precise and repeatable finger movements, we have developed a novel behavioral task paradigm which requires the subject to acquire virtual fingertip position targets. In the physical control condition, four rhesus macaques performed this task by moving all four fingers together in order to acquire a single target. This movement was equivalent to controlling the aperture of a power grasp. During this task performance, we recorded neural spikes from intracortical electrode arrays in primary motor cortex. Main results. Using a standard Kalman filter, we could reconstruct continuous finger movement offline with an average correlation of ρ  =  0.78 between actual and predicted position across four rhesus macaques. For two of the monkeys, this movement prediction was performed in real-time to enable direct brain control of the virtual hand. Compared to physical control, neural control performance was slightly degraded; however, the monkeys were still able to successfully perform the task with an average target acquisition rate of 83.1%. The monkeys’ ability to arbitrarily specify fingertip position was also quantified using an information throughput metric. During brain control task performance, the monkeys achieved an average 1.01 bits s-1 throughput, similar to that achieved in previous studies which decoded upper-arm movements to control computer cursors using a standard Kalman filter. Significance. This is, to our knowledge, the first demonstration of brain control of finger-level fine motor skills. We believe

Pentoxifylline, inflammation, and endothelial function in HIV-infected persons: a randomized, placebo-controlled trial.

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Samir K Gupta

Full Text Available Untreated HIV may increase the risk of cardiovascular events. Our preliminary in vitro and in vivo research suggests that pentoxifylline (PTX reduces vascular inflammation and improves endothelial function in HIV-infected persons not requiring antiretroviral therapy.We performed a randomized, placebo-controlled trial of PTX 400 mg orally thrice daily for 8 weeks in 26 participants. The primary endpoint was change in flow-mediated dilation (FMD of the brachial artery after 8 weeks. Nitroglycerin-mediated dilation (NTGMD and circulating markers of inflammation, cellular immune activation, coagulation, and metabolism were also assessed.The difference in mean absolute change (SD in FMD after 8 weeks between the placebo [-1.06 (1.45%] and PTX [-1.93 (3.03%] groups was not significant (P = 0.44. No differences in NTGMD were observed. The only significant between-group difference in the changes in biomarkers from baseline to week 8 was in soluble tumor necrosis factor receptor-1 (sTNFRI [-83.2 pg/mL in the placebo group vs. +65.9 pg/mL in the PTX group; P = 0.03]. PTX was generally well-tolerated.PTX did not improve endothelial function and unexpectedly increased the inflammatory biomarker sTNFRI in HIV-infected participants not requiring antiretroviral therapy. Additional interventional research is needed to reduce inflammation and cardiovascular risk in this population.ClinicalTrials.gov NCT00796822.

Blood-brain barrier disruption in CCL2 transgenic mice during pertussis toxin-induced brain inflammation

DEFF Research Database (Denmark)

Schellenberg, Angela E; Buist, Richard; Del Bigio, Marc R

2012-01-01

infiltrate into the brain parenchyma following the administration of pertussis toxin (PTx). METHODS: This study uses contrast-enhanced magnetic resonance imaging (MRI) to quantify the extent of blood-brain barrier (BBB) disruption in this model pre- and post-PTx administration compared to wild type mice....... Contrast-enhanced MR images were obtained before and 1, 3, and 5 days after PTx injection in each animal. After the final imaging session fluorescent dextran tracers were administered intravenously to each mouse and brains were examined histologically for cellular infiltrates, BBB leakage and tight...... junction protein. RESULTS: BBB breakdown, defined as a disruption of both the endothelium and glia limitans, was found only in CCL2 transgenic mice following PTx administration seen on MR images as focal areas of contrast enhancement and histologically as dextrans leaking from blood vessels. No evidence...

Stress, food, and inflammation: psychoneuroimmunology and nutrition at the cutting edge.

Science.gov (United States)

Kiecolt-Glaser, Janice K

2010-05-01

Inflammation is the common link among the leading causes of death. Mechanistic studies have shown how various dietary components can modulate key pathways to inflammation, including sympathetic activity, oxidative stress, transcription factor nuclear factor-kappaB activation, and proinflammatory cytokine production. Behavioral studies have demonstrated that stressful events and depression can also influence inflammation through these same processes. If the joint contributions of diet and behavior to inflammation were simply additive, they would be important. However, several far more intriguing interactive possibilities are discussed: stress influences food choices; stress can enhance maladaptive metabolic responses to unhealthy meals; and diet can affect mood as well as proinflammatory responses to stressors. Furthermore, because the vagus nerve innervates tissues involved in the digestion, absorption, and metabolism of nutrients, vagal activation can directly and profoundly influence metabolic responses to food, as well as inflammation; in turn, both depression and stress have well-documented negative effects on vagal activation, contributing to the lively interplay between the brain and the gut. As one example, omega-3 fatty acid intake can boost mood and vagal tone, dampen nuclear factor-kappaB activation and responses to endotoxin, and modulate the magnitude of inflammatory responses to stressors. A better understanding of how stressors, negative emotions, and unhealthy meals work together to enhance inflammation will benefit behavioral and nutritional research, as well as the broader biomedical community.

Comparison of 18F-fluoromethylcholine and 2-deoxy-D-glucose in the distribution of tumor and inflammation

International Nuclear Information System (INIS)

Kubota, Kazuo; Furumoto, Shozo; Iwata, Ren; Fukuda, Hiroshi; Kawamura, Kazunori; Ishiwata, Kiichi

2006-01-01

The distribution characteristics of 18 F-fluoromethylcholine ( 18 F-choline) in tumor and inflammatory tissue were compared with those of 14 C or 3 H-2-deoxyglucose (2DG) as a substitute for fluorodeoxyglucose (FDG). A solid tumor model of AH109A in the back of Donryu rats and an aseptic inflammation model of turpentine oil injection subcutaneously in rats were used for experiments. Tissue distribution was examined at 5, 30 and 60 min after injection of a mixture of 18 F-choline and 3 H-2DG. Double-tracer high-resolution autoradiographs (ARGs) of tumor and inflammation were obtained using 18 F-choline and 14 C-2DG. Whole body (WB) ARG was performed with 18 F-choline. Tumor uptake of 18 F-choline reached a peak at 30 min, when the tumor to blood ratio was 5.1. Both tumor and inflammation uptake of 2DG were higher than those of 18 F-choline. 18 F-choline uptake by inflammation was lower than that by tumor. The tumor to brain uptake ratio was 5.7 with 18 F-choline and 1.2 with 2DG. In the ARG of inflammation, linear or ring-like structures of 2DG uptake were observed in the wall of the abscess, but were not identified with 18 F-choline. Photomicrography showed that the uptake was limited to granulocytes, macrophages and fibroblasts, consistent with sub-acute or chronic inflammation. 18 F-choline uptake by inflammation was lower than that of 2DG in the tissue distribution study, and 18 F-choline uptake by abscess wall was significantly lower than that of 2DG in the autoradiography study. Our results may suggest the feasibility of 18 F-choline-PET imaging for the differential diagnosis of cancer and chronic inflammation in lung and brain. (author)

Milano summer particulate matter (PM10 triggers lung inflammation and extra pulmonary adverse events in mice.

Directory of Open Access Journals (Sweden)

Francesca Farina

Full Text Available Recent studies have suggested a link between particulate matter (PM exposure and increased mortality and morbidity associated with pulmonary and cardiovascular diseases; accumulating evidences point to a new role for air pollution in CNS diseases. The purpose of our study is to investigate PM10sum effects on lungs and extra pulmonary tissues. Milano PM10sum has been intratracheally instilled into BALB/c mice. Broncho Alveolar Lavage fluid, lung parenchyma, heart and brain were screened for markers of inflammation (cell counts, cytokines, ET-1, HO-1, MPO, iNOS, cytotoxicity (LDH, ALP, Hsp70, Caspase8-p18, Caspase3-p17 for a putative pro-carcinogenic marker (Cyp1B1 and for TLR4 pathway activation. Brain was also investigated for CD68, TNF-α, GFAP. In blood, cell counts were performed while plasma was screened for endothelial activation (sP-selectin, ET-1 and for inflammation markers (TNF-α, MIP-2, IL-1β, MPO. Genes up-regulation (HMOX1, Cyp1B1, IL-1β, MIP-2, MPO and miR-21 have been investigated in lungs and blood. Inflammation in the respiratory tract of PM10sum-treated mice has been confirmed in BALf and lung parenchyma by increased PMNs percentage, increased ET-1, MPO and cytokines levels. A systemic spreading of lung inflammation in PM10sum-treated mice has been related to the increased blood total cell count and neutrophils percentage, as well as to increased blood MPO. The blood-endothelium interface activation has been confirmed by significant increases of plasma ET-1 and sP-selectin. Furthermore PM10sum induced heart endothelial activation and PAHs metabolism, proved by increased ET-1 and Cyp1B1 levels. Moreover, PM10sum causes an increase in brain HO-1 and ET-1. These results state the translocation of inflammation mediators, ultrafine particles, LPS, metals associated to PM10sum, from lungs to bloodstream, thus triggering a systemic reaction, mainly involving heart and brain. Our results provided additional insight into the toxicity

Physical Activity Protects the Human Brain against Metabolic Stress Induced by a Postprandial and Chronic Inflammation

NARCIS (Netherlands)

Pruimboom, Leo; Raison, Charles L.; Muskiet, Frits A. J.

2015-01-01

In recent years, it has become clear that chronic systemic low-grade inflammation is at the root of many, if not all, typically Western diseases associated with the metabolic syndrome. While much focus has been given to sedentary lifestyle as a cause of chronic inflammation, it is less often

Controlling the brain: How electrical stimulation can be used as an effective treatment for many brain disorders

OpenAIRE

Van Dongen, M.

2010-01-01

Our brain is the center of our nervous system. Literally everything we do, from eating an apple to solving a Schrödinger equation, is controlled by it. Usually we don’t give much thought to the fact our brain is so utterly important, but imagine something starts to go drastically wrong inside the brain. Not being able to solve a Schrödinger equation might not be a big problem for the majority of people, but eating an apple is.

The Role of Dopamine in Inflammation-Associated Depression: Mechanisms and Therapeutic Implications.

Science.gov (United States)

Felger, Jennifer C

Studies investigating the impact of a variety of inflammatory stimuli on the brain and behavior have consistently reported evidence that inflammatory cytokines affect the basal ganglia and dopamine to mediate depressive symptoms related to motivation and motor activity. Findings have included inflammation-associated reductions in ventral striatal responses to hedonic reward, decreased dopamine and dopamine metabolites in cerebrospinal fluid, and decreased availability of striatal dopamine, all of which correlate with symptoms of anhedonia, fatigue, and psychomotor retardation. Similar relationships between alterations in dopamine-relevant corticostriatal reward circuitry and symptoms of anhedonia and psychomotor slowing have also been observed in patients with major depression who exhibit increased peripheral cytokines and other inflammatory markers, such as C-reactive protein. Of note, these inflammation-associated depressive symptoms are often difficult to treat in patients with medical illnesses or major depression. Furthermore, a wealth of literature suggests that inflammation can decrease dopamine synthesis, packaging, and release, thus sabotaging or circumventing the efficacy of standard antidepressant treatments. Herein, the mechanisms by which inflammation and cytokines affect dopamine neurotransmission are discussed, which may provide novel insights into treatment of inflammation-related behavioral symptoms that contribute to an inflammatory malaise.

Brain glucose sensing, glucokinase and neural control of metabolism and islet function.

Science.gov (United States)

Ogunnowo-Bada, E O; Heeley, N; Brochard, L; Evans, M L

2014-09-01

It is increasingly apparent that the brain plays a central role in metabolic homeostasis, including the maintenance of blood glucose. This is achieved by various efferent pathways from the brain to periphery, which help control hepatic glucose flux and perhaps insulin-stimulated insulin secretion. Also, critically important for the brain given its dependence on a constant supply of glucose as a fuel--emergency counter-regulatory responses are triggered by the brain if blood glucose starts to fall. To exert these control functions, the brain needs to detect rapidly and accurately changes in blood glucose. In this review, we summarize some of the mechanisms postulated to play a role in this and examine the potential role of the low-affinity hexokinase, glucokinase, in the brain as a key part of some of this sensing. We also discuss how these processes may become altered in diabetes and related metabolic diseases. © 2014 John Wiley & Sons Ltd.

Increased arterial inflammation in individuals with stage 3 chronic kidney disease

International Nuclear Information System (INIS)

Takx, Richard A.P.; MacNabb, Megan H.; Emami, Hamed; Abdelbaky, Amr; Lavender, Zachary R.; Singh, Parmanand; Di Carli, Marcelo; Taqueti, Viviany; Foster, Courtney; Mann, Jessica; Comley, Robert A.; Weber, Chek Ing Kiu; Tawakol, Ahmed

2016-01-01

While it is well known that patients with chronic kidney disease (CKD) are at increased risk for the development and progression of atherosclerosis, it is not known whether arterial inflammation is increased in mild CKD. The aim of this study was to compare arterial inflammation using 18 F-FDG PET/CT in patients with CKD and in matched controls. This retrospective study included 128 patients undergoing FDG PET/CT imaging for clinical indications, comprising 64 patients with stage 3 CKD and 64 control patients matched by age, gender, and cancer history. CKD was defined according to guidelines using a calculated glomerular filtration rate (eGFR). Arterial inflammation was measured in the ascending aorta as FDG uptake on PET. Background FDG uptake (venous, subcutaneous fat and muscle) were recorded. Coronary artery calcification (CAC) was assessed using the CT images. The impact of CKD on arterial inflammation and CAC was then assessed. Arterial inflammation was higher in patients with CKD than in matched controls (standardized uptake value, SUV: 2.41 ± 0.49 vs. 2.16 ± 0.43; p = 0.002). Arterial SUV correlated inversely with eGFR (r = -0.299, p = 0.001). Venous SUV was also significantly elevated in patients with CKD, while subcutaneous fat and muscle tissue SUVs did not differ between groups. Moreover, arterial SUV remained significantly elevated in patients with CKD compared to controls after correcting for muscle and fat background, and also remained significant after adjusting for clinical risk factors. Further, CKD was associated with arterial inflammation (SUV) independent of the presence of subclinical atherosclerosis (CAC). Moderate CKD is associated with increased arterial inflammation beyond that of controls. Further, the increased arterial inflammation is independent of presence of subclinical atherosclerosis. Current risk stratification tools may underestimate the presence of atherosclerosis in patients with CKD and thereby the risk of cardiovascular

Increased arterial inflammation in individuals with stage 3 chronic kidney disease

Energy Technology Data Exchange (ETDEWEB)

Takx, Richard A.P. [Massachusetts General Hospital and Harvard Medical School, Cardiac MR PET CT Program, Boston, MA (United States); University Medical Center Utrecht, Department of Radiology, Utrecht (Netherlands); MacNabb, Megan H.; Emami, Hamed; Abdelbaky, Amr; Lavender, Zachary R. [Massachusetts General Hospital and Harvard Medical School, Cardiac MR PET CT Program, Boston, MA (United States); Singh, Parmanand [Massachusetts General Hospital and Harvard Medical School, Cardiac MR PET CT Program, Boston, MA (United States); New York Presbyterian Hospital, Weill Cornell Medical College, Division of Cardiology, New York, NY (United States); Di Carli, Marcelo; Taqueti, Viviany; Foster, Courtney [Brigham and Women' s Hospital and Harvard Medical School, Division of Radiology, Department of Medicine, Boston, MA (United States); Mann, Jessica; Comley, Robert A.; Weber, Chek Ing Kiu [F. Hoffmann-La Roche Ltd., Basel (Switzerland); Tawakol, Ahmed [Massachusetts General Hospital and Harvard Medical School, Cardiac MR PET CT Program, Boston, MA (United States); Massachusetts General Hospital and Harvard Medical School, Cardiology Division, Boston, MA (United States); Massachusetts General Hospital, Boston, MA (United States)

2016-02-15

While it is well known that patients with chronic kidney disease (CKD) are at increased risk for the development and progression of atherosclerosis, it is not known whether arterial inflammation is increased in mild CKD. The aim of this study was to compare arterial inflammation using {sup 18}F-FDG PET/CT in patients with CKD and in matched controls. This retrospective study included 128 patients undergoing FDG PET/CT imaging for clinical indications, comprising 64 patients with stage 3 CKD and 64 control patients matched by age, gender, and cancer history. CKD was defined according to guidelines using a calculated glomerular filtration rate (eGFR). Arterial inflammation was measured in the ascending aorta as FDG uptake on PET. Background FDG uptake (venous, subcutaneous fat and muscle) were recorded. Coronary artery calcification (CAC) was assessed using the CT images. The impact of CKD on arterial inflammation and CAC was then assessed. Arterial inflammation was higher in patients with CKD than in matched controls (standardized uptake value, SUV: 2.41 ± 0.49 vs. 2.16 ± 0.43; p = 0.002). Arterial SUV correlated inversely with eGFR (r = -0.299, p = 0.001). Venous SUV was also significantly elevated in patients with CKD, while subcutaneous fat and muscle tissue SUVs did not differ between groups. Moreover, arterial SUV remained significantly elevated in patients with CKD compared to controls after correcting for muscle and fat background, and also remained significant after adjusting for clinical risk factors. Further, CKD was associated with arterial inflammation (SUV) independent of the presence of subclinical atherosclerosis (CAC). Moderate CKD is associated with increased arterial inflammation beyond that of controls. Further, the increased arterial inflammation is independent of presence of subclinical atherosclerosis. Current risk stratification tools may underestimate the presence of atherosclerosis in patients with CKD and thereby the risk of

Corpus callosum thickness on mid-sagittal MRI as a marker of brain volume: a pilot study in children with HIV-related brain disease and controls

Energy Technology Data Exchange (ETDEWEB)

Andronikou, Savvas [University of the Witwatersrand, Department of Radiology, Faculty of Health Sciences, Cape Town (South Africa); Ackermann, Christelle [University of Stellenbosch, Department of Radiology, Stellenbosch (South Africa); Laughton, Barbara; Cotton, Mark [Stellenbosch University and Tygerberg Children' s Hospital, Children' s Infectious Diseases Research Unit, Stellenbosch (South Africa); Tomazos, Nicollette [University of Cape Town, Faculty of Commerce, Department of Management Studies, Cape Town (South Africa); Spottiswoode, Bruce [University of Cape Town, MRC/UCT Medical Imaging Research Unit, Department of Human Biology, Cape Town (South Africa); Mauff, Katya [University of Cape Town, Department of Statistical Sciences, Cape Town (South Africa); Pettifor, John M. [University of the Witwatersrand, MRC/Wits Developmental Pathways for Health Research Unit, Department of Paediatrics, Faculty of Health Sciences, Witwatersrand (South Africa)

2015-07-15

Corpus callosum thickness measurement on mid-sagittal MRI may be a surrogate marker of brain volume. This is important for evaluation of diseases causing brain volume gain or loss, such as HIV-related brain disease and HIV encephalopathy. To determine if thickness of the corpus callosum on mid-sagittal MRI is a surrogate marker of brain volume in children with HIV-related brain disease and in controls without HIV. A retrospective MRI analysis in children (<5 years old) with HIV-related brain disease and controls used a custom-developed semi-automated tool, which divided the midline corpus callosum and measured its thickness in multiple locations. Brain volume was determined using volumetric analysis. Overall corpus callosum thickness and thickness of segments of the corpus callosum were correlated with overall and segmented (grey and white matter) brain volume. Forty-four children (33 HIV-infected patients and 11 controls) were included. Significant correlations included overall corpus callosum (mean) and total brain volume (P = 0.05); prefrontal corpus callosum maximum with white matter volume (P = 0.02); premotor corpus callosum mean with total brain volume (P = 0.04) and white matter volume (P = 0.02), premotor corpus callosum maximum with white matter volume (P = 0.02) and sensory corpus callosum mean with total brain volume (P = 0.02). Corpus callosum thickness correlates with brain volume both in HIV-infected patients and controls. (orig.)

Corpus callosum thickness on mid-sagittal MRI as a marker of brain volume: a pilot study in children with HIV-related brain disease and controls

International Nuclear Information System (INIS)

Andronikou, Savvas; Ackermann, Christelle; Laughton, Barbara; Cotton, Mark; Tomazos, Nicollette; Spottiswoode, Bruce; Mauff, Katya; Pettifor, John M.

2015-01-01

Corpus callosum thickness measurement on mid-sagittal MRI may be a surrogate marker of brain volume. This is important for evaluation of diseases causing brain volume gain or loss, such as HIV-related brain disease and HIV encephalopathy. To determine if thickness of the corpus callosum on mid-sagittal MRI is a surrogate marker of brain volume in children with HIV-related brain disease and in controls without HIV. A retrospective MRI analysis in children (<5 years old) with HIV-related brain disease and controls used a custom-developed semi-automated tool, which divided the midline corpus callosum and measured its thickness in multiple locations. Brain volume was determined using volumetric analysis. Overall corpus callosum thickness and thickness of segments of the corpus callosum were correlated with overall and segmented (grey and white matter) brain volume. Forty-four children (33 HIV-infected patients and 11 controls) were included. Significant correlations included overall corpus callosum (mean) and total brain volume (P = 0.05); prefrontal corpus callosum maximum with white matter volume (P = 0.02); premotor corpus callosum mean with total brain volume (P = 0.04) and white matter volume (P = 0.02), premotor corpus callosum maximum with white matter volume (P = 0.02) and sensory corpus callosum mean with total brain volume (P = 0.02). Corpus callosum thickness correlates with brain volume both in HIV-infected patients and controls. (orig.)

Systems Nutrigenomics Reveals Brain Gene Networks Linking Metabolic and Brain Disorders.

Science.gov (United States)

Meng, Qingying; Ying, Zhe; Noble, Emily; Zhao, Yuqi; Agrawal, Rahul; Mikhail, Andrew; Zhuang, Yumei; Tyagi, Ethika; Zhang, Qing; Lee, Jae-Hyung; Morselli, Marco; Orozco, Luz; Guo, Weilong; Kilts, Tina M; Zhu, Jun; Zhang, Bin; Pellegrini, Matteo; Xiao, Xinshu; Young, Marian F; Gomez-Pinilla, Fernando; Yang, Xia

2016-05-01

Nutrition plays a significant role in the increasing prevalence of metabolic and brain disorders. Here we employ systems nutrigenomics to scrutinize the genomic bases of nutrient-host interaction underlying disease predisposition or therapeutic potential. We conducted transcriptome and epigenome sequencing of hypothalamus (metabolic control) and hippocampus (cognitive processing) from a rodent model of fructose consumption, and identified significant reprogramming of DNA methylation, transcript abundance, alternative splicing, and gene networks governing cell metabolism, cell communication, inflammation, and neuronal signaling. These signals converged with genetic causal risks of metabolic, neurological, and psychiatric disorders revealed in humans. Gene network modeling uncovered the extracellular matrix genes Bgn and Fmod as main orchestrators of the effects of fructose, as validated using two knockout mouse models. We further demonstrate that an omega-3 fatty acid, DHA, reverses the genomic and network perturbations elicited by fructose, providing molecular support for nutritional interventions to counteract diet-induced metabolic and brain disorders. Our integrative approach complementing rodent and human studies supports the applicability of nutrigenomics principles to predict disease susceptibility and to guide personalized medicine. Copyright © 2016 The Authors. Published by Elsevier B.V. All rights reserved.

Role of inflammation in cardiopulmonary health effects of PM

International Nuclear Information System (INIS)

Donaldson, Ken; Mills, Nicholas; MacNee, William; Robinson, Simon; Newby, David

2005-01-01

The relationship between increased exposure to PM and adverse cardiovascular effects is well documented in epidemiological studies. Inflammation in the lungs, caused by deposited particles, can be seen as a key process that could mediate adverse effects on the cardiovascular system. There are at least three potential pathways that could lead from pulmonary inflammation to adverse cardiovascular effects. Firstly, inflammation in the lung could lead to systemic inflammation, which is well known to be linked to sudden death from cardiovascular causes. Systemic inflammation can lead to destabilization by activation of inflammatory processes in atheromatous plaques. Secondly, inflammation can cause an imbalance in coagulation factors that favor propagation of thrombi if thrombosis is initiated. Thirdly, inflammation could affect the autonomic nervous system activity in ways that could lead to alterations in the control of heart rhythm which could culminate in fatal dysrhythmia

Urinary Eosinophil Protein X in Childhood Asthma : Relation with Changes in Disease Control and Eosinophilic Airway Inflammation

NARCIS (Netherlands)

Nuijsink, Marianne; Hop, Wim C. J.; Sterk, Peter J.; Duiverman, Eric J.; De Jongste, Johan C.

2013-01-01

The aim of this study was to assess cross-sectional and longitudinal correlations between uEPX and other markers of asthma control and eosinophilic airway inflammation. Methods. We measured uEPX at baseline, after 1 year and after 2 years in 205 atopic asthmatic children using inhaled fluticasone.

Controlling the brain : How electrical stimulation can be used as an effective treatment for many brain disorders

NARCIS (Netherlands)

Van Dongen, M.

2010-01-01

Our brain is the center of our nervous system. Literally everything we do, from eating an apple to solving a Schrödinger equation, is controlled by it. Usually we don’t give much thought to the fact our brain is so utterly important, but imagine something starts to go drastically wrong inside the

The iconic memory skills of brain injury survivors and non-brain injured controls after visual scanning training.

Science.gov (United States)

McClure, J T; Browning, R T; Vantrease, C M; Bittle, S T

1994-01-01

Previous research suggests that traumatic brain injury (TBI) results in impairment of iconic memory abilities.We would like to acknowledge the contribution of Jeffrey D. Vantrease, who wrote the software program for the Iconic Memory procedure and measurement. This raises serious implications for brain injury rehabilitation. Most cognitive rehabilitation programs do not include iconic memory training. Instead it is common for cognitive rehabilitation programs to focus on attention and concentration skills, memory skills, and visual scanning skills.This study compared the iconic memory skills of brain-injury survivors and control subjects who all reached criterion levels of visual scanning skills. This involved previous training for the brain-injury survivors using popular visual scanning programs that allowed them to visually scan with response time and accuracy within normal limits. Control subjects required only minimal training to reach normal limits criteria. This comparison allows for the dissociation of visual scanning skills and iconic memory skills.The results are discussed in terms of their implications for cognitive rehabilitation and the relationship between visual scanning training and iconic memory skills.

On the need to better specify the concept of control in brain-computer-interfaces/neurofeedback research

Directory of Open Access Journals (Sweden)

Guilherme eWood

2014-09-01

Full Text Available Aiming at a better specification of the concept of control in brain-computer-interfaces (BCI and neurofeedback research, we propose to distinguish self-control of brain activity from the broader concept of BCI control, since the first describes a neurocognitive phenomenon and is only one of the many components of BCI control. Based on this distinction, we developed a framework based on dual-processes theory that describes the cognitive determinants of self-control of brain activity as the interplay of automatic vs. controlled information processing. Further, we distinguish between cognitive processes that are necessary and sufficient to achieve a given level of self-control of brain activity and those which are not. We discuss that those cognitive processes which are not necessary for the learning process can hamper self-control because they cannot be completely turned-off at any time. This framework aims at a comprehensive description of the cognitive determinants of the acquisition of self-control of brain activity underlying those classes of BCI which require the user to achieve regulation of brain activity as well as neurofeedback learning.

mTOR regulates metabolic adaptation of APCs in the lung and controls the outcome of allergic inflammation.

Science.gov (United States)

Sinclair, Charles; Bommakanti, Gayathri; Gardinassi, Luiz; Loebbermann, Jens; Johnson, Matthew Joseph; Hakimpour, Paul; Hagan, Thomas; Benitez, Lydia; Todor, Andrei; Machiah, Deepa; Oriss, Timothy; Ray, Anuradha; Bosinger, Steven; Ravindran, Rajesh; Li, Shuzhao; Pulendran, Bali

2017-09-08

Antigen-presenting cells (APCs) occupy diverse anatomical tissues, but their tissue-restricted homeostasis remains poorly understood. Here, working with mouse models of inflammation, we found that mechanistic target of rapamycin (mTOR)-dependent metabolic adaptation was required at discrete locations. mTOR was dispensable for dendritic cell (DC) homeostasis in secondary lymphoid tissues but necessary to regulate cellular metabolism and accumulation of CD103 + DCs and alveolar macrophages in lung. Moreover, while numbers of mTOR-deficient lung CD11b + DCs were not changed, they were metabolically reprogrammed to skew allergic inflammation from eosinophilic T helper cell 2 (T H 2) to neutrophilic T H 17 polarity. The mechanism for this change was independent of translational control but dependent on inflammatory DCs, which produced interleukin-23 and increased fatty acid oxidation. mTOR therefore mediates metabolic adaptation of APCs in distinct tissues, influencing the immunological character of allergic inflammation. Copyright © 2017 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works.

A brain-controlled lower-limb exoskeleton for human gait training

Science.gov (United States)

Liu, Dong; Chen, Weihai; Pei, Zhongcai; Wang, Jianhua

2017-10-01

Brain-computer interfaces have been a novel approach to translate human intentions into movement commands in robotic systems. This paper describes an electroencephalogram-based brain-controlled lower-limb exoskeleton for gait training, as a proof of concept towards rehabilitation with human-in-the-loop. Instead of using conventional single electroencephalography correlates, e.g., evoked P300 or spontaneous motor imagery, we propose a novel framework integrated two asynchronous signal modalities, i.e., sensorimotor rhythms (SMRs) and movement-related cortical potentials (MRCPs). We executed experiments in a biologically inspired and customized lower-limb exoskeleton where subjects (N = 6) actively controlled the robot using their brain signals. Each subject performed three consecutive sessions composed of offline training, online visual feedback testing, and online robot-control recordings. Post hoc evaluations were conducted including mental workload assessment, feature analysis, and statistics test. An average robot-control accuracy of 80.16% ± 5.44% was obtained with the SMR-based method, while estimation using the MRCP-based method yielded an average performance of 68.62% ± 8.55%. The experimental results showed the feasibility of the proposed framework with all subjects successfully controlled the exoskeleton. The current paradigm could be further extended to paraplegic patients in clinical trials.

Metallic gold reduces TNFalpha expression, oxidative DNA damage and pro-apoptotic signals after experimental brain injury

DEFF Research Database (Denmark)

Pedersen, Mie Ostergaard; Larsen, Agnete; Pedersen, Dan Sonne

2009-01-01

Brain injury represents a major health problem and may result in chronic inflammation and neurodegeneration. Due to antiinflammatory effects of gold, we have investigated the cerebral effects of metallic gold particles following a focal brain injury (freeze-lesion) in mice. Gold particles 20......-45 microm in size or the vehicle (placebo) were implanted in the cortical tissue followed by a cortical freeze-lesioning. At 1-2 weeks post-injury, brains were analyzed by using immunohistochemistry and markers of inflammation, oxidative stress and apoptosis. This study shows that gold treatment...

Energy Metabolism and Inflammation in Brain Aging and Alzheimer’s Disease

Science.gov (United States)

Yin, Fei; Sancheti, Harsh; Patil, Ishan; Cadenas, Enrique

2016-01-01

The high energy demand of the brain renders it sensitive to changes in energy fuel supply and mitochondrial function. Deficits in glucose availability and mitochondrial function are well-known hallmarks of brain aging and are particularly accentuated in neurodegenerative disorders such as Alzheimer’s disease. As important cellular sources of H2O2, mitochondrial dysfunction is usually associated with altered redox status. Bioenergetic deficits and chronic oxidative stress are both major contributors to cognitive decline associated with brain aging and Alzheimer’s disease. Neuroinflammatory changes, including microglial activation and production of inflammatory cytokines, are observed in neurodegenerative diseases and normal aging. The bioenergetic hypothesis advocates for sequential events from metabolic deficits to propagation of neuronal dysfunction, to aging, and to neurodegeneration, while the inflammatory hypothesis supports microglia activation as the driving force for neuroinflammation. Nevertheless, growing evidence suggests that these diverse mechanisms have redox dysregulation as a common denominator and connector. An independent view of the mechanisms underlying brain aging and neurodegeneration is being replaced by one that entails multiple mechanisms coordinating and interacting with each other. This review focuses on the alterations in energy metabolism and inflammatory responses and their connection via redox regulation in normal brain aging and Alzheimer’s disease. Interactions of these systems is reviewed based on basic research and clinical studies. PMID:27154981

Effects of Cinnamon, Cardamom, Saffron, and Ginger Consumption on Markers of Glycemic Control, Lipid Profile, Oxidative Stress, and Inflammation in Type 2 Diabetes Patients.

Science.gov (United States)

Azimi, Paria; Ghiasvand, Reza; Feizi, Awat; Hariri, Mitra; Abbasi, Behnoud

2014-01-01

Type 2 diabetes (T2D) may be caused by elevated oxidative stress, inflammation, and hyperglycemia. The phytochemicals in several herbal medicines are reported to effectively improve diabetes and to ameliorate diabetic complications. The aim of the present study was to determine the effects of cinnamon, cardamom, saffron, and ginger as supplementary remedies in T2D. This randomized controlled, clinical trial included 204 T2D patients. The participants were randomly assigned to four intervention groups receiving 3 glasses of black tea and either 3 g cardamom, or cinnamon, or ginger, or 1 g saffron and one control group which consumed only 3 tea glasses without any herbal medicine for 8 weeks. Markers of inflammation, oxidative stress, fasting blood sugar, lipid profile, and anthropometric measures were evaluated at baseline and after 8 weeks of intervention. After 8 weeks of intervention, cinnamon, cardamom, ginger, and saffron consumption had significant effects on total cholesterol, LDL, and HDL levels (p < 0.05) compared with controls. However, the herbal products did not have significant effects on measures of glycemic control, anthropometry, inflammation, and oxidative stress. In within-group comparisons only, cinnamon intake significantly decreased fasting blood sugar (FBS). The herbal remedies examined had significantly beneficial effects on cholesterol, but not on measures of glycemic control, oxidative stress, and inflammation. Based on the contradictory results reported in the literature, the effects of herbal medicine in diabetic patients should undergo further detailed investigation.

Orphan Nuclear Receptor ERRα Controls Macrophage Metabolic Signaling and A20 Expression to Negatively Regulate TLR-Induced Inflammation.

Science.gov (United States)

Yuk, Jae-Min; Kim, Tae Sung; Kim, Soo Yeon; Lee, Hye-Mi; Han, Jeongsu; Dufour, Catherine Rosa; Kim, Jin Kyung; Jin, Hyo Sun; Yang, Chul-Su; Park, Ki-Sun; Lee, Chul-Ho; Kim, Jin-Man; Kweon, Gi Ryang; Choi, Hueng-Sik; Vanacker, Jean-Marc; Moore, David D; Giguère, Vincent; Jo, Eun-Kyeong

2015-07-21

The orphan nuclear receptor estrogen-related receptor α (ERRα; NR3B1) is a key metabolic regulator, but its function in regulating inflammation remains largely unknown. Here, we demonstrate that ERRα negatively regulates Toll-like receptor (TLR)-induced inflammation by promoting Tnfaip3 transcription and fine-tuning of metabolic reprogramming in macrophages. ERRα-deficient (Esrra(-/-)) mice showed increased susceptibility to endotoxin-induced septic shock, leading to more severe pro-inflammatory responses than control mice. ERRα regulated macrophage inflammatory responses by directly binding the promoter region of Tnfaip3, a deubiquitinating enzyme in TLR signaling. In addition, Esrra(-/-) macrophages showed an increased glycolysis, but impaired mitochondrial respiratory function and biogenesis. Further, ERRα was required for the regulation of NF-κB signaling by controlling p65 acetylation via maintenance of NAD(+) levels and sirtuin 1 activation. These findings unravel a previously unappreciated role for ERRα as a negative regulator of TLR-induced inflammatory responses through inducing Tnfaip3 transcription and controlling the metabolic reprogramming. Copyright © 2015 Elsevier Inc. All rights reserved.

Urinary eosinophil protein X in childhood asthma: relation with changes in disease control and eosinophilic airway inflammation

NARCIS (Netherlands)

Nuijsink, Marianne; Hop, Wim C. J.; Sterk, Peter J.; Duiverman, Eric J.; de Jongste, Johan C.

2013-01-01

The aim of this study was to assess cross-sectional and longitudinal correlations between uEPX and other markers of asthma control and eosinophilic airway inflammation. Methods. We measured uEPX at baseline, after 1 year and after 2 years in 205 atopic asthmatic children using inhaled fluticasone.

Cognitive and emotional alterations are related to hippocampal inflammation in a mouse model of metabolic syndrome.

Science.gov (United States)

Dinel, Anne-Laure; André, Caroline; Aubert, Agnès; Ferreira, Guillaume; Layé, Sophie; Castanon, Nathalie

2011-01-01

Converging clinical data suggest that peripheral inflammation is likely involved in the pathogenesis of the neuropsychiatric symptoms associated with metabolic syndrome (MetS). However, the question arises as to whether the increased prevalence of behavioral alterations in MetS is also associated with central inflammation, i.e. cytokine activation, in brain areas particularly involved in controlling behavior. To answer this question, we measured in a mouse model of MetS, namely the diabetic and obese db/db mice, and in their healthy db/+ littermates emotional behaviors and memory performances, as well as plasma levels and brain expression (hippocampus; hypothalamus) of inflammatory cytokines. Our results shows that db/db mice displayed increased anxiety-like behaviors in the open-field and the elevated plus-maze (i.e. reduced percent of time spent in anxiogenic areas of each device), but not depressive-like behaviors as assessed by immobility time in the forced swim and tail suspension tests. Moreover, db/db mice displayed impaired spatial recognition memory (hippocampus-dependent task), but unaltered object recognition memory (hippocampus-independent task). In agreement with the well-established role of the hippocampus in anxiety-like behavior and spatial memory, behavioral alterations of db/db mice were associated with increased inflammatory cytokines (interleukin-1β, tumor necrosis factor-α and interleukin-6) and reduced expression of brain-derived neurotrophic factor (BDNF) in the hippocampus but not the hypothalamus. These results strongly point to interactions between cytokines and central processes involving the hippocampus as important contributing factor to the behavioral alterations of db/db mice. These findings may prove valuable for introducing novel approaches to treat neuropsychiatric complications associated with MetS.

Cognitive and emotional alterations are related to hippocampal inflammation in a mouse model of metabolic syndrome.

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Anne-Laure Dinel

Full Text Available Converging clinical data suggest that peripheral inflammation is likely involved in the pathogenesis of the neuropsychiatric symptoms associated with metabolic syndrome (MetS. However, the question arises as to whether the increased prevalence of behavioral alterations in MetS is also associated with central inflammation, i.e. cytokine activation, in brain areas particularly involved in controlling behavior. To answer this question, we measured in a mouse model of MetS, namely the diabetic and obese db/db mice, and in their healthy db/+ littermates emotional behaviors and memory performances, as well as plasma levels and brain expression (hippocampus; hypothalamus of inflammatory cytokines. Our results shows that db/db mice displayed increased anxiety-like behaviors in the open-field and the elevated plus-maze (i.e. reduced percent of time spent in anxiogenic areas of each device, but not depressive-like behaviors as assessed by immobility time in the forced swim and tail suspension tests. Moreover, db/db mice displayed impaired spatial recognition memory (hippocampus-dependent task, but unaltered object recognition memory (hippocampus-independent task. In agreement with the well-established role of the hippocampus in anxiety-like behavior and spatial memory, behavioral alterations of db/db mice were associated with increased inflammatory cytokines (interleukin-1β, tumor necrosis factor-α and interleukin-6 and reduced expression of brain-derived neurotrophic factor (BDNF in the hippocampus but not the hypothalamus. These results strongly point to interactions between cytokines and central processes involving the hippocampus as important contributing factor to the behavioral alterations of db/db mice. These findings may prove valuable for introducing novel approaches to treat neuropsychiatric complications associated with MetS.

Sex differences in the developing brain as a source of inherent risk.

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McCarthy, Margaret M

2016-12-01

Brain development diverges in males and females in response to androgen production by the fetal testis. This sexual differentiation of the brain occurs during a sensitive window and induces enduring neuroanatomical and physiological changes that profoundly impact behavior. What we know about the contribution of sex chromosomes is still emerging, highlighting the need to integrate multiple factors into understanding sex differences, including the importance of context. The cellular mechanisms are best modeled in rodents and have provided both unifying principles and surprising specifics. Markedly distinct signaling pathways direct differentiation in specific brain regions, resulting in mosaicism of relative maleness, femaleness, and sameness through-out the brain, while canalization both exaggerates and constrains sex differences. Non-neuronal cells and inflammatory mediators are found in greater number and at higher levels in parts of male brains. This higher baseline of inflammation is speculated to increase male vulnerability to developmental neuropsychiatric disorders that are triggered by inflammation.

Protective ventilation of preterm lambs exposed to acute chorioamnionitis does not reduce ventilation-induced lung or brain injury.

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Barton, Samantha K; Moss, Timothy J M; Hooper, Stuart B; Crossley, Kelly J; Gill, Andrew W; Kluckow, Martin; Zahra, Valerie; Wong, Flora Y; Pichler, Gerhard; Galinsky, Robert; Miller, Suzanne L; Tolcos, Mary; Polglase, Graeme R

2014-01-01

The onset of mechanical ventilation is a critical time for the initiation of cerebral white matter (WM) injury in preterm neonates, particularly if they are inadvertently exposed to high tidal volumes (VT) in the delivery room. Protective ventilation strategies at birth reduce ventilation-induced lung and brain inflammation and injury, however its efficacy in a compromised newborn is not known. Chorioamnionitis is a common antecedent of preterm birth, and increases the risk and severity of WM injury. We investigated the effects of high VT ventilation, after chorioamnionitis, on preterm lung and WM inflammation and injury, and whether a protective ventilation strategy could mitigate the response. Pregnant ewes (n = 18) received intra-amniotic lipopolysaccharide (LPS) 2 days before delivery, instrumentation and ventilation at 127±1 days gestation. Lambs were either immediately euthanased and used as unventilated controls (LPSUVC; n = 6), or were ventilated using an injurious high VT strategy (LPSINJ; n = 5) or a protective ventilation strategy (LPSPROT; n = 7) for a total of 90 min. Mean arterial pressure, heart rate and cerebral haemodynamics and oxygenation were measured continuously. Lungs and brains underwent molecular and histological assessment of inflammation and injury. LPSINJ lambs had poorer oxygenation than LPSPROT lambs. Ventilation requirements and cardiopulmonary and systemic haemodynamics were not different between ventilation strategies. Compared to unventilated lambs, LPSINJ and LPSPROT lambs had increases in pro-inflammatory cytokine expression within the lungs and brain, and increased astrogliosis (pVentilation after acute chorioamnionitis, irrespective of strategy used, increases haemodynamic instability and lung and cerebral inflammation and injury. Mechanical ventilation is a potential contributor to WM injury in infants exposed to chorioamnionitis.

Serum GGT activity and hsCRP level in patients with type 2 diabetes mellitus with good and poor glycemic control: An evidence linking oxidative stress, inflammation and glycemic control.

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Gohel, Mukesh G; Chacko, Anusha N

2013-12-20

Diabetes is undoubtedly one of the most challenging health problems in 21st century. Understanding the pathogenesis and preventing long term complications have been major goals of research in diabetes mellitus (DM). Research in the past few years has linked oxidative stress and inflammation to beta cell dysfunction. Aim of this study is to evaluate serum gamma-glutamyl transferase (GGT) activity (marker of oxidative stress) and high sensitivity C reactive protein (hsCRP) level (an inflammatory marker) in type 2 DM subjects with good and poor glycemic control. Further, we investigated correlation between serum GGT and hsCRP level with glycemic control (FBS, PP2BS, HbA1c) in subjects. A cross sectional study consists of 150 patients out of them 50 patients having type 2 DM with good control (Group II), 50 patients with type 2 DM with poor control (Group III) and 50 normal healthy control (Group I) were selected. Serum GGT, serum hsCRP, FBS, PP2BS, HbA1c, and other biochemical investigations include serum liver enzymes and lipids were measured. Mean serum GGT and hsCRP concentration were statistically significantly higher in group III patients compared to group I and group II subjects as well as increased in group II compared to group I (p stress and inflammation appears to be a key component and also associated with poor glycemic control and further pathogenesis of diabetes and its complications. All our finding suggesting a link between oxidative stress, inflammation and glycemic control in patient with type 2 diabetes mellitus.

Optogenetic control of human neurons in organotypic brain cultures

DEFF Research Database (Denmark)

Andersson, My; Avaliani, Natalia; Svensson, Andreas

2016-01-01

Optogenetics is one of the most powerful tools in neuroscience, allowing for selective control of specific neuronal populations in the brain of experimental animals, including mammals. We report, for the first time, the application of optogenetic tools to human brain tissue providing a proof......-of-concept for the use of optogenetics in neuromodulation of human cortical and hippocampal neurons as a possible tool to explore network mechanisms and develop future therapeutic strategies....

Ameliorating Amyloid-β Fibrils Triggered Inflammation via Curcumin-Loaded Polymeric Nanoconstructs

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Andrea Ameruoso

2017-10-01

Full Text Available Inflammation is a common hallmark in several diseases, including atherosclerosis, cancer, obesity, and neurodegeneration. In Alzheimer’s disease (AD, growing evidence directly correlates neuronal damage with inflammation of myeloid brain cells, such as microglia. Here, polymeric nanoparticles were engineered and characterized for the delivery of anti-inflammatory molecules to macrophages stimulated via direct incubation with amyloid-β fibers. 200 nm spherical polymeric nanoconstructs (SPNs and 1,000 nm discoidal polymeric nanoconstructs (DPNs were synthesized using poly(lactic-co-glycolic acid (PLGA, polyethylene glycol (PEG, and lipid chains as building blocks. First, the internalization propensity in macrophages of both nanoparticles was assessed via cytofluorimetric and confocal microscopy analyses, demonstrating that SPNs are by far more rapidly taken up as compared to DPNs (99.6 ± 0.11 vs 14.4 ± 0.06%, within 24 h. Then, Curcumin-loaded SPNs (Curc-SPNs were realized by encapsulating Curcumin, a natural anti-inflammatory molecule, within the PLGA core of SPNs. Finally, Curc-SPNs were shown to diminish up to 6.5-fold the production of pro-inflammatory cytokines—IL-1β; IL-6, and TNF-α—in macrophages stimulated via amyloid-β fibers. Although more sophisticated in vitro models and systematic analyses on the blood–brain barrier permeability are critically needed, these findings hold potential in the development of nanoparticles for modulating inflammation in AD.

Inflammation-mediated memory dysfunction and effects of a ketogenic diet in a murine model of multiple sclerosis.

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Do Young Kim

Full Text Available A prominent clinical symptom in multiple sclerosis (MS, a progressive disorder of the central nervous system (CNS due to heightened neuro-inflammation, is learning and memory dysfunction. Here, we investigated the effects of a ketogenic diet (KD on memory impairment and CNS-inflammation in a murine model of experimental autoimmune encephalomyelitis (EAE, using electrophysiological, behavioral, biochemical and in vivo imaging approaches. Behavioral spatial learning deficits were associated with motor disability in EAE mice, and were observed concurrently with brain inflammation. The KD improved motor disability in the EAE model, as well as CA1 hippocampal synaptic plasticity (long-term potentiation and spatial learning and memory (assessed with the Morris Water Maze. Moreover, hippocampal atrophy and periventricular lesions in EAE mice were reversed in KD-treated EAE mice. Finally, we found that the increased expression of inflammatory cytokines and chemokines, as well as the production of reactive oxygen species (ROS, in our EAE model were both suppressed by the KD. Collectively, our findings indicate that brain inflammation in EAE mice is associated with impaired spatial learning and memory function, and that KD treatment can exert protective effects, likely via attenuation of the robust immune response and increased oxidative stress seen in these animals.

Early invasion of brain parenchyma by African trypanosomes.

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Ute Frevert

Full Text Available Human African trypanosomiasis or sleeping sickness is a vector-borne parasitic disease that has a major impact on human health and welfare in sub-Saharan countries. Based mostly on data from animal models, it is currently thought that trypanosome entry into the brain occurs by initial infection of the choroid plexus and the circumventricular organs followed days to weeks later by entry into the brain parenchyma. However, Trypanosoma brucei bloodstream forms rapidly cross human brain microvascular endothelial cells in vitro and appear to be able to enter the murine brain without inflicting cerebral injury. Using a murine model and intravital brain imaging, we show that bloodstream forms of T. b. brucei and T. b. rhodesiense enter the brain parenchyma within hours, before a significant level of microvascular inflammation is detectable. Extravascular bloodstream forms were viable as indicated by motility and cell division, and remained detectable for at least 3 days post infection suggesting the potential for parasite survival in the brain parenchyma. Vascular inflammation, as reflected by leukocyte recruitment and emigration from cortical microvessels, became apparent only with increasing parasitemia at later stages of the infection, but was not associated with neurological signs. Extravascular trypanosomes were predominantly associated with postcapillary venules suggesting that early brain infection occurs by parasite passage across the neuroimmunological blood brain barrier. Thus, trypanosomes can invade the murine brain parenchyma during the early stages of the disease before meningoencephalitis is fully established. Whether individual trypanosomes can act alone or require the interaction from a quorum of parasites remains to be shown. The significance of these findings for disease development is now testable.

Control of Cross Talk between Angiogenesis and Inflammation by Mesenchymal Stem Cells for the Treatment of Ocular Surface Diseases

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Fei Li

2016-01-01

Full Text Available Angiogenesis is beneficial in the treatment of ischemic heart disease and peripheral artery disease. However, it facilitates inflammatory cell filtration and inflammation cascade that disrupt the immune and angiogenesis privilege of the avascular cornea, resulting in ocular surface diseases and even vision loss. Although great progress has been achieved, healing of severe ocular surface injury and immunosuppression of corneal transplantation are the most difficult and challenging step in the treatment of ocular surface disorders. Mesenchymal stem cells (MSCs, derived from various adult tissues, are able to differentiate into different cell types such as endothelial cells and fat cells. Although it is still under debate whether MSCs could give rise to functional corneal cells, recent results from different study groups showed that MSCs could improve corneal disease recovery through suppression of inflammation and modulation of immune cells. Thus, MSCs could become a promising tool for ocular surface disorders. In this review, we discussed how angiogenesis and inflammation are orchestrated in the pathogenesis of ocular surface disease. We overviewed and updated the knowledge of MSCs and then summarized the therapeutic potential of MSCs via control of angiogenesis, inflammation, and immune response in the treatment of ocular surface disease.

Evidence for a Heritable Brain Basis to Deviance-Promoting Deficits in Self-Control.

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Yancey, James R; Venables, Noah C; Hicks, Brian M; Patrick, Christopher J

2013-01-01

Classic criminological theories emphasize the role of impaired self-control in behavioral deviancy. Reduced amplitude of the P300 brain response is reliably observed in individuals with antisocial and substance-related problems, suggesting it may serve as a neurophysiological indicator of deficiencies in self-control that confer liability to deviancy. The current study evaluated the role of self-control capacity - operationalized by scores on a scale measure of trait disinhibition - in mediating the relationship between P300 brain response and behavioral deviancy in a sample of adult twins ( N =419) assessed for symptoms of antisocial/addictive disorders and P300 brain response. As predicted, greater disorder symptoms and higher trait disinhibition scores each predicted smaller P300 amplitude, and trait disinhibition mediated observed relations between antisocial/addictive disorders and P300 response. Further, twin modeling analyses revealed that trait disinhibition scores and disorder symptoms reflected a common genetic liability, and this genetic liability largely accounted for the observed phenotypic relationship between antisocial-addictive problems and P300 brain response. These results provide further evidence that heritable weaknesses in self-control capacity confer liability to antisocial/addictive outcomes and that P300 brain response indexes this dispositional liability.

Investigating depression-like and metabolic parameters in a chronic low-grade inflammation model

DEFF Research Database (Denmark)

Fischer, C. W.; Elfving, B.; Lund, S.

2012-01-01

that elevated markers of inflammation predict a poor response to treatment. Furthermore, increasing evidences show that metabolic abnormalities such as obesity and diabetes mellitus type 2 are associated with a low-grade inflammation. Objectives: The aim of this study is to investigate the effects of a systemic...... levels of pro-inflammatory cytokines (TNF-alpha, IL-1, IL-6) together with the expression of enzymes involved in the tryptophan-kynurenine pathway, will be analyzed in specific brain regions using real-time qPCR. Body weight and food intake was measured once a week, while fasting glucose and insulin...

Respiratory mechanics in brain injury: A review

OpenAIRE

Koutsoukou, Antonia; Katsiari, Maria; Orfanos, Stylianos E; Kotanidou, Anastasia; Daganou, Maria; Kyriakopoulou, Magdalini; Koulouris, Nikolaos G; Rovina, Nikoletta

2016-01-01

Several clinical and experimental studies have shown that lung injury occurs shortly after brain damage. The responsible mechanisms involve neurogenic pulmonary edema, inflammation, the harmful action of neurotransmitters, or autonomic system dysfunction. Mechanical ventilation, an essential component of life support in brain-damaged patients (BD), may be an additional traumatic factor to the already injured or susceptible to injury lungs of these patients thus worsening lung injury, in case ...

Maternal inflammation induces immune activation of fetal microglia and leads to disrupted microglia immune responses, behavior, and learning performance in adulthood.

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Schaafsma, Wandert; Basterra, Laura Bozal; Jacobs, Sabrina; Brouwer, Nieske; Meerlo, Peter; Schaafsma, Anne; Boddeke, Erik W G M; Eggen, Bart J L

2017-10-01

Maternal inflammation during pregnancy can have detrimental effects on embryonic development that persist during adulthood. However, the underlying mechanisms and insights in the responsible cell types are still largely unknown. Here we report the effect of maternal inflammation on fetal microglia, the innate immune cells of the central nervous system (CNS). In mice, a challenge with LPS during late gestation stages (days 15-16-17) induced a pro-inflammatory response in fetal microglia. Adult whole brain microglia of mice that were exposed to LPS during embryonic development displayed a persistent reduction in pro-inflammatory activation in response to a re-challenge with LPS. In contrast, hippocampal microglia of these mice displayed an increased inflammatory response to an LPS re-challenge. In addition, a reduced expression of brain-derived neurotrophic factor (BDNF) was observed in hippocampal microglia of LPS-offspring. Microglia-derived BDNF has been shown to be important for learning and memory processes. In line with these observations, behavioral- and learning tasks with mice that were exposed to maternal inflammation revealed reduced home cage activity, reduced anxiety and reduced learning performance in a T-maze. These data show that exposure to maternal inflammation during late gestation results in long term changes in microglia responsiveness during adulthood, which is different in nature in hippocampus compared to total brain microglia. Copyright © 2017 Elsevier Inc. All rights reserved.

Driving the brain towards creativity and intelligence: A network control theory analysis.

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Kenett, Yoed N; Medaglia, John D; Beaty, Roger E; Chen, Qunlin; Betzel, Richard F; Thompson-Schill, Sharon L; Qiu, Jiang

2018-01-04

High-level cognitive constructs, such as creativity and intelligence, entail complex and multiple processes, including cognitive control processes. Recent neurocognitive research on these constructs highlight the importance of dynamic interaction across neural network systems and the role of cognitive control processes in guiding such a dynamic interaction. How can we quantitatively examine the extent and ways in which cognitive control contributes to creativity and intelligence? To address this question, we apply a computational network control theory (NCT) approach to structural brain imaging data acquired via diffusion tensor imaging in a large sample of participants, to examine how NCT relates to individual differences in distinct measures of creative ability and intelligence. Recent application of this theory at the neural level is built on a model of brain dynamics, which mathematically models patterns of inter-region activity propagated along the structure of an underlying network. The strength of this approach is its ability to characterize the potential role of each brain region in regulating whole-brain network function based on its anatomical fingerprint and a simplified model of node dynamics. We find that intelligence is related to the ability to "drive" the brain system into easy to reach neural states by the right inferior parietal lobe and lower integration abilities in the left retrosplenial cortex. We also find that creativity is related to the ability to "drive" the brain system into difficult to reach states by the right dorsolateral prefrontal cortex (inferior frontal junction) and higher integration abilities in sensorimotor areas. Furthermore, we found that different facets of creativity-fluency, flexibility, and originality-relate to generally similar but not identical network controllability processes. We relate our findings to general theories on intelligence and creativity. Copyright © 2018 Elsevier Ltd. All rights reserved.

Exercise protects against high-fat diet-induced hypothalamic inflammation.

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Yi, Chun-Xia; Al-Massadi, Omar; Donelan, Elizabeth; Lehti, Maarit; Weber, Jon; Ress, Chandler; Trivedi, Chitrang; Müller, Timo D; Woods, Stephen C; Hofmann, Susanna M

2012-06-25

Hypothalamic inflammation is a potentially important process in the pathogenesis of high-fat diet-induced metabolic disorders that has recently received significant attention. Microglia are macrophage-like cells of the central nervous system which are activated by pro-inflammatory signals causing local production of specific interleukins and cytokines, and these in turn may further promote systemic metabolic disease. Whether or how this microglial activation can be averted or reversed is unknown. Since running exercise improves systemic metabolic health and has been found to promote neuronal survival as well as the recovery of brain functions after injury, we hypothesized that regular treadmill running may blunt the effect of western diet on hypothalamic inflammation. Using low-density lipoprotein receptor deficient (l dlr-/-) mice to better reflect human lipid metabolism, we first confirmed that microglial activation in the hypothalamus is severely increased upon exposure to a high-fat, or "western", diet. Moderate, but regular, treadmill running exercise markedly decreased hypothalamic inflammation in these mice. Furthermore, the observed decline in microglial activation was associated with an improvement of glucose tolerance. Our findings support the hypothesis that hypothalamic inflammation can be reversed by exercise and suggest that interventions to avert or reverse neuronal damage may offer relevant potential in obesity treatment and prevention. Copyright © 2012 Elsevier Inc. All rights reserved.

Salvianolic acid A alleviates ischemic brain injury through the inhibition of inflammation and apoptosis and the promotion of neurogenesis in mice.

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Chien, Mei-Yin; Chuang, Cheng-Hung; Chern, Chang-Ming; Liou, Kou-Tong; Liu, Der-Zen; Hou, Yu-Chang; Shen, Yuh-Chiang

2016-10-01

Salvianolic acid A (SalA), a chemical type of caffeic acid trimer, has drawn great attention for its potent bioactivities against ischemia-induced injury both in vitro and in vivo. In this study, we evaluated SalA's protective effects against acute ischemic stroke by inducing middle cerebral artery occlusion/reperfusion (MCAO) injuries in mice. Treatment of the mice with SalA (50 and 100μg/kg, i.v.) at 2h after MCAO enhanced their survival rate, improved their moving activity, and ameliorated the severity of brain infarction and apoptosis seen in the mice by diminishing pathological changes such as the extensive breakdown of the blood-brain barrier (BBB), nitrosative stress, and the activation of an inflammatory transcriptional factor p65 nuclear factor-kappa B (NF-κB) and a pro-apoptotic kinase p25/Cdk5. SalA also intensively limited cortical infarction and promoted the expression of neurogenesis protein near the peri-infarct cortex and subgranular zone of the hippocampal dentate gyrus by compromising the activation of GSK3β and p25/Cdk5, which in turn upregulated β-catenin, doublecortin (DCX), and Bcl-2, most possibly through the activation of PI3K/Akt signaling via the upregulation of brain-derived neurotrophic factor. We conclude that SalA blocks inflammatory responses by impairing NF-κB signaling, thereby limiting inflammation/nitrosative stress and preserving the integrity of the BBB; SalA also concomitantly promotes neurogenesis-related protein expression by compromising GSK3β/Cdk5 activity to enhance the expression levels of β-catenin/DCX and Bcl-2 for neuroprotection. Copyright © 2016 Elsevier Inc. All rights reserved.

Control of a nursing bed based on a hybrid brain-computer interface.

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Nengneng Peng; Rui Zhang; Haihua Zeng; Fei Wang; Kai Li; Yuanqing Li; Xiaobin Zhuang

2016-08-01

In this paper, we propose an intelligent nursing bed system which is controlled by a hybrid brain-computer interface (BCI) involving steady-state visual evoked potential (SSVEP) and P300. Specifically, the hybrid BCI includes an asynchronous brain switch based on SSVEP and P300, and a P300-based BCI. The brain switch is used to turn on/off the control system of the electric nursing bed through idle/control state detection, whereas the P300-based BCI is for operating the nursing bed. At the beginning, the user may focus on one group of flashing buttons in the graphic user interface (GUI) of the brain switch, which can simultaneously evoke SSVEP and P300, to switch on the control system. Here, the combination of SSVEP and P300 is used for improving the performance of the brain switch. Next, the user can control the nursing bed using the P300-based BCI. The GUI of the P300-based BCI includes 10 flashing buttons, which correspond to 10 functional operations, namely, left-side up, left-side down, back up, back down, bedpan open, bedpan close, legs up, legs down, right-side up, and right-side down. For instance, he/she can focus on the flashing button "back up" in the GUI of the P300-based BCI to activate the corresponding control such that the nursing bed is adjusted up. Eight healthy subjects participated in our experiment, and obtained an average accuracy of 93.75% and an average false positive rate (FPR) of 0.15 event/min. The effectiveness of our system was thus demonstrated.

Pluriformity of inflammation in multiple sclerosis shown by ultra-small iron oxide particle enhancement

NARCIS (Netherlands)

Vellinga, M.M.; Oude Engberink, R.D.; Seewann, A.; Pouwels, P.J.W.; Wattjes, M.P.; van der Pol, S.M.A.; Pering, C.; Polman, C.H.; de Vries, H.E.; Geurts, J.J.G.; Barkhof, F.

2008-01-01

Gadolinium-DTPA (Gd-DTPA) is routinely used as a marker for inflammation in MRI to visualize breakdown of the blood-brain barrier (BBB) in multiple sclerosis. Recent data suggest that ultra-small superparamagnetic particles of iron oxide (USPIO) can be used to visualize cellular infiltration,

Influence of electromagnetic field (1800 MHz on lipid peroxidation in brain, blood, liver and kidney in rats

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Paweł Bodera

2015-08-01

Full Text Available Objectives: The aim of this study is the evaluation of the influence of repeated (5 times for 15 min exposure to electromagnetic field (EMF of 1800 MHz frequency on tissue lipid peroxidation (LPO both in normal and inflammatory state, combined with analgesic treatment. Material and Methods: The concentration of malondialdehyde (MDA as the end-product of the lipid peroxidation (LPO was estimated in blood, liver, kidneys, and brain of Wistar rats, both healthy and those with complete Freund’s adjuvant (CFA-induced persistent paw inflammation. Results: The slightly elevated levels of the MDA in blood, kidney, and brain were observed among healthy rats in electromagnetic field (EMF-exposed groups, treated with tramadol (TRAM/EMF and exposed to the EMF. The malondialdehyde remained at the same level in the liver in all investigated groups: the control group (CON, the exposed group (EMF, treated with tramadol (TRAM as well as exposed to and treated with tramadol (TRAM/EMF. In the group of animals treated with the complete Freund’s adjuvant (CFA we also observed slightly increased values of the MDA in the case of the control group (CON and the exposed groups (EMF and TRAM/EMF. The MDA values concerning kidneys remained at the same levels in the control, exposed, and not-exposed group treated with tramadol. Results for healthy rats and animals with inflammation did not differ significantly. Conclusions: The electromagnetic field exposure (EMF, applied in the repeated manner together with opioid drug tramadol (TRAM, slightly enhanced lipid peroxidation level in brain, blood, and kidneys.

VEGF controls lung Th2 inflammation via the miR-1–Mpl (myeloproliferative leukemia virus oncogene)–P-selectin axis

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Vasavada, Hema; Zhang, Jian-ge; Ahangari, Farida; Niu, Naiqian; Liu, Qing; Lee, Chun Geun; Cohn, Lauren

2013-01-01

Asthma, the prototypic Th2-mediated inflammatory disorder of the lung, is an emergent disease worldwide. Vascular endothelial growth factor (VEGF) is a critical regulator of pulmonary Th2 inflammation, but the underlying mechanism and the roles of microRNAs (miRNAs) in this process have not been defined. Here we show that lung-specific overexpression of VEGF decreases miR-1 expression in the lung, most prominently in the endothelium, and a similar down-regulation occurs in lung endothelium in Th2 inflammation models. Intranasal delivery of miR-1 inhibited inflammatory responses to ovalbumin, house dust mite, and IL-13 overexpression. Blocking VEGF inhibited Th2-mediated lung inflammation, and this was restored by antagonizing miR-1. Using mRNA arrays, Argonaute pull-down assays, luciferase expression assays, and mutational analysis, we identified Mpl as a direct target of miR-1 and showed that VEGF controls the expression of endothelial Mpl during Th2 inflammation via the regulation of miR-1. In vivo knockdown of Mpl inhibited Th2 inflammation and indirectly inhibited the expression of P-selectin in lung endothelium. These experiments define a novel VEGF–miR-1–Mpl–P-selectin effector pathway in lung Th2 inflammation and herald the utility of miR-1 and Mpl as potential therapeutic targets for asthma. PMID:24043765

Scaffolds to Control Inflammation and Facilitate Dental Pulp Regeneration

Science.gov (United States)

Colombo, John S.; Moore, Amanda N.; Hartgerink, Jeffrey D.; D’Souza, Rena N.

2014-01-01

In dentistry, the maintenance of a vital dental pulp is of paramount importance, as teeth devitalized by root canal treatment may become more brittle and prone to structural failure over time. Advanced carious lesions can irreversibly damage the dental pulp by propagating a sustained inflammatory response throughout the tissue. While the inflammatory response initially drives tissue repair, sustained inflammation has an enormously destructive effect on the vital pulp, eventually leading to total necrosis of the tissue and necessitating its removal. The implications of tooth devitalization have driven significant interest in the development of bioactive materials that facilitate the regeneration of damaged pulp tissues by harnessing the capacity of the dental pulp for self-repair. In considering the process by which pulpitis drives tissue destruction, it is clear that an important step in supporting the regeneration of pulpal tissues is the attenuation of inflammation. Macrophages, key mediators of the immune response, may play a critical role in the resolution of pulpitis due to their ability to switch to a pro-resolution phenotype. This process can be driven by the resolvins, a family of molecules derived from fatty acids that show great promise as therapeutic agents. In this review, we outline the importance of preserving the capacity of the dental pulp to self-repair through the rapid attenuation of inflammation. Potential treatment modalities, such as shifting macrophages to a pro-resolving phenotype with resolvins are described, and a range of materials known to support the regeneration of dental pulp are presented. PMID:24698696

Matrix metalloproteinases in the brain and blood–brain barrier: Versatile breakers and makers

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Rempe, Ralf G; Hartz, Anika MS

2016-01-01

Matrix metalloproteinases are versatile endopeptidases with many different functions in the body in health and disease. In the brain, matrix metalloproteinases are critical for tissue formation, neuronal network remodeling, and blood–brain barrier integrity. Many reviews have been published on matrix metalloproteinases before, most of which focus on the two best studied matrix metalloproteinases, the gelatinases MMP-2 and MMP-9, and their role in one or two diseases. In this review, we provide a broad overview of the role various matrix metalloproteinases play in brain disorders. We summarize and review current knowledge and understanding of matrix metalloproteinases in the brain and at the blood–brain barrier in neuroinflammation, multiple sclerosis, cerebral aneurysms, stroke, epilepsy, Alzheimer’s disease, Parkinson’s disease, and brain cancer. We discuss the detrimental effects matrix metalloproteinases can have in these conditions, contributing to blood–brain barrier leakage, neuroinflammation, neurotoxicity, demyelination, tumor angiogenesis, and cancer metastasis. We also discuss the beneficial role matrix metalloproteinases can play in neuroprotection and anti-inflammation. Finally, we address matrix metalloproteinases as potential therapeutic targets. Together, in this comprehensive review, we summarize current understanding and knowledge of matrix metalloproteinases in the brain and at the blood–brain barrier in brain disorders. PMID:27323783

Airway inflammation in patients affected by obstructive sleep apnea syndrome.

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Salerno, F G; Carpagnano, E; Guido, P; Bonsignore, M R; Roberti, A; Aliani, M; Vignola, A M; Spanevello, A

2004-01-01

Obstructive sleep apnea syndrome (OSAS) has been shown to be associated to upper airway inflammation. The object of the present study was to establish the presence of bronchial inflammation in OSAS subjects. In 16 subjects affected by OSAS, and in 14 healthy volunteers, airway inflammation was detected by the cellular analysis of the induced sputum. OSAS patients, as compared to control subjects, showed a higher percentage of neutrophils (66.7+/-18.9 vs. 25.8+/-15.6) (Pbronchial inflammation characterized by a significant increase in neutrophils.

Selective estrogen receptor modulators as brain therapeutic agents

OpenAIRE

Arévalo, María Ángeles; Santos-Galindo, María; Lagunas, Natalia; Azcoitia, I.; García-Segura, Luis M.

2011-01-01

Selective estrogen receptor modulators (SERMs), used for the treatment of breast cancer, osteoporosis, and menopausal symptoms, affect the nervous system. Some SERMs trigger neuroprotective mechanisms and reduce neural damage in different experimental models of neural trauma, brain inflammation, neurodegenerative diseases, cognitive impairment, and affective disorders. New SERMs with specific actions on neurons and glial cells may represent promising therapeutic tools for the brain. © 2011 So...

MRI of idiopathic orbital inflammation and lymphoid disease with lesions in extraocular muscle

International Nuclear Information System (INIS)

Matsuda, Chiharu; Kotake, Fumio; Kawanishi, Masayuki; Saito, Kazuhiro; Abe, Kimihiko

2004-01-01

Of the disorders accompanied by hypertrophy of the extraocular muscles, differentiating between idiopathic orbital inflammation and malignant lymphoma is difficult but important to treatment and prognosis. In this study using MRI, shape, signal intensity, and enhancement effects were compared between idiopathic orbital inflammation and lymphoproliferative lesions. The subjects were 27 patients (8 with idiopathic orbital inflammation, 1 with reactive lymphoid hyperplasia, 3 with atypical lymphoid hyperplasia, and 15 with malignant lymphoma) and 10 normal controls. The evaluation items were: thickness of extraocular muscles, number of extraocular muscles involved signal intensity of extraocular muscles, and enhancement effects on extraocular muscles. When compared to control subjects (p<0.05) the attachment portion of extraocular muscles were significantly thicker in the patients with idiopathic orbital inflammation, atypical lymphoid hyperplasia, or malignant lymphoma; the most marked hypertrophy was observed in patients with malignant lymphoma. The number of extraocular muscles involved was 1.5 (mean) in the patients with idiopathic orbital inflammation, 1 in the patient with reactive lymphoid hyperplasia, 1.7 (mean) in the patients with atypical lymphoid hyperplasia, and 5.1 (mean) in those with malignant lymphoma. The signal intensity ratio on T1W-images did not significantly differ between the patients and controls for all the disorders investigated. Signal intensity ratio on T2W-images significantly differed between patients with atypical lymphoid hyperplasia or malignant lymphoma and the controls (p<0.05) but not between patients with idiopathic orbital inflammation and controls. Signal intensity ratio after contrast enhancement differed significantly only between patients with idiopathic orbital inflammation and controls (p<0.05). (author)

MRI-controlled interstitial ultrasound brain therapy: An initial in-vivo study

Science.gov (United States)

N'Djin, W. Apoutou; Burtnyk, Mathieu; Lipsman, Nir; Bronskill, Michael; Schwartz, Michael; Kucharczyk, Walter; Chopra, Rajiv

2012-11-01

The recent emergence at the clinical level of minimally-invasive focal therapy such as laser-induced thermal therapy (LITT) has demonstrated promise in the management of brain metastasis [1], although control over the spatial pattern of heating is limited. Delivery of HIFU from minimally-invasive applicators enables high spatial control of the heat deposition in biological tissues, large treatment volumes and high treatment rate in well chosen conditions [2,3]. In this study, the feasibility of MRI-guided interstitial ultrasound therapy in brain was studies in-vivo in a porcine model. A prototype system originally developed for transurethral ultrasound therapy [4,5,6] was used in this study. Two burr holes of 12 mm in diameter were created in the animal's skull to allow the insertion of the therapeutic ultrasound applicator (probe) into the brain at two locations (right and left frontal lobe). A 4-element linear ultrasound transducer (f = 8 MHz) was mounted at the tip of a 25-cm linear probe (6 mm in diameter). The target boundary was traced to cover in 2D a surface compatible with the treatment of a 2 cm brain tumor. Acoustic power of each element and rotation rate of the device were adjusted in real-time based on MR-thermometry feedback control to optimize heat deposition at the target boundary [2,4,5]. Two MRT-controlled ultrasound brain treatments per animal have been performed using a maximal surface acoustic power of 10W.cm-2. In all cases, it was possible to increase accurately the temperature of the brain tissues in the targeted region over the 55°C threshold necessary for the creation of irreversible thermal lesion. Tissue changes were visible on T1w contrast-enhanced images immediately after treatment. These changes were also evident on T2w FSE images taken 2 hours after the 1st treatment and correlated well with the temperature image. On average, the targeted volume was 4.7 ± 2.3 cm3 and the 55°C treated volume was 6.7 ± 4.4 cm3. The volumetric

[Brain repair after ischemic stroke: role of neurotransmitters in post-ischemic neurogenesis].

Science.gov (United States)

Sánchez-Mendoza, Eduardo; Bellver-Landete, Víctor; González, María Pilar; Merino, José Joaquín; Martínez-Murillo, Ricardo; Oset-Gasque, María Jesús

2012-11-01

Brain ischemia and reperfusion produce alterations in the microenvironment of the parenchyma, including ATP depletion, ionic homeostasis alterations, inflammation, release of multiple cytokines and abnormal release of neurotransmitters. As a consequence, the induction of proliferation and migration of neural stem cells towards the peri-infarct region occurs. The success of new neurorestorative treatments for damaged brain implies the need to know, with greater accuracy, the mechanisms in charge of regulating adult neurogenesis, both under physiological and pathological conditions. Recent evidence demonstrates that many neurotransmitters, glutamate in particular, control the subventricular zone, thus being part of the complex signalling network that influences the production of new neurons. Neurotransmitters provide a link between brain activity and subventricular zone neurogenesis. Therefore, a deeper knowledge of the role of neurotransmitters systems, such as glutamate and its transporters, in adult neurogenesis, may provide a valuable tool to be used as a neurorestorative therapy in this pathology.

Inhibition of Inflammation-Associated Olfactory Loss by Etanercept in an Inducible Olfactory Inflammation Mouse Model.

Science.gov (United States)

Jung, Yong Gi; Lane, Andrew P

2016-06-01

To determine the effect of a soluble human tumor necrosis factor alpha (TNF-α) receptor blocker (etanercept) on an inducible olfactory inflammation (IOI) mouse model. An in vivo study using a transgenic mouse model. Research laboratory. To study the impact of chronic inflammation on the olfactory system, a transgenic mouse model of chronic rhinosinusitis-associated olfactory loss was utilized (IOI mouse), expressing TNF-α in a temporally controlled fashion within the olfactory epithelium. In one group of mice (n = 4), etanercept was injected intraperitoneally (100 μg/dose, 3 times/week) concurrent with a 2-week period of TNF-α expression. A second group of mice (n = 2) underwent induction of TNF-α expression for 8 weeks, with etanercept treatment administered during the final 2 weeks of inflammation. Olfactory function was assayed by elecro-olfactogram (EOG), and olfactory tissue was processed for histology and immunohistochemical staining. Each group was compared with an equal-number control group. Compared with nontreated IOI mice, etanercept-treated IOI mice showed significantly improved EOG responses after 2 weeks (P loss of olfactory epithelium and no EOG response in nontreated IOI mice. However, in etanercept-treated mice, regeneration of olfactory epithelium was observed. Concomitant administration of etanercept in IOI mice results in interruption of TNF-α-induced olfactory loss and induction of neuroepithelial regeneration. This demonstrates that etanercept has potential utility as a tool for elucidating the role of TNF-α in other olfactory inflammation models. © American Academy of Otolaryngology—Head and Neck Surgery Foundation 2016.

Evidence for an inhibitory-control theory of the reasoning brain.

Science.gov (United States)

Houdé, Olivier; Borst, Grégoire

2015-01-01

In this article, we first describe our general inhibitory-control theory and, then, we describe how we have tested its specific hypotheses on reasoning with brain imaging techniques in adults and children. The innovative part of this perspective lies in its attempt to come up with a brain-based synthesis of Jean Piaget's theory on logical algorithms and Daniel Kahneman's theory on intuitive heuristics.

Region based Brain Computer Interface for a home control application.

Science.gov (United States)

Akman Aydin, Eda; Bay, Omer Faruk; Guler, Inan

2015-08-01

Environment control is one of the important challenges for disabled people who suffer from neuromuscular diseases. Brain Computer Interface (BCI) provides a communication channel between the human brain and the environment without requiring any muscular activation. The most important expectation for a home control application is high accuracy and reliable control. Region-based paradigm is a stimulus paradigm based on oddball principle and requires selection of a target at two levels. This paper presents an application of region based paradigm for a smart home control application for people with neuromuscular diseases. In this study, a region based stimulus interface containing 49 commands was designed. Five non-disabled subjects were attended to the experiments. Offline analysis results of the experiments yielded 95% accuracy for five flashes. This result showed that region based paradigm can be used to select commands of a smart home control application with high accuracy in the low number of repetitions successfully. Furthermore, a statistically significant difference was not observed between the level accuracies.

An Inflammation-Centric View of Neurological Disease: Beyond the Neuron

Directory of Open Access Journals (Sweden)

Stephen D. Skaper

2018-03-01

Full Text Available Inflammation is a complex biological response fundamental to how the body deals with injury and infection to eliminate the initial cause of cell injury and effect repair. Unlike a normally beneficial acute inflammatory response, chronic inflammation can lead to tissue damage and ultimately its destruction, and often results from an inappropriate immune response. Inflammation in the nervous system (“neuroinflammation”, especially when prolonged, can be particularly injurious. While inflammation per se may not cause disease, it contributes importantly to disease pathogenesis across both the peripheral (neuropathic pain, fibromyalgia and central [e.g., Alzheimer disease, Parkinson disease, multiple sclerosis, motor neuron disease, ischemia and traumatic brain injury, depression, and autism spectrum disorder] nervous systems. The existence of extensive lines of communication between the nervous system and immune system represents a fundamental principle underlying neuroinflammation. Immune cell-derived inflammatory molecules are critical for regulation of host responses to inflammation. Although these mediators can originate from various non-neuronal cells, important sources in the above neuropathologies appear to be microglia and mast cells, together with astrocytes and possibly also oligodendrocytes. Understanding neuroinflammation also requires an appreciation that non-neuronal cell—cell interactions, between both glia and mast cells and glia themselves, are an integral part of the inflammation process. Within this context the mast cell occupies a key niche in orchestrating the inflammatory process, from initiation to prolongation. This review will describe the current state of knowledge concerning the biology of neuroinflammation, emphasizing mast cell-glia and glia-glia interactions, then conclude with a consideration of how a cell's endogenous mechanisms might be leveraged to provide a therapeutic strategy to target neuroinflammation.

Integrative Analysis of Disease Signatures Shows Inflammation Disrupts Juvenile Experience-Dependent Cortical Plasticity

Science.gov (United States)

Smith, Milo R.; Burman, Poromendro

2016-01-01

Throughout childhood and adolescence, periods of heightened neuroplasticity are critical for the development of healthy brain function and behavior. Given the high prevalence of neurodevelopmental disorders, such as autism, identifying disruptors of developmental plasticity represents an essential step for developing strategies for prevention and intervention. Applying a novel computational approach that systematically assessed connections between 436 transcriptional signatures of disease and multiple signatures of neuroplasticity, we identified inflammation as a common pathological process central to a diverse set of diseases predicted to dysregulate plasticity signatures. We tested the hypothesis that inflammation disrupts developmental cortical plasticity in vivo using the mouse ocular dominance model of experience-dependent plasticity in primary visual cortex. We found that the administration of systemic lipopolysaccharide suppressed plasticity during juvenile critical period with accompanying transcriptional changes in a particular set of molecular regulators within primary visual cortex. These findings suggest that inflammation may have unrecognized adverse consequences on the postnatal developmental trajectory and indicate that treating inflammation may reduce the burden of neurodevelopmental disorders. PMID:28101530

Mindcontrol: A web application for brain segmentation quality control.

Science.gov (United States)

Keshavan, Anisha; Datta, Esha; M McDonough, Ian; Madan, Christopher R; Jordan, Kesshi; Henry, Roland G

2018-04-15

Tissue classification plays a crucial role in the investigation of normal neural development, brain-behavior relationships, and the disease mechanisms of many psychiatric and neurological illnesses. Ensuring the accuracy of tissue classification is important for quality research and, in particular, the translation of imaging biomarkers to clinical practice. Assessment with the human eye is vital to correct various errors inherent to all currently available segmentation algorithms. Manual quality assurance becomes methodologically difficult at a large scale - a problem of increasing importance as the number of data sets is on the rise. To make this process more efficient, we have developed Mindcontrol, an open-source web application for the collaborative quality control of neuroimaging processing outputs. The Mindcontrol platform consists of a dashboard to organize data, descriptive visualizations to explore the data, an imaging viewer, and an in-browser annotation and editing toolbox for data curation and quality control. Mindcontrol is flexible and can be configured for the outputs of any software package in any data organization structure. Example configurations for three large, open-source datasets are presented: the 1000 Functional Connectomes Project (FCP), the Consortium for Reliability and Reproducibility (CoRR), and the Autism Brain Imaging Data Exchange (ABIDE) Collection. These demo applications link descriptive quality control metrics, regional brain volumes, and thickness scalars to a 3D imaging viewer and editing module, resulting in an easy-to-implement quality control protocol that can be scaled for any size and complexity of study. Copyright © 2017 The Authors. Published by Elsevier Inc. All rights reserved.

Proinflammatory Adhesion Molecules Facilitate Polychlorinated Biphenyl–Mediated Enhancement of Brain Metastasis Formation

OpenAIRE

Sipos, Eszter; Chen, Lei; András, Ibolya E.; Wrobel, Jagoda; Zhang, Bei; Pu, Hong; Park, Minseon; Eum, Sung Yong; Toborek, Michal

2012-01-01

Polychlorinated biphenyls (PCBs) are environmental toxicants that cause vascular inflammation and facilitate the development of brain metastases. The crucial event in metastasis formation is adhesion of blood-borne tumor cells to the vascular endothelium, followed by their transcapillary migration. The aim of the present study was to examine the mechanisms of PCB118-induced brain metastasis formation at the blood-brain barrier level with the focus on tumor cell adhesion to the brain endotheli...

Early Intravenous Delivery of Human Brain Stromal Cells Modulates Systemic Inflammation and Leads to Vasoprotection in Traumatic Spinal Cord Injury.

Science.gov (United States)

Badner, Anna; Vawda, Reaz; Laliberte, Alex; Hong, James; Mikhail, Mirriam; Jose, Alejandro; Dragas, Rachel; Fehlings, Michael

2016-08-01

: Spinal cord injury (SCI) is a life-threatening condition with multifaceted complications and limited treatment options. In SCI, the initial physical trauma is closely followed by a series of secondary events, including inflammation and blood spinal cord barrier (BSCB) disruption, which further exacerbate injury. This secondary pathology is partially mediated by the systemic immune response to trauma, in which cytokine production leads to the recruitment/activation of inflammatory cells. Because early intravenous delivery of mesenchymal stromal cells (MSCs) has been shown to mitigate inflammation in various models of neurologic disease, this study aimed to assess these effects in a rat model of SCI (C7-T1, 35-gram clip compression) using human brain-derived stromal cells. Quantitative polymerase chain reaction for a human-specific DNA sequence was used to assess cell biodistribution/clearance and confirmed that only a small proportion (approximately 0.001%-0.002%) of cells are delivered to the spinal cord, with the majority residing in the lung, liver, and spleen. Intriguingly, although cell populations drastically declined in all aforementioned organs, there remained a persistent population in the spleen at 7 days. Furthermore, the cell infusion significantly increased splenic and circulating levels of interleukin-10-a potent anti-inflammatory cytokine. Through this suppression of the systemic inflammatory response, the cells also reduced acute spinal cord BSCB permeability, hemorrhage, and lesion volume. These early effects further translated into enhanced functional recovery and tissue sparing 10 weeks after SCI. This work demonstrates an exciting therapeutic approach whereby a minimally invasive cell-transplantation procedure can effectively reduce secondary damage after SCI through systemic immunomodulation. Central nervous system pericytes (perivascular stromal cells) have recently gained significant attention within the scientific community. In addition to

Cobalt-55 positron emission tomography in traumatic brain injury : A pilot study

NARCIS (Netherlands)

Jansen, HML; vanderNaalt, J; vanZomeren, AH; Paans, AMJ; VeenmavanderDuin, L; Hew, JM; Pruim, J; Minderhoud, JM; Korf, J

Traumatic brain injury is usually assessed with the Glasgow coma scale (GCS), CT, or MRI. After such injury, the injured brain tissue is characterised by calcium mediated neuronal damage and inflammation. Positron emission tomography with the isotope cobalt-55 (Go-PET) as a calcium tracer enables

Comparisons of [18F]-1-deoxy-1-fluoro-scyllo-inositol with [18F]-FDG for PET imaging of inflammation, breast and brain cancer xenografts in athymic mice

International Nuclear Information System (INIS)

McLarty, Kristin; Moran, Matthew D.; Scollard, Deborah A.; Chan, Conrad; Sabha, Nesrin; Mukherjee, Joydeep; Guha, Abhijit; McLaurin, JoAnne; Nitz, Mark; Houle, Sylvain; Wilson, Alan A.; Reilly, Raymond M.; Vasdev, Neil

2011-01-01

Introduction: The aim of the study was to evaluate the uptake of [ 18 F]-1-deoxy-1-fluoro-scyllo-inositol ([ 18 F]-scyllo-inositol) in human breast cancer (BC) and glioma xenografts, as well as in inflammatory tissue, in immunocompromised mice. Studies of [ 18 F]-2-fluoro-2-deoxy-D-glucose ([ 18 F]-FDG) under the same conditions were also performed. Methods: Radiosynthesis of [ 18 F]-scyllo-inositol was automated using a commercial synthesis module. Tumour, inflammation and normal tissue uptakes were evaluated by biodistribution studies and positron emission tomography (PET) imaging using [ 18 F]-scyllo-inositol and [ 18 F]-FDG in mice bearing subcutaneous MDA-MB-231, MCF-7 and MDA-MB-361 human BC xenografts, intracranial U-87 MG glioma xenografts and turpentine-induced inflammation. Results: The radiosynthesis of [ 18 F]-scyllo-inositol was automated with good radiochemical yields (24.6%±3.3%, uncorrected for decay, 65±2 min, n=5) and high specific activities (≥195 GBq/μmol at end of synthesis). Uptake of [ 18 F]-scyllo-inositol was greatest in MDA-MB-231 BC tumours and was comparable to that of [ 18 F]-FDG (4.6±0.5 vs. 5.5±2.1 %ID/g, respectively; P=.40), but was marginally lower in MDA-MB-361 and MCF-7 xenografts. Uptake of [ 18 F]-scyllo-inositol in inflammation was lower than [ 18 F]-FDG. While uptake of [ 18 F]-scyllo-inositol in intracranial U-87 MG xenografts was significantly lower than [ 18 F]-FDG, the tumour-to-brain ratio was significantly higher (10.6±2.5 vs. 2.1±0.6; P=.001). Conclusions: Consistent with biodistribution studies, uptake of [ 18 F]-scyllo-inositol was successfully visualized by PET imaging in human BC and glioma xenografts, with lower accumulation in inflammatory tissue than [ 18 F]-FDG. The tumour-to-brain ratio of [ 18 F]-scyllo-inositol was also significantly higher than that of [ 18 F]-FDG for visualizing intracranial glioma xenografts in NOD SCID mice, giving a better contrast. -- Graphical Abstract: Display Omitted

Suppression of Th17-polarized airway inflammation by rapamycin.

Science.gov (United States)

Joean, Oana; Hueber, Anja; Feller, Felix; Jirmo, Adan Chari; Lochner, Matthias; Dittrich, Anna-Maria; Albrecht, Melanie

2017-11-10

Because Th17-polarized airway inflammation correlates with poor control in bronchial asthma and is a feature of numerous other difficult-to-treat inflammatory lung diseases, new therapeutic approaches for this type of airway inflammation are necessary. We assessed different licensed anti-inflammatory agents with known or expected efficacy against Th17-polarization in mouse models of Th17-dependent airway inflammation. Upon intravenous transfer of in vitro derived Th17 cells and intranasal challenge with the corresponding antigen, we established acute and chronic murine models of Th17-polarised airway inflammation. Consecutively, we assessed the efficacy of methylprednisolone, roflumilast, azithromycin, AM80 and rapamycin against acute or chronic Th17-dependent airway inflammation. Quantifiers for Th17-associated inflammation comprised: bronchoalveolar lavage (BAL) differential cell counts, allergen-specific cytokine and immunoglobulin secretion, as well as flow cytometric phenotyping of pulmonary inflammatory cells. Only rapamycin proved effective against acute Th17-dependent airway inflammation, accompanied by increased plasmacytoid dendritic cells (pDCs) and reduced neutrophils as well as reduced CXCL-1 levels in BAL. Chronic Th17-dependent airway inflammation was unaltered by rapamycin treatment. None of the other agents showed efficacy in our models. Our results demonstrate that Th17-dependent airway inflammation is difficult to treat with known agents. However, we identify rapamycin as an agent with inhibitory potential against acute Th17-polarized airway inflammation.

Self-reported parenting style is associated with children's inflammation and immune activation.

Science.gov (United States)

Byrne, Michelle L; Badcock, Paul B; Simmons, Julian G; Whittle, Sarah; Pettitt, Adam; Olsson, Craig A; Mundy, Lisa K; Patton, George C; Allen, Nicholas B

2017-04-01

Family environments and parenting have been associated with inflammation and immune activation in children and adolescents; however, it remains unclear which specific aspects of parenting drive this association. In this study, we cross-sectionally examined the association between 5 discrete parenting styles and inflammation and immune activation in late childhood. Data were drawn from 102 families (55 with female children, mean age 9.50 years, SD = 0.34) participating in the Imaging Brain Development in the Childhood to Adolescence Transition Study. Children provided saliva samples from which inflammation (C-reactive protein) and immune competence/activation (secretory immunoglobulin A) were measured. Parents completed the Alabama Parenting Questionnaire, which measures 5 aspects of parenting style-positive parental involvement, positive disciplinary techniques, consistency in disciplinary techniques, corporal punishment, and monitoring and supervision. Results showed that higher scores on the poor parental monitoring scale were associated with higher levels of both inflammation and immune activation in children. This study highlights parental monitoring and supervision as a specific aspect of parenting behavior that may be important for children's physical and mental health. (PsycINFO Database Record (c) 2017 APA, all rights reserved).

Controlled release of celecoxib inhibits inflammation, bone cysts and osteophyte formation in a preclinical model of osteoarthritis.

Science.gov (United States)

Tellegen, A R; Rudnik-Jansen, I; Pouran, B; de Visser, H M; Weinans, H H; Thomas, R E; Kik, M J L; Grinwis, G C M; Thies, J C; Woike, N; Mihov, G; Emans, P J; Meij, B P; Creemers, L B; Tryfonidou, M A

2018-11-01

Major hallmarks of osteoarthritis (OA) are cartilage degeneration, inflammation and osteophyte formation. COX-2 inhibitors counteract inflammation-related pain, but their prolonged oral use entails the risk for side effects. Local and prolonged administration in biocompatible and degradable drug delivery biomaterials could offer an efficient and safe treatment for the long-term management of OA symptoms. Therefore, we evaluated the disease-modifying effects and the optimal dose of polyesteramide microspheres delivering the COX-2 inhibitor celecoxib in a rat OA model. Four weeks after OA induction by anterior cruciate ligament transection and partial medial meniscectomy, 8-week-old female rats (n = 6/group) were injected intra-articular with celecoxib-loaded microspheres at three dosages (0.03, 0.23 or 0.39 mg). Unloaded microspheres served as control. During the 16-week follow-up, static weight bearing and plasma celecoxib concentrations were monitored. Post-mortem, micro-computed tomography and knee joint histology determined progression of synovitis, osteophyte formation, subchondral bone changes, and cartilage integrity. Systemic celecoxib levels were below the detection limit 6 days upon delivery. Systemic and local adverse effects were absent. Local delivery of celecoxib reduced the formation of osteophytes, subchondral sclerosis, bone cysts and calcified loose bodies, and reduced synovial inflammation, while cartilage histology was unaffected. Even though the effects on pain could not be evualated directly in the current model, our results suggest the application of celecoxib-loaded microspheres holds promise as novel, safe and effective treatment for inflammation and pain in OA.

Ethanol extracts from Portulaca oleracea L. attenuated ischemia/reperfusion induced rat neural injury through inhibition of HMGB1 induced inflammation

Science.gov (United States)

Zheng, Chenggang; Liu, Chen; Wang, Wanyin; Tang, Gusheng; Dong, Liwei; Zhou, Juan; Zhong, Zhengrong

2016-01-01

It is well demonstrated that the high mobility group box 1 (HMGB1) mediated inflammation has been implicated as one of the important causes for brain damage induced by cerebral ischemia/reperfusion (I/R). In the present study, we assessed the neuro-protective and anti-inflammation effects of the ethanol extracts from Portulaca oleracea L. (EEPO) against cerebral I/R injury in the rat transient middle cerebral artery occlusion (tMCAO) model. Rats were administrated with their respective treatment for 7 days before the MCA occlusion. After that, rats were intraperitoneal injection with chloral hydrate and sacrificed by decapitation, then the serum and brain tissue were collected. The neurological deficit score, infarct size and brain edema were tested. The levels of serum cytokine as TNF-α, IL-1β, INF-γ, IL-6, and HMGB1 and LDH were detected. The protein level of tissue or nucleus HMGB1, IκB and p-p65 were tested, too. The results showed that pretreatment with EEPO significantly decreased the neurological deficit score, infarct size and brain edema. Moreover, EEPO decreased rat serum cytokine level and rat right cortices p-p65 and IκB protein level. In conclusion all these results suggested that pretreatment with EEFPO provided significant protection against cerebral I/R injury in rats might by virtue of its anti-inflammation property through inhibition of increase of neuleus HMGB1. PMID:27904702

Airway inflammation in Japanese COPD patients compared with smoking and nonsmoking controls

Science.gov (United States)

Ishikawa, Nobuhisa; Hattori, Noboru; Kohno, Nobuoki; Kobayashi, Akihiro; Hayamizu, Tomoyuki; Johnson, Malcolm

2015-01-01

Purpose To assess the importance of inflammation in chronic obstructive pulmonary disease (COPD) by measuring airway and systemic inflammatory biomarkers in Japanese patients with the disease and relevant control groups. Patients and methods This was the first study of its type in Japanese COPD patients. It was a non-treatment study in which 100 participants were enrolled into one of three groups: nonsmoking controls, current or ex-smoking controls, and COPD patients. All participants underwent standard lung function assessments and provided sputum and blood samples from which the numbers of inflammatory cells and concentrations of biomarkers were measured, using standard procedures. Results The overall trends observed in levels of inflammatory cells and biomarkers in sputum and blood in COPD were consistent with previous reports in Western studies. Increasing levels of neutrophils, interleukin 8 (IL-8), surfactant protein D (SP-D), and Krebs von den Lungen 6 (KL-6) in sputum and clara cell 16 (CC-16), high-sensitivity C-reactive protein (hs-CRP), and KL-6 in serum and plasma fibrinogen were seen in the Japanese COPD patients compared with the non-COPD control participants. In sputum, significant correlations were seen between total cell count and matrix metalloproteinase 9 (MMP-9; Pbenefit in disease management of COPD in Japan. PMID:25670894

No mediating effects of glycemic control and inflammation on the association between vitamin D and lung function in the general population.

Science.gov (United States)

Kaul, Anne; Gläser, Sven; Hannemann, Anke; Stubbe, Beate; Felix, Stefan B; Nauck, Matthias; Ewert, Ralf; Friedrich, Nele

2017-04-01

Vitamin D deficiency is discussed to be associated with lung health. While former studies focused on subjects suffering from pulmonary diseases, we aimed to investigate the association of 25-hydroxy vitamin D [25(OH)D] with lung function in the general population and examined whether mediating effects of inflammation, glycemic control or renal function exist. 1404 participants from the Study of Health in Pomerania with pulmonary function testing assessed by expiratory volume in 1 s (FEV 1 ), forced vital capacity (FVC), total lung capacity and Krogh index were used. Adjusted analysis of variance, linear regression models and mediation analyses were performed. Significant positive associations between 25(OH)D levels and FEV 1 , FVC and Krogh index were found. Mediator analyses revealed no mediating effect of inflammation (fibrinogen), glycemic control (HbA1c) or renal function (eGFR) on associations with FEV 1 or FVC. With respect to Krogh-Index, the association to 25(OH)D was slightly mediated by fibrinogen with a proportion mediated of 9.7%. Significant positive associations of 25(OH)D with lung function were revealed in a general population. The proposed mediating effects of inflammation, glycemic control and renal function on these relations were not confirmed. Further studies examining the causality of the association between 25(OH)D and lung function are necessary. Copyright © 2017 Elsevier Ltd. All rights reserved.

Low-dose memantine attenuated morphine addictive behavior through its anti-inflammation and neurotrophic effects in rats.

Science.gov (United States)

Chen, Shiou-Lan; Tao, Pao-Luh; Chu, Chun-Hsien; Chen, Shih-Heng; Wu, Hsiang-En; Tseng, Leon F; Hong, Jau-Shyong; Lu, Ru-Band

2012-06-01

Opioid abuse and dependency are international problems. Studies have shown that neuronal inflammation and degeneration might be related to the development of opioid addiction. Thus, using neuroprotective agents might be beneficial for treating opioid addiction. Memantine, an Alzheimer's disease medication, has neuroprotective effects in vitro and in vivo. In this study, we evaluated whether a low dose of memantine prevents opioid-induced drug-seeking behavior in rats and analyzed its mechanism. A conditioned-place-preference test was used to investigate the morphine-induced drug-seeking behaviors in rats. We found that a low-dose (0.2-1 mg/kg) of subcutaneous memantine significantly attenuated the chronic morphine-induced place-preference in rats. To clarify the effects of chronic morphine and low-dose memantine, serum and brain levels of cytokines and brain-derived neurotrophic factor (BDNF) were measured. After 6 days of morphine treatment, cytokine (IL-1β, IL-6) levels had significantly increased in serum; IL-1β and IL-6 mRNA levels had significantly increased in the nucleus accumbens and medial prefrontal cortex, both addiction-related brain areas; and BDNF levels had significantly decreased, both in serum and in addiction-related brain areas. Pretreatment with low-dose memantine significantly attenuated chronic morphine-induced increases in serum and brain cytokines. Low-dose memantine also significantly potentiated serum and brain BDNF levels. We hypothesize that neuronal inflammation and BDNF downregulation are related to the progression of opioid addiction. We hypothesize that the mechanism low-dose memantine uses to attenuate morphine-induced addiction behavior is its anti-inflammatory and neurotrophic effects.

Homeostasis, inflammation, and disease susceptibility.

Science.gov (United States)

Kotas, Maya E; Medzhitov, Ruslan

2015-02-26

While modernization has dramatically increased lifespan, it has also witnessed the increasing prevalence of diseases such as obesity, hypertension, and type 2 diabetes. Such chronic, acquired diseases result when normal physiologic control goes awry and may thus be viewed as failures of homeostasis. However, while nearly every process in human physiology relies on homeostatic mechanisms for stability, only some have demonstrated vulnerability to dysregulation. Additionally, chronic inflammation is a common accomplice of the diseases of homeostasis, yet the basis for this connection is not fully understood. Here we review the design of homeostatic systems and discuss universal features of control circuits that operate at the cellular, tissue, and organismal levels. We suggest a framework for classification of homeostatic signals that is based on different classes of homeostatic variables they report on. Finally, we discuss how adaptability of homeostatic systems with adjustable set points creates vulnerability to dysregulation and disease. This framework highlights the fundamental parallels between homeostatic and inflammatory control mechanisms and provides a new perspective on the physiological origin of inflammation. Copyright © 2015 Elsevier Inc. All rights reserved.

Omics-Based Approach Reveals Complement-Mediated Inflammation in Chronic Lymphocytic Inflammation With Pontine Perivascular Enhancement Responsive to Steroids (CLIPPERS

Directory of Open Access Journals (Sweden)

Morten Blaabjerg

2018-04-01

Full Text Available ObjectiveChronic lymphocytic inflammation with pontine perivascular enhancement responsive to steroids (CLIPPERS is a rare syndrome with relapsing brainstem/cerebellar symptoms. To examine the pathogenic processes and investigate potential biomarkers, we analyzed combined materials of brain and cerebrospinal fluid (CSF by comprehensive methodologies.Materials and methodsTo identify major pathways of perivascular inflammation in CLIPPERS, we first compared the CSF proteome (n = 5 to a neurodegenerative condition, Alzheimer’s disease (AD, n = 5. Activation of complement was confirmed by immunohistochemistry (IHC on CLIPPERS brain samples (n = 3 and by ELISA in the CSF. For potential biomarkers, we used biomarker arrays, and compared inflammatory and vessel-associated proteins in the CSF of CLIPPERS (n = 5 with another inflammatory relapsing CNS disease, multiple sclerosis (RMS, n = 9 and healthy subjects (HS, n = 7.ResultsTwo hundred and seven proteins in the CSF discriminated CLIPPERS from AD. The complement cascade, immunoglobulins, and matrix proteins were among the most frequently represented pathways. Pathway analysis of upstream regulators suggested the importance of vascular cell adhesion protein 1 (VCAM1, IFN-γ, interleukin (IL-1, and IL-10. Differential regulation of more than 10 complement proteins of the 3 complement pathways in the CSF pointed to the role of complement activation. IHC on brain samples confirmed the perivascular complement activation, i.e., deposition of C3bc, C3d, and the terminal C5b-9 complement complex that partially overlapped with accumulation of IgG in the vessel wall. Besides endothelial cell damage, reactivity to smooth muscle actin was lost in the walls of inflamed vessels, but the glia limitans was preserved. The semi-quantitative array indicated that increased level of IL-8/CXCL8 (p < 0.05, eotaxin/CCL11 (p < 0.01, and granulocyte colony-stimulating factor (p < 0.05 in

Seizure Control and Memory Impairment Are Related to Disrupted Brain Functional Integration in Temporal Lobe Epilepsy.

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Park, Chang-Hyun; Choi, Yun Seo; Jung, A-Reum; Chung, Hwa-Kyoung; Kim, Hyeon Jin; Yoo, Jeong Hyun; Lee, Hyang Woon

2017-01-01

Brain functional integration can be disrupted in patients with temporal lobe epilepsy (TLE), but the clinical relevance of this disruption is not completely understood. The authors hypothesized that disrupted functional integration over brain regions remote from, as well as adjacent to, the seizure focus could be related to clinical severity in terms of seizure control and memory impairment. Using resting-state functional MRI data acquired from 48 TLE patients and 45 healthy controls, the authors mapped functional brain networks and assessed changes in a network parameter of brain functional integration, efficiency, to examine the distribution of disrupted functional integration within and between brain regions. The authors assessed whether the extent of altered efficiency was influenced by seizure control status and whether the degree of altered efficiency was associated with the severity of memory impairment. Alterations in the efficiency were observed primarily near the subcortical region ipsilateral to the seizure focus in TLE patients. The extent of regional involvement was greater in patients with poor seizure control: it reached the frontal, temporal, occipital, and insular cortices in TLE patients with poor seizure control, whereas it was limited to the limbic and parietal cortices in TLE patients with good seizure control. Furthermore, TLE patients with poor seizure control experienced more severe memory impairment, and this was associated with lower efficiency in the brain regions with altered efficiency. These findings indicate that the distribution of disrupted brain functional integration is clinically relevant, as it is associated with seizure control status and comorbid memory impairment.

Cerebral control and survival after stereotactic radiotherapy of brain metastases

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Arnold, Elmar Till

2014-01-01

This retrospective study, including 275 patients who underwent stereotactic radiotherapy due to brain metastases between 2003 and 2008, investigates influencing factors regarding cerebral control and survival, symptomatic effects and a potential benefit for patients older than 70 years. We were able to identify risk factors for remote brain failure which leads to a therapeutic recommendation. Furthermore we confirm a positive symptomatic effect and a benefit of stereotactic readiotherapy for patients over 70 years.

The Sputum Colour Chart as a predictor of lung inflammation, proteolysis and damage in non-cystic fibrosis bronchiectasis: a case-control analysis.

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Goeminne, Pieter C; Vandooren, Jennifer; Moelants, Eva A; Decraene, Ann; Rabaey, Evelyn; Pauwels, Ans; Seys, Sven; Opdenakker, Ghislain; Proost, Paul; Dupont, Lieven J

2014-02-01

Non-cystic fibrosis bronchiectasis (NCFB) is characterized by a vicious cycle of airway infection, inflammation and structural damage with inappropriate mucus clearance. Our aim was to relate the value of proteolytic enzymes, proteolytic enzyme activity and inflammatory markers to disease severity and symptoms in patients with NCFB. Sputum induction in NCFB patients and healthy controls was performed. Sputum was analysed for total and differential cell count, markers of inflammation (CXCL8 (also known as interleukin-8) and tumour necrosis factor-α (TNF-α)) and proteolytic enzymes (neutrophil elastase (NE), gelatin zymography and total gelatinolytic activity (TGA)). Each patient was evaluated by spirometry, Leicester Cough Questionnaire (LCQ) and Sputum Colour Chart (SCC). Patient files were analysed to determine Pseudomonas aeruginosa colonization status. The computed tomography (CT) closest to the date sputum induction was scored by a radiologist. NCFB patients showed significantly higher neutrophils, CXCL8, TNF-α, NE and TGA than healthy controls. TGA subanalysis showed that the majority of the activity was NE (82 ± 6.4%). Residual activity was mainly zinc ion-dependent matrix metalloproteinase (MMP) activity (18 ± 6.4%). Subanalysis showed that patients with chronic Pseudomonas aeruginosa colonization had more activated MMP-9. Correlations were seen between proteolytic enzymes and inflammation and disease severity (spirometry and CT score), but not with the LCQ. SCC was associated with increased markers of inflammation, proteolytic enzymes and worse CT score. We show that sputum purulence assessment in daily clinical practice using the SCC is a quick and easy tool that reflects severity of inflammation, destruction and proteolytic enzymatic activity/presence. © 2013 The Authors. Respirology © 2013 Asian Pacific Society of Respirology.

Inflammatory cause of metabolic syndrome via brain stress and NF-κB

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Cai, Dongsheng; Liu, Tiewen

2012-01-01

Metabolic syndrome, a network of medical disorders that greatly increase the risk for developing metabolic and cardiovascular diseases, has reached epidemic levels in many areas of today's world. Despite this alarming medicare situation, scientific understandings on the root mechanisms of metabolic syndrome are still limited, and such insufficient knowledge contributes to the relative lack of effective treatments or preventions for related diseases. Recent interdisciplinary studies from neuroendocrinology and neuroimmunology fields have revealed that overnutrition can trigger intracellular stresses to cause inflammatory changes mediated by molecules that control innate immunity. This type of nutrition-related molecular inflammation in the central nervous system, particularly in the hypothalamus, can form a common pathogenic basis for the induction of various metabolic syndrome components such as obesity, insulin resistance, and hypertension. Proinflammatory NF-κB pathway has been revealed as a key molecular system for pathologic induction of brain inflammation, which translates overnutrition and resulting intracellular stresses into central neuroendocrine and neural dysregulations of energy, glucose, and cardiovascular homeostasis, collectively leading to metabolic syndrome. This article reviews recent research advances in the neural mechanisms of metabolic syndrome and related diseases from the perspective of pathogenic induction by intracellular stresses and NF-κB pathway of the brain. PMID:22328600

Cognitive control of drug craving inhibits brain reward regions in cocaine abusers

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Volkow, N.D.; Fowler, J.; Wang, G.J.; Telang, F.; Logan, J.; Jayne, M.; Ma, Y.; Pradhan, K.; Wong, C.T.; Swanson, J.M.

2010-01-01

Loss of control over drug taking is considered a hallmark of addiction and is critical in relapse. Dysfunction of frontal brain regions involved with inhibitory control may underlie this behavior. We evaluated whether addicted subjects when instructed to purposefully control their craving responses to drug-conditioned stimuli can inhibit limbic brain regions implicated in drug craving. We used PET and 2-deoxy-2[18F]fluoro-D-glucose to measure brain glucose metabolism (marker of brain function) in 24 cocaine abusers who watched a cocaine-cue video and compared brain activation with and without instructions to cognitively inhibit craving. A third scan was obtained at baseline (without video). Statistical parametric mapping was used for analysis and corroborated with regions of interest. The cocaine-cue video increased craving during the no-inhibition condition (pre 3 ± 3, post 6 ± 3; p < 0.001) but not when subjects were instructed to inhibit craving (pre 3 ± 2, post 3 ± 3). Comparisons with baseline showed visual activation for both cocaine-cue conditions and limbic inhibition (accumbens, orbitofrontal, insula, cingulate) when subjects purposefully inhibited craving (p < 0.001). Comparison between cocaine-cue conditions showed lower metabolism with cognitive inhibition in right orbitofrontal cortex and right accumbens (p < 0.005), which was associated with right inferior frontal activation (r = -0.62, p < 0.005). Decreases in metabolism in brain regions that process the predictive (nucleus accumbens) and motivational value (orbitofrontal cortex) of drug-conditioned stimuli were elicited by instruction to inhibit cue-induced craving. This suggests that cocaine abusers may retain some ability to inhibit craving and that strengthening fronto-accumbal regulation may be therapeutically beneficial in addiction.

Cognitive control of drug craving inhibits brain reward regions in cocaine abusers

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Volkow, N.D.; Fowler, J.; Wang, G.J.; Telang, F.; Logan, J.; Jayne, M.; Ma, Y.; Pradhan, K.; Wong, C.T.; Swanson, J.M.

2010-01-01

Loss of control over drug taking is considered a hallmark of addiction and is critical in relapse. Dysfunction of frontal brain regions involved with inhibitory control may underlie this behavior. We evaluated whether addicted subjects when instructed to purposefully control their craving responses to drug-conditioned stimuli can inhibit limbic brain regions implicated in drug craving. We used PET and 2-deoxy-2[18F]fluoro-D-glucose to measure brain glucose metabolism (marker of brain function) in 24 cocaine abusers who watched a cocaine-cue video and compared brain activation with and without instructions to cognitively inhibit craving. A third scan was obtained at baseline (without video). Statistical parametric mapping was used for analysis and corroborated with regions of interest. The cocaine-cue video increased craving during the no-inhibition condition (pre 3 {+-} 3, post 6 {+-} 3; p < 0.001) but not when subjects were instructed to inhibit craving (pre 3 {+-} 2, post 3 {+-} 3). Comparisons with baseline showed visual activation for both cocaine-cue conditions and limbic inhibition (accumbens, orbitofrontal, insula, cingulate) when subjects purposefully inhibited craving (p < 0.001). Comparison between cocaine-cue conditions showed lower metabolism with cognitive inhibition in right orbitofrontal cortex and right accumbens (p < 0.005), which was associated with right inferior frontal activation (r = -0.62, p < 0.005). Decreases in metabolism in brain regions that process the predictive (nucleus accumbens) and motivational value (orbitofrontal cortex) of drug-conditioned stimuli were elicited by instruction to inhibit cue-induced craving. This suggests that cocaine abusers may retain some ability to inhibit craving and that strengthening fronto-accumbal regulation may be therapeutically beneficial in addiction.

Intrauterine infection/inflammation during pregnancy and offspring brain damages: Possible mechanisms involved

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Golan Hava

2004-04-01

Full Text Available Abstract Intrauterine infection is considered as one of the major maternal insults during pregnancy. Intrauterine infection during pregnancy could lead to brain damage of the developmental fetus and offspring. Effects on the fetal, newborn, and adult central nervous system (CNS may include signs of neurological problems, developmental abnormalities and delays, and intellectual deficits. However, the mechanisms or pathophysiology that leads to permanent brain damage during development are complex and not fully understood. This damage may affect morphogenic and behavioral phenotypes of the developed offspring, and that mice brain damage could be mediated through a final common pathway, which includes over-stimulation of excitatory amino acid receptor, over-production of vascularization/angiogenesis, pro-inflammatory cytokines, neurotrophic factors and apoptotic-inducing factors.

MICROGLIA ACTIVATION AS A BIOMARKER FOR TRAUMATIC BRAIN INJURY

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Diana G Hernadez-Ontiveros

2013-03-01

Full Text Available Traumatic brain injury (TBI has become the signature wound of wars in Afghanistan and Iraq. Injury may result from a mechanical force, a rapid acceleration-deceleration movement, or a blast wave. A cascade of secondary cell death events ensues after the initial injury. In particular, multiple inflammatory responses accompany TBI. A series of inflammatory cytokines and chemokines spreads to normal brain areas juxtaposed to the core impacted tissue. Among the repertoire of immune cells involved, microglia is a key player in propagating inflammation to tissues neighboring the core site of injury. Neuroprotective drug trials in TBI have failed, likely due to their sole focus on abrogating neuronal cell death and ignoring the microglia response despite these inflammatory cells’ detrimental effects on the brain. Another relevant point to consider is the veracity of results of animal experiments due to deficiencies in experimental design, such as incomplete or inadequate method description, data misinterpretation and reporting may introduce bias and give false-positive results. Thus, scientific publications should follow strict guidelines that include randomization, blinding, sample-size estimation and accurate handling of all data (Landis et al., 2012. A prolonged state of inflammation after brain injury may linger for years and predispose patients to develop other neurological disorders, such as Alzheimer’s disease. TBI patients display progressive and long-lasting impairments in their physical, cognitive, behavioral, and social performance. Here, we discuss inflammatory mechanisms that accompany TBI in an effort to increase our understanding of the dynamic pathological condition as the disease evolves over time and begin to translate these findings for defining new and existing inflammation-based biomarkers and treatments for TBI.

Cold stress-induced brain injury regulates TRPV1 channels and the PI3K/AKT signaling pathway.

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Liu, Ying; Liu, Yunen; Jin, Hongxu; Cong, Peifang; Zhang, Yubiao; Tong, Changci; Shi, Xiuyun; Liu, Xuelei; Tong, Zhou; Shi, Lin; Hou, Mingxiao

2017-09-01

Transient receptor potential vanilloid 1 (TRPV1) is a nonselective cation channel that interacts with several intracellular proteins in vivo, including calmodulin and Phosphatidylinositol-3-Kinase/Protein Kinase B (PI3K/Akt). TRPV1 activation has been reported to exert neuroprotective effects. The aim of this study was to examine the impact of cold stress on the mouse brain and the underlying mechanisms of TRPV1 involvement. Adult male C57BL/6 mice were subjected to cold stress (4°C for 8h per day for 2weeks). The behavioral deficits of the mice were then measured using the Morris water maze. Expression levels of brain injury-related proteins and mRNA were measured by western blot, immunofluorescence or RT-PCR analysis. The mice displayed behavioral deficits, inflammation and changes in brain injury markers following cold stress. As expected, upregulated TRPV1 expression levels and changes in PI3K/Akt expression were found. The TRPV1 inhibitor reduced the levels of brain injury-related proteins and inflammation. These data suggest that cold stress can induce brain injury, possibly through TRPV1 activation and the PI3K/Akt signaling pathway. Suppression of inflammation by inhibition of TRPV1 and the PI3K/Akt pathway may be helpful to prevent cold stress-induced brain injury. Copyright © 2017 Elsevier B.V. All rights reserved.

The role of inflammation and interleukin-1 in acute cerebrovascular disease

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Galea J

2013-08-01

Full Text Available James Galea,1 David Brough21Manchester Academic Health Sciences Center, Brain Injury Research Group, Clinical Sciences Building, Salford Royal Foundation Trust, Salford, UK; 2Faculty of Life Sciences, University of Manchester, AV Hill Building, Manchester, UKAbstract: Acute cerebrovascular disease can affect people at all stages of life, from neonates to the elderly, with devastating consequences. It is responsible for up to 10% of deaths worldwide, is a major cause of disability, and represents an area of real unmet clinical need. Acute cerebrovascular disease is multifactorial with many mechanisms contributing to a complex pathophysiology. One of the major processes worsening disease severity and outcome is inflammation. Pro-inflammatory cytokines of the interleukin (IL-1 family are now known to drive damaging inflammatory processes in the brain. The aim of this review is to discuss the recent literature describing the role of IL-1 in acute cerebrovascular disease and to provide an update on our current understanding of the mechanisms of IL-1 production. We also discuss the recent literature where the effects of IL-1 have been targeted in animal models, thus reviewing potential future strategies that may limit the devastating effects of acute cerebrovascular disease.Keywords: cerebral ischemia, stroke, inflammation, microglia, interleukin-1, caspase-1

Twenty-four hours hypothermia has temporary efficacy in reducing brain infarction and inflammation in aged rats

DEFF Research Database (Denmark)

Sandu, Raluca Elena; Buga, Ana Maria; Balseanu, Adrian Tudor

2016-01-01

in aged animals. Because the duration of hypothermia in most clinical trials is between 24 and 48 hours, we questioned whether 24 hours exposure to gaseous hypothermia confers the same neuroprotective efficacy as 48 hours exposure. We found that a shorter exposure to hypothermia transiently reduced both...... inflammation and infarct size. However, after 1 week, the infarct size became even larger than in controls and after 2 weeks there was no beneficial effect on regenerative processes such as neurogenesis. Behaviorally, hypothermia also had a limited beneficial effect. Finally, after hydrogen sulfide......-induced hypothermia, the poststroke aged rats experienced a persistent sleep impairment during their active nocturnal period. Our data suggest that cellular events that are delayed by hypothermia in aged rats may, in the long term, rebound, and diminish the beneficial effects....

Incidence of adult brain cancers is higher in countries where the protozoan parasite Toxoplasma gondii is common

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Thomas, Frédéric; Lafferty, Kevin D.; Brodeur, Jacques; Elguero, Eric; Gauthier-Clerc, Michel; Missé, Dorothée

2012-01-01

We explored associations between the common protozoan parasite Toxoplasma gondii and brain cancers in human populations. We predicted that T. gondii could increase the risk of brain cancer because it is a long-lived parasite that encysts in the brain, where it provokes inflammation and inhibits apoptosis. We used a medical geography approach based on the national incidence of brain cancers and seroprevalence of T. gondii. We corrected reports of incidence for national gross domestic product because wealth probably increases the ability to detect cancer. We also included gender, cell phone use and latitude as variables in our initial models. Prevalence of T. gondii explained 19 per cent of the residual variance in brain cancer incidence after controlling for the positive effects of gross domestic product and latitude among nations. Infection with T. gondii was associated with a 1.8-fold increase in the risk of brain cancers across the range of T. gondii prevalence in our dataset (4–67%). These results, though correlational, suggest that T. gondii should be investigated further as a possible oncogenic pathogen of humans.

Metalloproteinases control brain inflammation induced by pertussis toxin in mice overexpressing the chemokine CCL2 in the central nervous system

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Toft-Hansen, Henrik; Buist, Richard; Sun, Xue-Jun

2006-01-01

Inflammatory leukocytes infiltrate the CNS parenchyma in neuroinflammation. This involves cellular migration across various structures associated with the blood-brain barrier: the vascular endothelium, the glia limitans, and the perivascular space between them. Leukocytes accumulate spontaneously...

Stereotactic radiotherapy following surgery for brain metastasis: Predictive factors for local control and radionecrosis.

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Doré, M; Martin, S; Delpon, G; Clément, K; Campion, L; Thillays, F

2017-02-01

To evaluate local control and adverse effects after postoperative hypofractionated stereotactic radiosurgery in patients with brain metastasis. We reviewed patients who had hypofractionated stereotactic radiosurgery (7.7Gy×3 prescribed to the 70% isodose line, with 2mm planning target volume margin) following resection from March 2008 to January 2014. The primary endpoint was local failure defined as recurrence within the surgical cavity. Secondary endpoints were distant failure rates and the occurrence of radionecrosis. Out of 95 patients, 39.2% had metastatic lesions from a non-small cell lung cancer primary tumour. The median Graded Prognostic Assessment score was 3 (48% of patients). One-year local control rates were 84%. Factors associated with improved local control were no cavity enhancement on pre-radiation MRI (P<0.00001), planning target volume less than 12cm 3 (P=0.005), Graded Prognostic Assessment score 2 or above (P=0.009). One-year distant cerebral control rates were 56%. Thirty-three percent of patients received whole brain radiation therapy. Histologically proven radionecrosis of brain tissue occurred in 7.2% of cases. The size of the preoperative lesion and the volume of healthy brain tissue receiving 21Gy (V 21 ) were both predictive of the incidence of radionecrosis (P=0.010 and 0.036, respectively). Adjuvant hypofractionated stereotactic radiosurgery to the postoperative cavity in patients with brain metastases results in excellent local control in selected patients, helps delay the use of whole brain radiation, and is associated with a relatively low risk of radionecrosis. Copyright © 2016 Société française de radiothérapie oncologique (SFRO). Published by Elsevier SAS. All rights reserved.

MicroRNA-orchestrated pathophysiologic control in gut homeostasis and inflammation.

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Lee, Juneyoung; Park, Eun Jeong; Kiyono, Hiroshi

2016-05-01

The intestine represents the largest and most elaborate immune system organ, in which dynamic and reciprocal interplay among numerous immune and epithelial cells, commensal microbiota, and external antigens contributes to establishing both homeostatic and pathologic conditions. The mechanisms that sustain gut homeostasis are pivotal in maintaining gut health in the harsh environment of the gut lumen. Intestinal epithelial cells are critical players in creating the mucosal platform for interplay between host immune cells and luminal stress inducers. Thus, knowledge of the epithelial interface between immune cells and the luminal environment is a prerequisite for a better understanding of gut homeostasis and pathophysiologies such as inflammation. In this review, we explore the importance of the epithelium in limiting or promoting gut inflammation (e.g., inflammatory bowel disease). We also introduce recent findings on how small RNAs such as microRNAs orchestrate pathophysiologic gene regulation. [BMB Reports 2016; 49(5): 263-269].

Persistent Inflammation Alters the Function of the Endogenous Brain Stem Cell Compartment

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Pluchino, Stefano; Muzio, Luca; Alfaro-Cervello, Clara; Salani, Giuliana; Porcheri, Cristina; Brambilla, Elena; Cavasinni, Francesca; Bergamaschi, Andrea; Garcia-Verdugo, Jose Manuel; Comi, Giancarlo; Martino, Gianvito; Imitola, Jaime; Deleidi, Michela; Khoury, Samia Joseph

2008-01-01

Endogenous neural stem/precursor cells (NPCs) are considered a functional reservoir for promoting tissue homeostasis and repair after injury, therefore regenerative strategies that mobilize these cells have recently been proposed. Despite evidence of increased neurogenesis upon acute inflammatory insults (e.g. ischaemic stroke), the plasticity of the endogenous brain stem cell compartment in chronic CNS inflammatory disorders remains poorly characterized. Here we show that persistent brain in...

Widespread inflammation in CLIPPERS syndrome indicated by autopsy and ultra-high-field 7T MRI

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Blaabjerg, Morten; Ruprecht, Klemens; Sinnecker, Tim

2016-01-01

, and axonal damage, and (3) the possibility of lymphoma. RESULTS: In the autopsy case, perivascular inflammation dominated by CD4+ T cells was not only detected in the brainstem and cerebellum but also in brain areas with normal appearance on 3.0T MRI, including supratentorial regions and cranial nerve roots...

Neuroprotective Effect of Curcumin Against Cerebral Ischemia-Reperfusion Via Mediating Autophagy and Inflammation.

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Huang, Lifa; Chen, Chengwei; Zhang, Xin; Li, Xu; Chen, Zupeng; Yang, Chao; Liang, Xiaolong; Zhu, Guochong; Xu, Zhen

2018-01-01

Curcumin, a polyphenolic compound extracted from Curcuma longa, has drawn attention for its effective bioactivities against ischemia-induced injury. This study aimed to evaluate the neuroprotective effect of curcumin and investigate the underlying mechanism that mediates autophagy and inflammation in an animal model of middle cerebral artery occlusion (MCAO) in rats. Curcumin was delivered to Sprague Dawley male rats at a dose of 200 mg/kg curcumin by intraperitoneal injection 30 min after ischemia-reperfusion (I/R). LY294002, a specific inhibitor of the PI3K/Akt/mTOR pathway, as well as anisomycin, an activator of TLR4/p38/MAPK, was administered by ventricle injection 30 min before MCAO. The same volume of saline was given as a control. Brain infarction and neurological function were determined 24 h post-MCAO. Immunoblotting and immunofluorescence were used to detect alterations in autophagy-relevant proteins Akt, p-Akt, mTOR, p-mTOR, LC3-II, and LC3-I, and inflammation-related proteins TLR4, p-38, p-p38, and IL-1 in the ipsilateral hemisphere. Cerebral I/R injury resulted in significant alterations of LC3-II/LC3-I, IL-1, TLR4, and p-p38. Curcumin in MCAO rats significantly improved brain damage and neurological function by upregulating p-Akt and p-mTOR and downregulating LC3-II/LC3-I, IL-1, TLR4, p-38, and p-p38. However, these protective effects against ischemia could be suppressed when LY294002 or anisomycin was included. Curcumin exerts neuroprotective effects by attenuating autophagic activities through mediating the PI3K/Akt/mTOR pathway, while also suppressing an inflammatory reaction by regulating the TLR4/p38/MAPK pathway. Furthermore, this study indicates that curcumin could be an effective therapy for patients afflicted with ischemia.

The bidirectional gut-brain-microbiota axis as a potential nexus between traumatic brain injury, inflammation, and disease.

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Sundman, Mark H; Chen, Nan-Kuei; Subbian, Vignesh; Chou, Ying-Hui

2017-11-01

As head injuries and their sequelae have become an increasingly salient matter of public health, experts in the field have made great progress elucidating the biological processes occurring within the brain at the moment of injury and throughout the recovery thereafter. Given the extraordinary rate at which our collective knowledge of neurotrauma has grown, new insights may be revealed by examining the existing literature across disciplines with a new perspective. This article will aim to expand the scope of this rapidly evolving field of research beyond the confines of the central nervous system (CNS). Specifically, we will examine the extent to which the bidirectional influence of the gut-brain axis modulates the complex biological processes occurring at the time of traumatic brain injury (TBI) and over the days, months, and years that follow. In addition to local enteric signals originating in the gut, it is well accepted that gastrointestinal (GI) physiology is highly regulated by innervation from the CNS. Conversely, emerging data suggests that the function and health of the CNS is modulated by the interaction between 1) neurotransmitters, immune signaling, hormones, and neuropeptides produced in the gut, 2) the composition of the gut microbiota, and 3) integrity of the intestinal wall serving as a barrier to the external environment. Specific to TBI, existing pre-clinical data indicates that head injuries can cause structural and functional damage to the GI tract, but research directly investigating the neuronal consequences of this intestinal damage is lacking. Despite this void, the proposed mechanisms emanating from a damaged gut are closely implicated in the inflammatory processes known to promote neuropathology in the brain following TBI, which suggests the gut-brain axis may be a therapeutic target to reduce the risk of Chronic Traumatic Encephalopathy and other neurodegenerative diseases following TBI. To better appreciate how various peripheral

Cerebral autoregulation control of blood flow in the brain

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Payne, Stephen

2016-01-01

This Brief provides a comprehensive introduction to the control of blood flow in the brain. Beginning with the basic physiology of autoregulation, the author goes on to discuss measurement techniques, mathematical models, methods of analysis, and relevant clinical conditions, all within this single volume. The author draws together this disparate field, and lays the groundwork for future research directions. The text gives an up-to-date review of the state of the art in cerebral autoregulation, which is particularly relevant as cerebral autoregulation moves from the laboratory to the bedside. Cerebral Autoregulation will be useful to researchers in the physical sciences such as mathematical biology, medical physics, and biomedical engineering whose work is concerned with the brain. Researchers in the medical sciences and clinicians dealing with the brain and blood flow, as well as industry professionals developing techniques such as ultrasound, MRI, and CT will also find this Brief of interest.

Phase II randomized, double-blind, placebo-controlled study of whole-brain irradiation with concomitant chloroquine for brain metastases

International Nuclear Information System (INIS)

Rojas-Puentes, Luis L; Gonzalez-Pinedo, Marcelino; Crismatt, Alejando; Ortega-Gomez, Alette; Gamboa-Vignolle, Carlos; Nuñez-Gomez, Rodrigo; Dorantes-Gallareta, Yusmiren; Arce-Salinas, Claudia; Arrieta, Oscar

2013-01-01

Chloroquine (CLQ), an antimalarial drug, has a lysosomotropic effect associated with increased radiationsensibility, which is mediated by the leakage of hydrolytic enzymes, increased apoptosis, autophagy and increased oxidative stress in vitro. In this phase II study, we evaluated the efficacy and safety of radiosensibilization using CLQ concomitant with 30 Gray (Gy) of whole-brain irradiation (WBI) to treat patients with brain metastases (BM) from solid tumors. Seventy-three eligible patients were randomized. Thirty-nine patients received WBI (30 Gy in 10 fractions over 2 weeks) concomitant with 150 mg of CLQ for 4 weeks (the CLQ arm). Thirty-four patients received the same schedule of WBI concomitant with a placebo for 4 weeks (the control arm). All the patients were evaluated for quality of life (QoL) using the EORTC Quality of Life (QoL) Questionnaire (EORTC QLQ-C30) (Mexican version) before beginning radiotherapy and one month later. The overall response rate (ORR) was 54% for the CLQ arm and 55% for the control arm (p=0.92). The progression-free survival of brain metastases (BMPFS) rates at one year were 83.9% (95% CI 69.4-98.4) for the CLQ arm and 55.1% (95% CI 33.6-77.6) for the control arm. Treatment with CLQ was independently associated with increased BMPFS (RR 0.31,95% CI [0.1-0.9], p=0.046).The only factor that was independently associated with increased overall survival (OS) was the presence of< 4 brain metastases (RR 1.9, 95% CI [1.12-3.3], p=0.017). WBI was associated with improvements in cognitive and emotional function but also with worsened nausea in both patients groups. No differences in QoL or toxicity were found between the study arms. Treatment with CLQ plus WBI improved the control of BM (compared with the control arm) with no increase in toxicity; however, CLQ did not improve the RR or OS. A phase III clinical trial is warranted to confirm these findings

Control of a visual keyboard using an electrocorticographic brain-computer interface.

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Krusienski, Dean J; Shih, Jerry J

2011-05-01

Brain-computer interfaces (BCIs) are devices that enable severely disabled people to communicate and interact with their environments using their brain waves. Most studies investigating BCI in humans have used scalp EEG as the source of electrical signals and focused on motor control of prostheses or computer cursors on a screen. The authors hypothesize that the use of brain signals obtained directly from the cortical surface will more effectively control a communication/spelling task compared to scalp EEG. A total of 6 patients with medically intractable epilepsy were tested for the ability to control a visual keyboard using electrocorticographic (ECOG) signals. ECOG data collected during a P300 visual task paradigm were preprocessed and used to train a linear classifier to subsequently predict the intended target letters. The classifier was able to predict the intended target character at or near 100% accuracy using fewer than 15 stimulation sequences in 5 of the 6 people tested. ECOG data from electrodes outside the language cortex contributed to the classifier and enabled participants to write words on a visual keyboard. This is a novel finding because previous invasive BCI research in humans used signals exclusively from the motor cortex to control a computer cursor or prosthetic device. These results demonstrate that ECOG signals from electrodes both overlying and outside the language cortex can reliably control a visual keyboard to generate language output without voice or limb movements.

The Probable Effects of Cytokines in Intrauterine Infections and Perinatal Brain Injury

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Mehmet Oflaz

2013-10-01

Full Text Available Perinatal brain injuries and the subsequent development of cerebral palsy are closely associated with intrauterine infections and inflammatory response. Premature prenatal rupture of membranes and premature births are also closely linked to infections and inflammation, and the presence of both infection / inflammation and premature birth together greatly increase the risk for cerebral palsy. Periventricular leukolamacia, a common neonatal brain white matter lesion, is a major risk factor for cerebral palsy. Inflammatory cytokines released during the course of intrauterine infection play an important role in the genesis of brain white matter lesion. Maternal intrauterine infection appears to increase the risk of preterm delivery, which in turn is associated with an increased risk of intraventricular hemorrhage, neonatal white matter damage, and subsequent cerebral palsy. Proinflammatory cytokines IL-1, IL-6 and Tumor necrosis factor-%u03B1 might be the link between prenatal intrauterine infection and neonatal brain damage, and interrupting the proinflammatory cytokine cascade might prevent later disability in those born near the end of the second trimester.

Metaplasticity and Behavior: How Training and Inflammation Affect Plastic Potential within the Spinal Cord and Recovery after Injury

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James W Grau

2014-09-01

Full Text Available Research has shown that spinal circuits have the capacity to adapt in response to training, nociceptive stimulation and peripheral inflammation. These changes in neural function are mediated by physiological and neurochemical systems analogous to those that support plasticity within the hippocampus (e.g., long-term potentiation and the NMDA receptor. As observed in the hippocampus, engaging spinal circuits can have a lasting impact on plastic potential, enabling or inhibiting the capacity to learn. These effects are related to the concept of metaplasticity. Behavioral paradigms are described that induce metaplastic effects within the spinal cord. Uncontrollable/unpredictable stimulation, and peripheral inflammation, induce a form of maladaptive plasticity that inhibits spinal learning. Conversely, exposure to controllable or predictable stimulation engages a form of adaptive plasticity that counters these maladaptive effects and enables learning. Adaptive plasticity is tied to an up-regulation of brain derived neurotrophic factor (BDNF. Maladaptive plasticity is linked to processes that involve kappa opioids, the metabotropic glutamate (mGlu receptor, glia, and the cytokine tumor necrosis factor (TNF. Uncontrollable nociceptive stimulation also impairs recovery after a spinal contusion injury and fosters the development of pain (allodynia. These adverse effects are related to an up-regulation of TNF and a down-regulation of BDNF and its receptor (TrkB. In the absence of injury, brain systems quell the sensitization of spinal circuits through descending serotonergic fibers and the serotonin 1A (5HT 1A receptor. This protective effect is blocked by surgical anesthesia. Disconnected from the brain, intracellular Cl- concentrations increase (due to a down-regulation of the cotransporter KCC2, which causes GABA to have an excitatory effect. It is suggested that BDNF has a restorative effect because it up-regulates KCC2 and re-establishes GABA

Airway inflammation in Japanese COPD patients compared with smoking and nonsmoking controls

Directory of Open Access Journals (Sweden)

Ishikawa N

2015-01-01

Full Text Available Nobuhisa Ishikawa,1 Noboru Hattori,2 Nobuoki Kohno,2 Akihiro Kobayashi,3 Tomoyuki Hayamizu,4 Malcolm Johnson5 1Department of Respiratory Medicine, Hiroshima Prefectural Hospital, Hiroshima, Japan; 2Department of Molecular and Internal Medicine, Hiroshima University, Hiroshima, Japan; 3Biomedical Data Science Department, 4Medical Affairs Respiratory Department, GlaxoSmithKline Shibuya-ku, Tokyo, Japan; 5Respiratory Global Franchise, GlaxoSmithKline, Uxbridge, UK Purpose: To assess the importance of inflammation in chronic obstructive pulmonary disease (COPD by measuring airway and systemic inflammatory biomarkers in Japanese patients with the disease and relevant control groups.Patients and methods: This was the first study of its type in Japanese COPD patients. It was a non-treatment study in which 100 participants were enrolled into one of three groups: nonsmoking controls, current or ex-smoking controls, and COPD patients. All participants underwent standard lung function assessments and provided sputum and blood samples from which the numbers of inflammatory cells and concentrations of biomarkers were measured, using standard procedures.Results: The overall trends observed in levels of inflammatory cells and biomarkers in sputum and blood in COPD were consistent with previous reports in Western studies. Increasing levels of neutrophils, interleukin 8 (IL-8, surfactant protein D (SP-D, and Krebs von den Lungen 6 (KL-6 in sputum and clara cell 16 (CC-16, high-sensitivity C-reactive protein (hs-CRP, and KL-6 in serum and plasma fibrinogen were seen in the Japanese COPD patients compared with the non-COPD control participants. In sputum, significant correlations were seen between total cell count and matrix metalloproteinase 9 (MMP-9; P<0.001, neutrophils and MMP-9 (P<0.001, macrophages and KL-6 (P<0.01, total cell count and IL-8 (P<0.05, neutrophils and IL-8 (P<0.05, and macrophages and MMP-9 (P<0.05. Significant correlations were also

Evidence from intrinsic activity that asymmetry of the human brain is controlled by multiple factors.

Science.gov (United States)

Liu, Hesheng; Stufflebeam, Steven M; Sepulcre, Jorge; Hedden, Trey; Buckner, Randy L

2009-12-01

Cerebral lateralization is a fundamental property of the human brain and a marker of successful development. Here we provide evidence that multiple mechanisms control asymmetry for distinct brain systems. Using intrinsic activity to measure asymmetry in 300 adults, we mapped the most strongly lateralized brain regions. Both men and women showed strong asymmetries with a significant, but small, group difference. Factor analysis on the asymmetric regions revealed 4 separate factors that each accounted for significant variation across subjects. The factors were associated with brain systems involved in vision, internal thought (the default network), attention, and language. An independent sample of right- and left-handed individuals showed that hand dominance affects brain asymmetry but differentially across the 4 factors supporting their independence. These findings show the feasibility of measuring brain asymmetry using intrinsic activity fluctuations and suggest that multiple genetic or environmental mechanisms control cerebral lateralization.

Fecal markers of intestinal inflammation and intestinal permeability are elevated in Parkinson's disease.

Science.gov (United States)

Schwiertz, Andreas; Spiegel, Jörg; Dillmann, Ulrich; Grundmann, David; Bürmann, Jan; Faßbender, Klaus; Schäfer, Karl-Herbert; Unger, Marcus M

2018-02-12

Intestinal inflammation and increased intestinal permeability (both possibly fueled by dysbiosis) have been suggested to be implicated in the multifactorial pathogenesis of Parkinson's disease (PD). The objective of the current study was to investigate whether fecal markers of inflammation and impaired intestinal barrier function corroborate this pathogenic aspect of PD. In a case-control study, we quantitatively analyzed established fecal markers of intestinal inflammation (calprotectin and lactoferrin) and fecal markers of intestinal permeability (alpha-1-antitrypsin and zonulin) in PD patients (n = 34) and controls (n = 28, group-matched for age) by enzyme-linked immunosorbent assay. The study design controlled for potential confounding factors. Calprotectin, a fecal marker of intestinal inflammation, and two fecal markers of increased intestinal permeability (alpha-1-antitrypsin and zonulin) were significantly elevated in PD patients compared to age-matched controls. Lactoferrin, as a second fecal marker of intestinal inflammation, showed a non-significant trend towards elevated concentrations in PD patients. None of the four fecal markers correlated with disease severity, PD subtype, dopaminergic therapy, or presence of constipation. Fecal markers reflecting intestinal inflammation and increased intestinal permeability have been primarily investigated in inflammatory bowel disease so far. Our data indicate that calprotectin, alpha-1-antitrypsin and zonulin could be useful non-invasive markers in PD as well. Even though these markers are not disease-specific, they corroborate the hypothesis of an intestinal inflammation as contributing factor in the pathogenesis of PD. Further investigations are needed to determine whether calprotectin, alpha-1-antitrypsin and zonulin can be used to define PD subgroups and to monitor the effect of interventions in PD. Copyright © 2018 Elsevier Ltd. All rights reserved.

STING Signaling Promotes Inflammation in Experimental Acute Pancreatitis.

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Zhao, Qinglan; Wei, Yi; Pandol, Stephen J; Li, Lingyin; Habtezion, Aida

2018-05-01

Acute pancreatitis (AP) is characterized by severe inflammation and acinar cell death. Transmembrane protein 173 (TMEM173 or STING) is a DNA sensor adaptor protein on immune cells that recognizes cytosolic nucleic acids and transmits signals that activate production of interferons and the innate immune response. We investigated whether leukocyte STING signaling mediates inflammation in mice with AP. We induced AP in C57BL/6J mice (control) and C57BL/6J-Tmem173gt/J mice (STING-knockout mice) by injection of cerulein or placement on choline-deficient DL-ethionine supplemented diet. In some mice, STING signaling was induced by administration of a pharmacologic agonist. AP was also induced in C57BL/6J mice with bone marrow transplants from control or STING-knockout mice and in mice with disruption of the cyclic GMP-AMP synthase (Cgas) gene. Pancreata were collected, analyzed by histology, and acini were isolated and analyzed by flow cytometry, quantitative polymerase chain reaction, immunoblots, and enzyme-linked immunosorbent assay. Bone-marrow-derived macrophages were collected from mice and tested for their ability to detect DNA from dying acinar cells in the presence and absence of deoxyribonuclease (DNaseI). STING signaling was activated in pancreata from mice with AP but not mice without AP. STING-knockout mice developed less severe AP (less edema, inflammation, and markers of pancreatic injury) than control mice, whereas mice given a STING agonist developed more severe AP than controls. In immune cells collected from pancreata, STING was expressed predominantly in macrophages. Levels of cGAS were increased in mice with vs without AP, and cGAS-knockout mice had decreased edema, inflammation, and other markers of pancreatic injury upon induction of AP than control mice. Wild-type mice given bone marrow transplants from STING-knockout mice had less pancreatic injury and lower serum levels of lipase and pancreatic trypsin activity following induction of AP than

Comparisons of [{sup 18}F]-1-deoxy-1-fluoro-scyllo-inositol with [{sup 18}F]-FDG for PET imaging of inflammation, breast and brain cancer xenografts in athymic mice

Energy Technology Data Exchange (ETDEWEB)

McLarty, Kristin; Moran, Matthew D. [Department of Psychiatry, University of Toronto, Toronto, ON, M5T 1R8 (Canada); PET Centre, Centre for Addiction and Mental Health, Toronto, ON, M5T 1R8 (Canada); Scollard, Deborah A.; Chan, Conrad [Department of Pharmaceutical Sciences, University of Toronto, Toronto, ON, M5S 3M2 (Canada); Sabha, Nesrin; Mukherjee, Joydeep; Guha, Abhijit [Arthur and Sonia Labatt Brain Tumour Research Centre, Hospital for Sick Children, University of Toronto, ON, M5G 1X8 (Canada); McLaurin, JoAnne [Centre for Research in Neurodegenerative Diseases, University of Toronto, Toronto, ON, M5S 3H2 (Canada); Nitz, Mark [Department of Chemistry, University of Toronto, Toronto, ON, M5S 3H6 (Canada); Houle, Sylvain; Wilson, Alan A. [Department of Psychiatry, University of Toronto, Toronto, ON, M5T 1R8 (Canada); PET Centre, Centre for Addiction and Mental Health, Toronto, ON, M5T 1R8 (Canada); Reilly, Raymond M., E-mail: raymond.reilly@utoronto.ca [Department of Pharmaceutical Sciences, University of Toronto, Toronto, ON, M5S 3M2 (Canada); Toronto General Research Institute, University Health Network, Toronto, ON, M5G 2M9 (Canada); Department of Medical Imaging, University of Toronto, Toronto, ON, M5S 3M2 (Canada); Vasdev, Neil, E-mail: neil.vasdev@utoronto.ca [Department of Psychiatry, University of Toronto, Toronto, ON, M5T 1R8 (Canada); PET Centre, Centre for Addiction and Mental Health, Toronto, ON, M5T 1R8 (Canada)

2011-10-15

Introduction: The aim of the study was to evaluate the uptake of [{sup 18}F]-1-deoxy-1-fluoro-scyllo-inositol ([{sup 18}F]-scyllo-inositol) in human breast cancer (BC) and glioma xenografts, as well as in inflammatory tissue, in immunocompromised mice. Studies of [{sup 18}F]-2-fluoro-2-deoxy-D-glucose ([{sup 18}F]-FDG) under the same conditions were also performed. Methods: Radiosynthesis of [{sup 18}F]-scyllo-inositol was automated using a commercial synthesis module. Tumour, inflammation and normal tissue uptakes were evaluated by biodistribution studies and positron emission tomography (PET) imaging using [{sup 18}F]-scyllo-inositol and [{sup 18}F]-FDG in mice bearing subcutaneous MDA-MB-231, MCF-7 and MDA-MB-361 human BC xenografts, intracranial U-87 MG glioma xenografts and turpentine-induced inflammation. Results: The radiosynthesis of [{sup 18}F]-scyllo-inositol was automated with good radiochemical yields (24.6%{+-}3.3%, uncorrected for decay, 65{+-}2 min, n=5) and high specific activities ({>=}195 GBq/{mu}mol at end of synthesis). Uptake of [{sup 18}F]-scyllo-inositol was greatest in MDA-MB-231 BC tumours and was comparable to that of [{sup 18}F]-FDG (4.6{+-}0.5 vs. 5.5{+-}2.1 %ID/g, respectively; P=.40), but was marginally lower in MDA-MB-361 and MCF-7 xenografts. Uptake of [{sup 18}F]-scyllo-inositol in inflammation was lower than [{sup 18}F]-FDG. While uptake of [{sup 18}F]-scyllo-inositol in intracranial U-87 MG xenografts was significantly lower than [{sup 18}F]-FDG, the tumour-to-brain ratio was significantly higher (10.6{+-}2.5 vs. 2.1{+-}0.6; P=.001). Conclusions: Consistent with biodistribution studies, uptake of [{sup 18}F]-scyllo-inositol was successfully visualized by PET imaging in human BC and glioma xenografts, with lower accumulation in inflammatory tissue than [{sup 18}F]-FDG. The tumour-to-brain ratio of [{sup 18}F]-scyllo-inositol was also significantly higher than that of [{sup 18}F]-FDG for visualizing intracranial glioma xenografts in

Inflammatory diseases of the brain

International Nuclear Information System (INIS)

Haehnel, Stefan

2009-01-01

This book provides a comprehensive overview of inflammatory brain diseases from a neuroradiological point of view. Such diseases may be either infectious (e.g., viral encephalitis and pyogenic brain abscess) or non-infectious (e.g., multiple sclerosis), and many of these entities are becoming increasingly important for differential diagnosis, particularly in immunocompromised persons. Neuroimaging contributes greatly to the differentiation of infectious and noninfectious brain diseases and to the distinction between brain inflammation and other, for instance neoplastic, diseases. In order to ensure a standardized approach throughout the book, each chapter is subdivided into three principal sections: epidemiology, clinical presentation and therapy; imaging; and differential diagnosis. A separate chapter addresses technical and methodological issues and imaging protocols. All of the authors are recognized experts in their fields, and numerous high-quality and informative illustrations are included. This book will be of great value not only to neuroradiologists but also to neurologists, neuropediatricians, and general radiologists. (orig.)

Inflammatory diseases of the brain

Energy Technology Data Exchange (ETDEWEB)

Haehnel, Stefan (ed.) [University of Heidelberg Medical Center (Germany). Div. of Neuroradiology

2009-07-01

This book provides a comprehensive overview of inflammatory brain diseases from a neuroradiological point of view. Such diseases may be either infectious (e.g., viral encephalitis and pyogenic brain abscess) or non-infectious (e.g., multiple sclerosis), and many of these entities are becoming increasingly important for differential diagnosis, particularly in immunocompromised persons. Neuroimaging contributes greatly to the differentiation of infectious and noninfectious brain diseases and to the distinction between brain inflammation and other, for instance neoplastic, diseases. In order to ensure a standardized approach throughout the book, each chapter is subdivided into three principal sections: epidemiology, clinical presentation and therapy; imaging; and differential diagnosis. A separate chapter addresses technical and methodological issues and imaging protocols. All of the authors are recognized experts in their fields, and numerous high-quality and informative illustrations are included. This book will be of great value not only to neuroradiologists but also to neurologists, neuropediatricians, and general radiologists. (orig.)

Temporal coding of brain patterns for direct limb control in humans

Directory of Open Access Journals (Sweden)

Gernot Mueller-Putz

2010-06-01

Full Text Available For individuals with a high spinal cord injury (SCI not only the lower limbs, but also the upper extremities are paralyzed. A neuroprosthesis can be used to restore the lost hand and arm function in those tetraplegics. The main problem for this group of individuals, however, is the reduced ability to voluntarily operate device controllers. A Brain-Computer Interface provides a non-manual alternative to conventional input devices by translating brain activity patterns into control commands. We show that the temporal coding of individual mental imagery pattern can be used to control two independent degrees of freedom – grasp and elbow function - of an artificial robotic arm by utilizing a minimum number of EEG scalp electrodes. We describe the procedure from the initial screening to the final application. From eight naïve subjects participating on-line feedback experiments, four were able to voluntarily control an artificial arm by inducing one motor imagery pattern derived from one EEG derivation only.

A balance of activity in brain control and reward systems predicts self-regulatory outcomes.

Science.gov (United States)

Lopez, Richard B; Chen, Pin-Hao A; Huckins, Jeremy F; Hofmann, Wilhelm; Kelley, William M; Heatherton, Todd F

2017-05-01

Previous neuroimaging work has shown that increased reward-related activity following exposure to food cues is predictive of self-control failure. The balance model suggests that self-regulation failures result from an imbalance in reward and executive control mechanisms. However, an open question is whether the relative balance of activity in brain systems associated with executive control (vs reward) supports self-regulatory outcomes when people encounter tempting cues in daily life. Sixty-nine chronic dieters, a population known for frequent lapses in self-control, completed a food cue-reactivity task during an fMRI scanning session, followed by a weeklong sampling of daily eating behaviors via ecological momentary assessment. We related participants' food cue activity in brain systems associated with executive control and reward to real-world eating patterns. Specifically, a balance score representing the amount of activity in brain regions associated with self-regulatory control, relative to automatic reward-related activity, predicted dieters' control over their eating behavior during the following week. This balance measure may reflect individual self-control capacity and be useful for examining self-regulation success in other domains and populations. © The Author (2017). Published by Oxford University Press.

Perineural inflammation in morphea (localized scleroderma): systematic characterization of a poorly recognized but potentially useful histopathological feature.

Science.gov (United States)

Dhaliwal, Catharine A; MacKenzie, Andrew I; Biswas, Asok

2014-01-01

The association between morphea and perineural inflammation has been reported sporadically but never studied systematically. To assess the prevalence and nature of perineural inflammation in various clinicopathologic stages of morphea and a cohort of other inflammatory dermatoses, 80 morphea and 36 control skin biopsies were studied using hematoxylin/eosin and S100 stains. Perineural inflammation was semiquantitatively analyzed (scored), which along with the pattern (concentric vs. marginal) and cellular composition was compared in the two groups. Perineural inflammation was identified in 84% and 61% of morphea and control cases, respectively. Examination of only routinely stained sections could still detect this feature in 58% of morphea and 33% of control biopsies. Mean perineural inflammation score in morphea (0.65) was significantly higher than in the control group (0.23) (p morphea cases. Although perineural inflammation is common in morphea, it is not unusual to find this feature in other inflammatory conditions. Nevertheless, perineural inflammation can serve as an important diagnostic adjunct in difficult cases of morphea if one considers its greater intensity, predominantly concentric pattern and the tendency to show plasma cell neurotropism. © 2013 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

Randomised clinical trial: evaluation of the efficacy of mesalazine (mesalamine) suppositories in patients with ulcerative colitis and active rectal inflammation -- a placebo-controlled study.

Science.gov (United States)

Watanabe, M; Nishino, H; Sameshima, Y; Ota, A; Nakamura, S; Hibi, T

2013-08-01

Mesalazine suppositories are recommended and widely used as the standard therapy in induction and maintenance of remission for proctitis. To evaluate the efficacy of mesalazine suppositories in patients with ulcerative colitis (UC) and rectal inflammation; and in patient groups categorised by the extent of lesions. This study was a phase III multicentre, randomised, double-blind, placebo-controlled, parallel-group study. Mild-to-moderate UC patients with rectal inflammation were randomly assigned either a 1 g mesalazine or placebo suppository. The suppository was administered in the rectum once daily for 4 weeks. The primary efficacy end point was the rate of endoscopic remission (mucosal score of 0 or 1) after 4 weeks. The endoscopic remission rates after 4 weeks in the mesalazine and placebo suppository groups were 81.5% and 29.7%, respectively, and the superiority of mesalazine to placebo was confirmed (P suppositories in all types of UC patients with rectal inflammation was confirmed for the first time in a double-blind, placebo-controlled, parallel-group study (JapicCTI- 111421). © 2013 John Wiley & Sons Ltd.

Endoplasmic reticulum stress increases brain MAPK signaling, inflammation and renin-angiotensin system activity and sympathetic nerve activity in heart failure.

Science.gov (United States)

Wei, Shun-Guang; Yu, Yang; Weiss, Robert M; Felder, Robert B

2016-10-01

We previously reported that endoplasmic reticulum (ER) stress is induced in the subfornical organ (SFO) and the hypothalamic paraventricular nucleus (PVN) of heart failure (HF) rats and is reduced by inhibition of mitogen-activated protein kinase (MAPK) signaling. The present study further examined the relationship between brain MAPK signaling, ER stress, and sympathetic excitation in HF. Sham-operated (Sham) and HF rats received a 4-wk intracerebroventricular (ICV) infusion of vehicle (Veh) or the ER stress inhibitor tauroursodeoxycholic acid (TUDCA, 10 μg/day). Lower mRNA levels of the ER stress biomarkers GRP78, ATF6, ATF4, and XBP-1s in the SFO and PVN of TUDCA-treated HF rats validated the efficacy of the TUDCA dose. The elevated levels of phosphorylated p44/42 and p38 MAPK in SFO and PVN of Veh-treated HF rats, compared with Sham rats, were significantly reduced in TUDCA-treated HF rats as shown by Western blot and immunofluorescent staining. Plasma norepinephrine levels were higher in Veh-treated HF rats, compared with Veh-treated Sham rats, and were significantly lower in the TUDCA-treated HF rats. TUDCA-treated HF rats also had lower mRNA levels for angiotensin converting enzyme, angiotensin II type 1 receptor, tumor necrosis factor-α, interleukin-1β, cyclooxygenase-2, and NF-κB p65, and a higher mRNA level of IκB-α, in the SFO and PVN than Veh-treated HF rats. These data suggest that ER stress contributes to the augmented sympathetic activity in HF by inducing MAPK signaling, thereby promoting inflammation and renin-angiotensin system activity in key cardiovascular regulatory regions of the brain.

Rab GTPases in Immunity and Inflammation.

Science.gov (United States)

Prashar, Akriti; Schnettger, Laura; Bernard, Elliott M; Gutierrez, Maximiliano G

2017-01-01

Strict spatiotemporal control of trafficking events between organelles is critical for maintaining homeostasis and directing cellular responses. This regulation is particularly important in immune cells for mounting specialized immune defenses. By controlling the formation, transport and fusion of intracellular organelles, Rab GTPases serve as master regulators of membrane trafficking. In this review, we discuss the cellular and molecular mechanisms by which Rab GTPases regulate immunity and inflammation.

CSF inflammation and axonal damage are increased and correlate in progressive multiple sclerosis

DEFF Research Database (Denmark)

Romme Christensen, Jeppe; Börnsen, Lars; Khademi, Mohsen

2013-01-01

BACKGROUND: The mechanism underlying disease progression in progressive multiple sclerosis (MS) is uncertain. Pathological studies found widespread inflammation in progressive MS brains correlating with disease progression and axonal damage. OBJECTIVES: To study cerebrospinal fluid (CSF) biomarkers...... and clarify whether inflammation and axonal damage are associated in progressive MS. METHODS: Using enzyme-linked immunosorbent assay (ELISA), we analysed CSF from 40 secondary progressive (SPMS), 21 primary progressive (PPMS), and 36 relapsing-remitting (RRMS) and 20 non-inflammatory neurological disease...... (NIND) patients. Twenty-two of the SPMS patients participated in an MBP8298 peptide clinical trial and had CSF follow-up after one year. RESULTS: Compared to NIND patients, inflammatory biomarkers osteopontin and matrix metalloproteinase-9 (MMP9) were increased in all MS patients while CXCL13...

Subthalamic Nucleus Deep Brain Stimulation Changes Velopharyngeal Control in Parkinson's Disease

Science.gov (United States)

Hammer, Michael J.; Barlow, Steven M.; Lyons, Kelly E.; Pahwa, Rajesh

2011-01-01

Purpose: Adequate velopharyngeal control is essential for speech, but may be impaired in Parkinson's disease (PD). Bilateral subthalamic nucleus deep brain stimulation (STN DBS) improves limb function in PD, but the effects on velopharyngeal control remain unknown. We tested whether STN DBS would change aerodynamic measures of velopharyngeal…

Disruption of the blood–brain barrier in pigs naturally infected with Taenia solium, untreated and after anthelmintic treatment

Science.gov (United States)

Guerra-Giraldez, Cristina; Marzal, Miguel; Cangalaya, Carla; Balboa, Diana; Orrego, Miguel Ángel; Paredes, Adriana; Gonzales-Gustavson, Eloy; Arroyo, Gianfranco; García, Hector H.; González, Armando E.; Mahanty, Siddhartha; Nash, Theodore E.

2014-01-01

Neurocysticercosis is a widely prevalent disease in the tropics that causes seizures and a variety of neurological symptoms in most of the world. Experimental models are limited and do not allow assessment of the degree of inflammation around brain cysts. The vital dye Evans Blue (EB) was injected into 11 pigs naturally infected with Taenia solium cysts to visually identify the extent of disruption of the blood brain barrier. A total of 369 cysts were recovered from the 11 brains and classified according to the staining of their capsules as blue or unstained. The proportion of cysts with blue capsules was significantly higher in brains from pigs that had received anthelmintic treatment 48 and 120 h before the EB infusion, indicating a greater compromise of the blood brain barrier due to treatment. The model could be useful for understanding the pathology of treatment-induced inflammation in neurocysticercosis. PMID:23684909

Mechanism of brain tumor headache.

Science.gov (United States)

Taylor, Lynne P

2014-04-01

Headaches occur commonly in all patients, including those who have brain tumors. Using the search terms "headache and brain tumors," "intracranial neoplasms and headache," "facial pain and brain tumors," "brain neoplasms/pathology," and "headache/etiology," we reviewed the literature from the past 78 years on the proposed mechanisms of brain tumor headache, beginning with the work of Penfield. Most of what we know about the mechanisms of brain tumor associated headache come from neurosurgical observations from intra-operative dural and blood vessel stimulation as well as intra-operative observations and anecdotal information about resolution of headache symptoms with various tumor-directed therapies. There is an increasing overlap between the primary and secondary headaches and they may actually share a similar biological mechanism. While there can be some criticism that the experimental work with dural and arterial stimulation produced head pain and not actual headache, when considered with the clinical observations about headache type, coupled with improvement after treatment of the primary tumor, we believe that traction on these structures, coupled with increased intracranial pressure, is clearly part of the genesis of brain tumor headache and may also involve peripheral sensitization with neurogenic inflammation as well as a component of central sensitization through trigeminovascular afferents on the meninges and cranial vessels. © 2014 American Headache Society.

Experiencing Brain-Computer Interface Control

NARCIS (Netherlands)

van de Laar, B.L.A.

2016-01-01

Brain-Computer Interfaces (BCIs) are systems that extract information from the user’s brain activity and employ it in some way in an interactive system. While historically BCIs were mainly catered towards paralyzed or otherwise physically handicapped users, the last couple of years applications with

Reconfiguration of brain network architecture to support executive control in aging.

Science.gov (United States)

Gallen, Courtney L; Turner, Gary R; Adnan, Areeba; D'Esposito, Mark

2016-08-01

Aging is accompanied by declines in executive control abilities and changes in underlying brain network architecture. Here, we examined brain networks in young and older adults during a task-free resting state and an N-back task and investigated age-related changes in the modular network organization of the brain. Compared with young adults, older adults showed larger changes in network organization between resting state and task. Although young adults exhibited increased connectivity between lateral frontal regions and other network modules during the most difficult task condition, older adults also exhibited this pattern of increased connectivity during less-demanding task conditions. Moreover, the increase in between-module connectivity in older adults was related to faster task performance and greater fractional anisotropy of the superior longitudinal fasciculus. These results demonstrate that older adults who exhibit more pronounced network changes between a resting state and task have better executive control performance and greater structural connectivity of a core frontal-posterior white matter pathway. Copyright © 2016 Elsevier Inc. All rights reserved.

Sleep duration and age-related changes in brain structure and cognitive performance.

Science.gov (United States)

Lo, June C; Loh, Kep Kee; Zheng, Hui; Sim, Sam K Y; Chee, Michael W L

2014-07-01

To investigate the contribution of sleep duration and quality to age-related changes in brain structure and cognitive performance in relatively healthy older adults. Community-based longitudinal brain and cognitive aging study using a convenience sample. Participants were studied in a research laboratory. Relatively healthy adults aged 55 y and older at study commencement. N/A. Participants underwent magnetic resonance imaging and neuropsychological assessment every 2 y. Subjective assessments of sleep duration and quality and blood samples were obtained. Each hour of reduced sleep duration at baseline augmented the annual expansion rate of the ventricles by 0.59% (P = 0.007) and the annual decline rate in global cognitive performance by 0.67% (P = 0.050) in the subsequent 2 y after controlling for the effects of age, sex, education, and body mass index. In contrast, global sleep quality at baseline did not modulate either brain or cognitive aging. High-sensitivity C-reactive protein, a marker of systemic inflammation, showed no correlation with baseline sleep duration, brain structure, or cognitive performance. In healthy older adults, short sleep duration is associated with greater age-related brain atrophy and cognitive decline. These associations are not associated with elevated inflammatory responses among short sleepers. Lo JC, Loh KK, Zheng H, Sim SK, Chee MW. Sleep duration and age-related changes in brain structure and cognitive performance.

Monitoring and control of amygdala neurofeedback involves distributed information processing in the human brain.

Science.gov (United States)

Paret, Christian; Zähringer, Jenny; Ruf, Matthias; Gerchen, Martin Fungisai; Mall, Stephanie; Hendler, Talma; Schmahl, Christian; Ende, Gabriele

2018-03-30

Brain-computer interfaces provide conscious access to neural activity by means of brain-derived feedback ("neurofeedback"). An individual's abilities to monitor and control feedback are two necessary processes for effective neurofeedback therapy, yet their underlying functional neuroanatomy is still being debated. In this study, healthy subjects received visual feedback from their amygdala response to negative pictures. Activation and functional connectivity were analyzed to disentangle the role of brain regions in different processes. Feedback monitoring was mapped to the thalamus, ventromedial prefrontal cortex (vmPFC), ventral striatum (VS), and rostral PFC. The VS responded to feedback corresponding to instructions while rPFC activity differentiated between conditions and predicted amygdala regulation. Control involved the lateral PFC, anterior cingulate, and insula. Monitoring and control activity overlapped in the VS and thalamus. Extending current neural models of neurofeedback, this study introduces monitoring and control of feedback as anatomically dissociated processes, and suggests their important role in voluntary neuromodulation. © 2018 Wiley Periodicals, Inc.

Inflammation and Heart Disease

Science.gov (United States)

... Disease Venous Thromboembolism Aortic Aneurysm More Inflammation and Heart Disease Updated:Jun 13,2017 Understand the risks of ... inflammation causes cardiovascular disease, inflammation is common for heart disease and stroke patients and is thought to be ...

Inhibition of systemic inflammation by central action of the neuropeptide alpha-melanocyte- stimulating hormone.

Science.gov (United States)

Delgado Hernàndez, R; Demitri, M T; Carlin, A; Meazza, C; Villa, P; Ghezzi, P; Lipton, J M; Catania, A

1999-01-01

The neuropeptide alpha-melanocyte stimulating hormone (alpha-MSH) reduces fever and acute inflammation in the skin when administered centrally. The aim of the present research was to determine whether central alpha-MSH can also reduce signs of systemic inflammation in mice with endotoxemia. Increases in serum tumor necrosis factor-alpha and nitric oxide, induced by intraperitoneal administration of endotoxin, were modulated by central injection of a small concentration of alpha-MSH. Inducible nitric oxide synthase (iNOS) activity and iNOS mRNA in lungs and liver were likewise modulated by central alpha-MSH. Lung myeloperoxidase activity, a marker of neutrophil infiltration, was increased in endotoxemic mice; the increase was significantly less in lungs of mice treated with central alpha-MSH. Intraperitoneal administration of the small dose of alpha-MSH that was effective centrally did not alter any of the markers of inflammation. In experiments using immunoneutralization of central alpha-MSH, we tested the idea that endogenous peptide induced within the brain during systemic inflammation modulates host responses to endotoxic challenge in peripheral tissues. The data showed that proinflammatory agents induced by endotoxin in the circulation, lungs, and liver were significantly greater after blockade of central alpha-MSH. The results suggest that anti-inflammatory influences of neural origin that are triggered by alpha-MSH could be used to treat systemic inflammation.

Erythropoietin in traumatic brain injury: study protocol for a randomised controlled trial.

LENUS (Irish Health Repository)

Nichol, Alistair

2015-02-08

Traumatic brain injury is a leading cause of death and disability worldwide. Laboratory and clinical studies demonstrate a possible beneficial effect of erythropoietin in improving outcomes in the traumatic brain injury cohort. However, there are concerns regarding the association of erythropoietin and thrombosis in the critically ill. A large-scale, multi-centre, blinded, parallel-group, placebo-controlled, randomised trial is currently underway to address this hypothesis.

Rab GTPases in Immunity and Inflammation

Directory of Open Access Journals (Sweden)

Akriti Prashar

2017-09-01

Full Text Available Strict spatiotemporal control of trafficking events between organelles is critical for maintaining homeostasis and directing cellular responses. This regulation is particularly important in immune cells for mounting specialized immune defenses. By controlling the formation, transport and fusion of intracellular organelles, Rab GTPases serve as master regulators of membrane trafficking. In this review, we discuss the cellular and molecular mechanisms by which Rab GTPases regulate immunity and inflammation.

Psychoneuroimmunology meets neuropsychopharmacology: translational implications of the impact of inflammation on behavior.

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Haroon, Ebrahim; Raison, Charles L; Miller, Andrew H

2012-01-01

The potential contribution of chronic inflammation to the development of neuropsychiatric disorders such as major depression has received increasing attention. Elevated biomarkers of inflammation, including inflammatory cytokines and acute-phase proteins, have been found in depressed patients, and administration of inflammatory stimuli has been associated with the development of depressive symptoms. Data also have demonstrated that inflammatory cytokines can interact with multiple pathways known to be involved in the development of depression, including monoamine metabolism, neuroendocrine function, synaptic plasticity, and neurocircuits relevant to mood regulation. Further understanding of mechanisms by which cytokines alter behavior have revealed a host of pharmacologic targets that may be unique to the impact of inflammation on behavior and may be especially relevant to the treatment and prevention of depression in patients with evidence of increased inflammation. Such targets include the inflammatory signaling pathways cyclooxygenase, p38 mitogen-activated protein kinase, and nuclear factor-κB, as well as the metabolic enzyme, indoleamine-2,3-dioxygenase, which breaks down tryptophan into kynurenine. Other targets include the cytokines themselves in addition to chemokines, which attract inflammatory cells from the periphery to the brain. Psychosocial stress, diet, obesity, a leaky gut, and an imbalance between regulatory and pro-inflammatory T cells also contribute to inflammation and may serve as a focus for preventative strategies relevant to both the development of depression and its recurrence. Taken together, identification of mechanisms by which cytokines influence behavior may reveal a panoply of personalized treatment options that target the unique contributions of the immune system to depression.

Exercise training in older patients with systolic heart failure: Adherence, exercise capacity, inflammation and glycemic control

DEFF Research Database (Denmark)

Prescott, Eva; Hjardem-Hansen, Rasmus; Dela, Flemming

2009-01-01

markers of glycemic control (glucose, insulin, glycerol, free fatty acids, HbA1c), inflammation and endothelial function (hsCRP, orosomucoid, interleukin 6, TNF-alpha, urine-orosomucoid and -albumin/creatinin), lipid metabolism, NT-proBNP or other regulatory hormones (cortisol, epinephrine and IGF-1......). There were no changes in quality of life. Conclusions. The effect of exercise training in these older CHF-patients was not as impressive as reported in younger and more selected patients. More studies on the efficiency of exercise training that reflect the age- and co-morbidity of the majority of CHF...

Early postnatal exposure to intermittent hypoxia in rodents is proinflammatory, impairs white matter integrity, and alters brain metabolism.

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Darnall, Robert A; Chen, Xi; Nemani, Krishnamurthy V; Sirieix, Chrystelle M; Gimi, Barjor; Knoblach, Susan; McEntire, Betty L; Hunt, Carl E

2017-07-01

BackgroundPreterm infants are frequently exposed to intermittent hypoxia (IH) associated with apnea and periodic breathing that may result in inflammation and brain injury that later manifests as cognitive and executive function deficits. We used a rodent model to determine whether early postnatal exposure to IH would result in inflammation and brain injury.MethodsRat pups were exposed to IH from P2 to P12. Control animals were exposed to room air. Cytokines were analyzed in plasma and brain tissue at P13 and P18. At P20-P22, diffusion tensor imaging (DTI) and magnetic resonance spectroscopy (MRS) were performed.ResultsPups exposed to IH had increased plasma Gro/CXCL1 and cerebellar IFN-γ and IL-1β at P13, and brainstem enolase at P18. DTI showed a decrease in FA and AD in the corpus callosum (CC) and cingulate gyrus, and an increase in RD in the CC. MRS revealed decreases in NAA/Cho, Cr, Tau/Cr, and Gly/Cr; increases in TCho and GPC in the brainstem; and decreases in NAA/Cho in the hippocampus.ConclusionsWe conclude that early postnatal exposure to IH, similar in magnitude to that experienced in human preterm infants, is associated with evidence for proinflammatory changes, decreases in white matter integrity, and metabolic changes consistent with hypoxia.

Age Drives Distortion of Brain Metabolic, Vascular and Cognitive Functions, and the Gut Microbiome

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Jared D. Hoffman

2017-09-01

Full Text Available Advancing age is the top risk factor for the development of neurodegenerative disorders, including Alzheimer’s disease (AD. However, the contribution of aging processes to AD etiology remains unclear. Emerging evidence shows that reduced brain metabolic and vascular functions occur decades before the onset of cognitive impairments, and these reductions are highly associated with low-grade, chronic inflammation developed in the brain over time. Interestingly, recent findings suggest that the gut microbiota may also play a critical role in modulating immune responses in the brain via the brain-gut axis. In this study, our goal was to identify associations between deleterious changes in brain metabolism, cerebral blood flow (CBF, gut microbiome and cognition in aging, and potential implications for AD development. We conducted our study with a group of young mice (5–6 months of age and compared those to old mice (18–20 months of age by utilizing metabolic profiling, neuroimaging, gut microbiome analysis, behavioral assessments and biochemical assays. We found that compared to young mice, old mice had significantly increased levels of numerous amino acids and fatty acids that are highly associated with inflammation and AD biomarkers. In the gut microbiome analyses, we found that old mice had increased Firmicutes/Bacteroidetes ratio and alpha diversity. We also found impaired blood-brain barrier (BBB function and reduced CBF as well as compromised learning and memory and increased anxiety, clinical symptoms often seen in AD patients, in old mice. Our study suggests that the aging process involves deleterious changes in brain metabolic, vascular and cognitive functions, and gut microbiome structure and diversity, all which may lead to inflammation and thus increase the risk for AD. Future studies conducting comprehensive and integrative characterization of brain aging, including crosstalk with peripheral systems and factors, will be necessary to

Tributyltin induces oxidative damage, inflammation and apoptosis via disturbance in blood–brain barrier and metal homeostasis in cerebral cortex of rat brain: An in vivo and in vitro study

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Mitra, Sumonto; Gera, Ruchi; Siddiqui, Waseem A.; Khandelwal, Shashi

2013-01-01

Highlights: • Sustainable blood–brain barrier disruption was found by single acute dose of TBTC (up to 1 week). • Imbalance in essential metal homeostasis in the cortical tissue may lead to oxidative stress. • Astroglial activation and inflammation resulted in neuronal loss. • TBTC primarily induced apoptosis as found in in-vitro study via activation of calcium, p38 signaling, ROS and caspases. • Calcium inhibitors and anti-oxidants showed protective efficacy in TBTC induced cell death. - Abstract: Tributyltin (TBT), a member of the organotin family, is primarily used for its biocidal activity. Persistent environmental levels of TBT pose threat to the ecosystem. Since neurotoxic influence of TBT remains elusive, we therefore, studied its effect on cerebral cortex of male Wistar rats. A single oral dose of Tributyltin-Chloride (TBTC) (10, 20, 30 mg/kg) was administered and the animals were sacrificed on day 3 and day 7. Blood–brain barrier permeability remained disrupted significantly till day 7 with all the doses of TBTC. Pro-oxidant metal levels (Fe, Cu) were increased with a concomitant decrease in Zn. ROS generation was substantially raised resulting in oxidative damage (increased protein carbonylation and lipid peroxidation) with marked decline in tissue antioxidant status (GSH/GSSG levels). Protein expression studies indicated astrocyte activation, upregulation of inflammatory molecules (IL-6, Cox-2 and NF-κB) and simultaneous elevation in the apoptotic index (Bax/Bcl2). Neurodegeneration was evident by reduced neurofilament expression and increased calpain cleaved Tau levels. The in-vitro study demonstrated involvement of calcium and signaling molecules (p38), with downstream activation of caspase-3 and -8, and apoptotic cell death was evident by nuclear fragmentation, DNA laddering and Annexin V binding experiments. Ca 2+ inhibitors (BAPTA-AM, EGTA, and RR) and free radical scavengers (NAC and biliprotein [C-PC]) increased cell viability (MTT

Toll-Like Receptors, Inflammation, and Calcific Aortic Valve Disease

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Carmen García-Rodríguez

2018-03-01

Full Text Available Inflammation, the primary response of innate immunity, is essential to initiate the calcification process underlying calcific aortic valve disease (CAVD, the most prevalent valvulopathy in Western countries. The pathogenesis of CAVD is multifactorial and includes inflammation, hemodynamic factors, fibrosis, and active calcification. In the development of CAVD, both innate and adaptive immune responses are activated, and accumulating evidences show the central role of inflammation in the initiation and propagation phases of the disease, being the function of Toll-like receptors (TLR particularly relevant. These receptors act as sentinels of the innate immune system by recognizing pattern molecules from both pathogens and host-derived molecules released after tissue damage. TLR mediate inflammation via NF-κB routes within and beyond the immune system, and play a crucial role in the control of infection and the maintenance of tissue homeostasis. This review outlines the current notions about the association between TLR signaling and the ensuing development of inflammation and fibrocalcific remodeling in the pathogenesis of CAVD. Recent data provide new insights into the inflammatory and osteogenic responses underlying the disease and further support the hypothesis that inflammation plays a mechanistic role in the initiation and progression of CAVD. These findings make TLR signaling a potential target for therapeutic intervention in CAVD.

Microglial activation induced by brain trauma is suppressed by post-injury treatment with a PARP inhibitor

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d'Avila Joana C

2012-02-01

Full Text Available Abstract Background Traumatic brain injury (TBI induces activation of microglia. Activated microglia can in turn increase secondary injury and impair recovery. This innate immune response requires hours to days to become fully manifest, thus providing a clinically relevant window of opportunity for therapeutic intervention. Microglial activation is regulated in part by poly(ADP-ribose polymerase-1 (PARP-1. Inhibition of PARP-1 activity suppresses NF-kB-dependent gene transcription and thereby blocks several aspects of microglial activation. Here we evaluated the efficacy of a PARP inhibitor, INO-1001, in suppressing microglial activation after cortical impact in the rat. Methods Rats were subjected to controlled cortical impact and subsequently treated with 10 mg/kg of INO-1001 (or vehicle alone beginning 20 - 24 hours after the TBI. Brains were harvested at several time points for histological evaluation of inflammation and neuronal survival, using markers for microglial activation (morphology and CD11b expression, astrocyte activation (GFAP, and neuronal survival (NeuN. Rats were also evaluated at 8 weeks after TBI using measures of forelimb dexterity: the sticky tape test, cylinder test, and vermicelli test. Results Peak microglial and astrocyte activation was observed 5 to 7 days after this injury. INO-1001 significantly reduced microglial activation in the peri-lesion cortex and ipsilateral hippocampus. No rebound inflammation was observed in rats that were treated with INO-1001 or vehicle for 12 days followed by 4 days without drug. The reduced inflammation was associated with increased neuronal survival in the peri-lesion cortex and improved performance on tests of forelimb dexterity conducted 8 weeks after TBI. Conclusions Treatment with a PARP inhibitor for 12 days after TBI, with the first dose given as long as 20 hours after injury, can reduce inflammation and improve histological and functional outcomes.

Inflaming the diseased brain: a role for tainted melanins.

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Jeitner, T M; Kalogiannis, M; Patrick, P A; Gomolin, I; Palaia, T; Ragolia, L; Brand, D; Delikatny, E J

2015-05-01

Inflammation plays a crucial role in neurodegenerative diseases, but the irritants responsible for this response remain largely unknown. This report addressed the hypothesis that hypochlorous acid reacts with dopamine to produce melanic precipitates that promote cerebral inflammation. Spectrophotometric studies demonstrated that nM amounts of HOCl and dopamine react within seconds. A second-order rate constant for the reaction of HOCl and dopamine of 2.5 × 10(4)M(-1)s(-1) was obtained by measuring loss of dopaminergic fluorescence due to HOCl. Gravimetric measurements, electron microscopy, elemental analysis, and a novel use of flow cytometry confirmed that the major product of this reaction is a precipitate with an average diameter of 1.5 μm. Flow cytometry was also used to demonstrate the preferential reaction of HOCl with dopamine rather than albumin. Engulfment of the chlorodopamine particulates by phagocytes in vitro caused these cells to release TNFα and die. Intrastriatal administration of 10(6) particles also increased the content of TNFα in the brain and led to a 50% loss of the dopaminergic neurons in the nigra. These studies indicate that HOCl and dopamine react quickly and preferentially with each other to produce particles that promote inflammation and neuronal death in the brain. Copyright © 2015 Elsevier B.V. All rights reserved.

Brain mechanisms that control sleep and waking

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Siegel, Jerome

This review paper presents a brief historical survey of the technological and early research that laid the groundwork for recent advances in sleep-waking research. A major advance in this field occurred shortly after the end of World War II with the discovery of the ascending reticular activating system (ARAS) as the neural source in the brain stem of the waking state. Subsequent research showed that the brain stem activating system produced cortical arousal via two pathways: a dorsal route through the thalamus and a ventral route through the hypothalamus and basal forebrain. The nuclei, pathways, and neurotransmitters that comprise the multiple components of these arousal systems are described. Sleep is now recognized as being composed of two very different states: rapid eye movements (REMs) sleep and non-REM sleep. The major findings on the neural mechanisms that control these two sleep states are presented. This review ends with a discussion of two current views on the function of sleep: to maintain the integrity of the immune system and to enhance memory consolidation.

Digit ratio (2D:4D) in primary brain tumor patients: A case-control study.

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Bunevicius, Adomas; Tamasauskas, Sarunas; Deltuva, Vytenis Pranas; Tamasauskas, Arimantas; Sliauzys, Albertas; Bunevicius, Robertas

2016-12-01

The second-to-fourth digit ratio (2D:4D) reflects prenatal estrogen and testosterone exposure, and is established in utero. Sex steroids are implicated in development and progression of primary brain tumors. To investigate whether there is a link between 2D:4D ratio and primary brain tumors, and age at presentation. Digital images of the right and left palms of 85 primary brain tumor patients (age 56.96±13.68years; 71% women) and 106 (age 54.31±13.68years; 68% women) gender and age matched controls were obtained. The most common brain tumor diagnoses were meningioma (41%), glioblastoma (20%) and pituitary adenoma (16%). Right and left 2D:4D ratios, and right minus left 2D:4D (D r-l ) were compared between patients and controls, and were correlated with age. Right and left 2D:4D ratios were significantly lower in primary brain tumor patients relative to controls (t=-4.28, pbrain tumor patients and controls (p=0.27). In meningioma and glioma patients, age at presentation correlated negatively with left 2D:4D ratio (rho=-0.42, p=0.01 and rho=-0.36, p=0.02, respectively) and positively with D r-l (rho=0.45, p=0.009 and rho=0.65, p=0.04, respectively). Right and left hand 2D:4D ratios are lower in primary brain tumor patients relative to healthy individuals suggesting greater prenatal testosterone and lower prenatal estrogen exposure in brain tumor patients. Greater age at presentation is associated with greater D r-l and with lower left 2D:4D ratio of meningioma and glioma patients. Due to small sample size our results should be considered preliminary and interpreted with caution. Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.

Moderate-intensity interval training increases serum brain-derived neurotrophic factor level and decreases inflammation in Parkinson's disease patients.

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Zoladz, J A; Majerczak, J; Zeligowska, E; Mencel, J; Jaskolski, A; Jaskolska, A; Marusiak, J

2014-06-01

It has been demonstrated that physical training increases serum brain-derived neurotrophic factor (BDNF) in healthy people. The aim of this study was to establish the effect of physical training on the basal serum level of the BDNF in the Parkinson's disease patients (PD patients) in relation to their health status. Twelve PD patients (mean ± S.E.M: age 70 ± 3 years; body mass 70 ± 2 kg; height 163 ± 3 cm) performed a moderate-intensity interval training (three 1-hour training sessions weekly), lasting 8 weeks. Basal serum BDNF in the PD patients before training amounted to 10,977 ± 756 pg x mL(-1) and after 8 weeks of training it has increased to 14,206 ± 1256 pg x mL(-1) (i.e. by 34%, P=0.03). This was accompanied by an attenuation of total Unified Parkinson's Disease Rating Scale (UPDRS) (P=0.01). The training resulted also in a decrease of basal serum soluble vascular cell adhesion molecule 1 (sVCAM-1) (P=0.001) and serum tumor necrosis factor-α (TNF-α) (P=0.03) levels. We have concluded that the improvement of health status of the Parkinson's disease patients after training could be related to the increase of serum BDNF level caused by the attenuated inflammation in those patients.

Monocyte Trafficking to the Brain with Stress and Inflammation: A Novel Axis of Immune-to-Brain Communication that Influences Mood and Behavior

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Eric S Wohleb

2015-01-01

Full Text Available Psychological stressors cause physiological, immunological, and behavioral alterations in humans and rodents that can be maladaptive and negatively affect quality of life. Several lines of evidence indicate that psychological stress disrupts key functional interactions between the immune system and brain that ultimately affects mood and behavior. For example, activation of microglia, the resident innate immune cells of the brain, has been implicated as a key regulator of mood and behavior in the context of prolonged exposure to psychological stress. Emerging evidence implicates a novel neuroimmune circuit involving microglia activation and sympathetic outflow to the peripheral immune system that further reinforces stress-related behaviors by facilitating the recruitment of inflammatory monocytes to the brain. Evidence from various rodent models, including repeated social defeat (RSD, revealed that trafficking of monocytes to the brain promoted the establishment of anxiety-like behaviors following prolonged stress exposure. In addition, new evidence implicates monocyte trafficking from the spleen to the brain as key regulator of recurring anxiety following exposure to prolonged stress. The purpose of this review is to discuss mechanisms that cause stress-induced monocyte re-distribution in the brain and how dynamic interactions between microglia, endothelial cells, and brain macrophages lead to maladaptive behavioral responses.

Effects of an Encapsulated Fruit and Vegetable Juice Concentrate on Obesity-Induced Systemic Inflammation: A Randomised Controlled Trial

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Evan J. Williams

2017-02-01

Full Text Available Phytochemicals from fruit and vegetables reduce systemic inflammation. This study examined the effects of an encapsulated fruit and vegetable (F&V juice concentrate on systemic inflammation and other risk factors for chronic disease in overweight and obese adults. A double-blinded, parallel, randomized placebo-controlled trial was conducted in 56 adults aged ≥40 years with a body mass index (BMI ≥28 kg/m2. Before and after eight weeks daily treatment with six capsules of F&V juice concentrate or placebo, peripheral blood gene expression (microarray, quantitative polymerase chain reaction (qPCR, plasma tumour necrosis factor (TNFα (enzyme-linked immunosorbent assay (ELISA, body composition (Dual-energy X-ray absorptiometry (DEXA and lipid profiles were assessed. Following consumption of juice concentrate, total cholesterol, low-density lipoprotein (LDL cholesterol and plasma TNFα decreased and total lean mass increased, while there was no change in the placebo group. In subjects with high systemic inflammation at baseline (serum C-reactive protein (CRP ≥3.0 mg/mL who were supplemented with the F&V juice concentrate (n = 16, these effects were greater, with decreased total cholesterol, LDL cholesterol and plasma TNFα and increased total lean mass; plasma CRP was unchanged by the F&V juice concentrate following both analyses. The expression of several genes involved in lipogenesis, the nuclear factor-κB (NF-κB and 5′ adenosine monophosphate-activated protein kinase (AMPK signalling pathways was altered, including phosphomevalonate kinase (PMVK, zinc finger AN1-type containing 5 (ZFAND5 and calcium binding protein 39 (CAB39, respectively. Therefore, F&V juice concentrate improves the metabolic profile, by reducing systemic inflammation and blood lipid profiles and, thus, may be useful in reducing the risk of obesity-induced chronic disease.

Surveillance, Phagocytosis, and Inflammation: How Never-Resting Microglia Influence Adult Hippocampal Neurogenesis

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Amanda Sierra

2014-01-01

Full Text Available Microglia cells are the major orchestrator of the brain inflammatory response. As such, they are traditionally studied in various contexts of trauma, injury, and disease, where they are well-known for regulating a wide range of physiological processes by their release of proinflammatory cytokines, reactive oxygen species, and trophic factors, among other crucial mediators. In the last few years, however, this classical view of microglia was challenged by a series of discoveries showing their active and positive contribution to normal brain functions. In light of these discoveries, surveillant microglia are now emerging as an important effector of cellular plasticity in the healthy brain, alongside astrocytes and other types of inflammatory cells. Here, we will review the roles of microglia in adult hippocampal neurogenesis and their regulation by inflammation during chronic stress, aging, and neurodegenerative diseases, with a particular emphasis on their underlying molecular mechanisms and their functional consequences for learning and memory.

Cyanotoxins at low doses induce apoptosis and inflammatory effects in murine brain cells: Potential implications for neurodegenerative diseases

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Larissa Takser

Full Text Available Cyanotoxins have been shown to be highly toxic for mammalian cells, including brain cells. However, little is known about their effect on inflammatory pathways. This study investigated whether mammalian brain and immune cells can be a target of certain cyanotoxins, at doses approximating those in the guideline levels for drinking water, either alone or in mixtures. We examined the effects on cellular viability, apoptosis and inflammation signalling of several toxins on murine macrophage-like RAW264.7, microglial BV-2 and neuroblastoma N2a cell lines. We tested cylindrospermopsin (CYN, microcystin-LR (MC-LR, and anatoxin-a (ATX-a, individually as well as their mixture. In addition, we studied the neurotoxins β-N-methylamino-l-alanine (BMAA and its isomer 2,4-diaminobutyric acid (DAB, as well as the mixture of both. Cellular viability was determined by the MTT assay. Apoptosis induction was assessed by measuring the activation of caspases 3/7. Cell death and inflammation are the hallmarks of neurodegenerative diseases. Thus, our final step was to quantify the expression of a major proinflammatory cytokine TNF-α by ELISA. Our results show that CYN, MC-LR and ATX-a, but not BMAA and DAB, at low doses, especially when present in a mixture at threefold less concentrations than individual compounds are 3–15 times more potent at inducing apoptosis and inflammation. Our results suggest that common cyanotoxins at low doses have a potential to induce inflammation and apoptosis in immune and brain cells. Further research of the neuroinflammatory effects of these compounds in vivo is needed to improve safety limit levels for cyanotoxins in drinking water and food. Keywords: Cyanotoxins, Low doses, Apoptosis, Inflammation, Brain cells, Neurodegenerative diseases

A brain-computer interface controlled mail client.

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Yu, Tianyou; Li, Yuanqing; Long, Jinyi; Wang, Cong

2013-01-01

In this paper, we propose a brain-computer interface (BCI) based mail client. This system is controlled by hybrid features extracted from scalp-recorded electroencephalographic (EEG). We emulate the computer mouse by the motor imagery-based mu rhythm and the P300 potential. Furthermore, an adaptive P300 speller is included to provide text input function. With this BCI mail client, users can receive, read, write mails, as well as attach files in mail writing. The system has been tested on 3 subjects. Experimental results show that mail communication with this system is feasible.

Traumatic Brain Injuries during Development: Implications for Alcohol Abuse

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Zachary M. Weil

2017-07-01

Full Text Available Traumatic brain injuries are strongly related to alcohol intoxication as by some estimates half or more of all brain injuries involve at least one intoxicated individual. Additionally, there is mounting evidence that traumatic brain injuries can themselves serve as independent risk factors for the development of alcohol use disorders, particularly when injury occurs during juvenile or adolescent development. Here, we will review the epidemiological and experimental evidence for this phenomenon and discuss potential psychosocial mediators including attenuation of negative affect and impaired decision making as well as neurochemical mediators including disruption in the glutamatergic, GABAergic, and dopaminergic signaling pathways and increases in inflammation.

Brain and behavioral inhibitory control of kindergartners facing negative emotions.

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Farbiash, Tali; Berger, Andrea

2016-09-01

Inhibitory control (IC) - one of the most critical functions underlying a child's ability to self-regulate - develops significantly throughout the kindergarten years. Experiencing negative emotions imposes challenges on executive functioning and may specifically affect IC. In this study, we examined kindergartners' IC and its related brain activity during a negative emotional situation: 58 children (aged 5.5-6.5 years) performed an emotion-induction Go/NoGo task. During this task, we recorded children's performance and brain activity, focusing on the fronto-central N2 component in the event-related potential (ERP) and the power of its underlying theta frequency. Compared to Go trials, inhibition of NoGo trials was associated with larger N2 amplitudes and theta power. The negative emotional experience resulted in better IC performance and, at the brain level, in larger theta power. Source localization of this effect showed that the brain activity related to IC during the negative emotional experience was principally generated in the posterior frontal regions. Furthermore, the band power measure was found to be a more sensitive index for children's inhibitory processes than N2 amplitudes. This is the first study to focus on kindergartners' IC while manipulating their emotional experience to induce negative emotions. Our findings suggest that a kindergartner's experience of negative emotion can result in improved IC and increases in associated aspects of brain activity. Our results also suggest the utility of time-frequency analyses in the study of brain processes associated with response inhibition in young children. © 2015 John Wiley & Sons Ltd.

Establishment of minimal positive-control conditions to ensure brain safety during rapid development of emergency vaccines.

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Baek, Hyekyung; Kim, Kwang Ho; Park, Min Young; Kim, Kyeongryun; Ko, Bokyeong; Seo, Hyung Seok; Kim, Byoung Soo; Hahn, Tae-Wook; Yi, Sun Shin

2017-08-31

With the increase in international human and material exchanges, contagious and infectious epidemics are occurring. One of the effective methods of epidemic inhibition is the rapid development and supply of vaccines. Considering the safety of the brain during vaccine development is very important. However, manuals for brain safety assays for new vaccines are not uniform or effective globally. Therefore, the aim of this study is to establish a positive-control protocol for an effective brain safety test to enhance rapid vaccine development. The blood-brain barrier's tight junctions provide selective defense of the brain; however, it is possible to destroy these important microstructures by administering lipopolysaccharides (LPSs), thereby artificially increasing the permeability of brain parenchyma. In this study, test conditions are established so that the degree of brain penetration or brain destruction of newly developed vaccines can be quantitatively identified. The most effective conditions were suggested by measuring time-dependent expressions of tight junction biomarkers (zonula occludens-1 [ZO-1] and occludin) in two types of mice (C57BL/6 and ICR) following exposure to two types of LPS ( Salmonella and Escherichia ). In the future, we hope that use of the developed positive-control protocol will help speed up the determination of brain safety of novel vaccines.

[Technological advances and micro-inflammation in dialysis patients].

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Ferro, Giuseppe; Ravaglia, Fiammetta; Ferrari, Elisa; Romoli, Elena; Michelassi, Stefano; Caiani, David; Pizzarelli, Francesco

2015-01-01

As currently performed, on line hemodiafiltration reduces, but does not normalize, the micro-inflammation of uremic patients. Recent technological advances make it possible to further reduce the inflammation connected to the dialysis treatment. 
Short bacterial DNA fragments are pro-inflammatory and can be detected in the dialysis fluids. However, their determination is not currently within normal controls of the quality of the dialysate. The scenario may change once the analysis of these fragments yields reliable, inexpensive, quick and easy to evaluate the results. At variance with standard bicarbonate dialysate, Citrate dialysate induces far less inflammation both for the well-known anti-inflammatory effect of such buffer and also because it is completely acetate free, e.g. a definitely pro-inflammatory buffer. However, the extensive use of citrate dialysate in chronic dialysis is prevented because of concerns about its potential calcium lowering effect. In our view, high convective exchange on line hemodiafiltration performed with dialysate, whose sterility and a-pirogenicity is guaranteed by increasingly sophisticated controls and with citrate buffer whose safety is certified, can serve as the gold standard of dialysis treatments in future.

The effect of almonds on inflammation and oxidative stress in Chinese patients with type 2 diabetes mellitus: a randomized crossover controlled feeding trial

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Almond consumption is associated with ameliorations in obesity, hyperlipidemia, hypertension, and hyperglycemia. The hypothesis of this 12-wk randomized, crossover, controlled feeding trial was that almond consumption would ameliorate inflammation and oxidative stress in Chinese patients with type 2...

Excessive sleep need following traumatic brain injury: a case-control study of 36 patients.

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Sommerauer, Michael; Valko, Philipp O; Werth, Esther; Baumann, Christian R

2013-12-01

Increased sleep need following traumatic brain injury, referred to in this study as post-traumatic pleiosomnia, is common, but so far its clinical impact and therapeutic implications have not been characterized. We present a case-control study of 36 patients with post-traumatic pleiosomnia, defined by an increased sleep need of at least 2 h per 24 h after traumatic brain injury, compared to 36 controls. We assessed detailed history, sleep-activity patterns with sleep logs and actigraphy, nocturnal sleep with polysomnography and daytime sleep propensity with multiple sleep latency tests. Actigraphy recordings revealed that traumatic brain injury (TBI) patients had longer estimated sleep durations than controls (10.8 h per 24 h, compared to 7.3 h). When using sleep logs, TBI patients underestimated their sleep need. During nocturnal sleep, patients had higher amounts of slow-wave sleep than controls (20 versus 13.8%). Multiple sleep latency tests revealed excessive daytime sleepiness in 15 patients (42%), and 10 of them had signs of chronic sleep deprivation. We conclude that post-traumatic pleiosomnia may be even more frequent than reported previously, because affected patients often underestimate their actual sleep need. Furthermore, these patients exhibit an increase in slow-wave sleep which may reflect recovery mechanisms, intrinsic consequences of diffuse brain damage or relative sleep deprivation. © 2013 European Sleep Research Society.

Control of Drosophila Type I and Type II central brain neuroblast proliferation by bantam microRNA

DEFF Research Database (Denmark)

Weng, Ruifen; Cohen, Stephen M

2015-01-01

Post-transcriptional regulation of stem cell self-renewal by microRNAs is emerging as an important mechanism controlling tissue homeostasis. Here, we provide evidence that bantam microRNA controls neuroblast number and proliferation in the Drosophila central brain. Bantam also supports proliferat......Post-transcriptional regulation of stem cell self-renewal by microRNAs is emerging as an important mechanism controlling tissue homeostasis. Here, we provide evidence that bantam microRNA controls neuroblast number and proliferation in the Drosophila central brain. Bantam also supports...

Inflammatory injury to the neonatal brain – what can we do?

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Noa eOfek-shlomai

2014-04-01

Full Text Available Abstract Perinatal brain damage is one of the leading causes of life long disability. This damage could be hypoxic-ischemic, inflammatory or both.This mini-review discusses different interventions aiming at minimizing inflammatory processes in the neonatal brain, both before and after insult. Current options of anti-inflammatory measures for neonates remain quite limited. We describe current anti-inflammatory intervention strategies such as avoiding perinatal infection and inflammation, and reducing exposure to inflammatory processes. We describe the known effects of anti-inflammatory drugs such as steroids, antibiotics, and indomethacin, and the possible anti-inflammatory role of other substances such as IL-1receptor antagonists, erythropoietin, caffeine, estradiol, insulin like growth factor and melatonin as well as endogenous protectors, and genetic regulation of inflammation. If successful, these may decrease mortality and long term morbidity among term and preterm infants.

The effects of overnight nutrient intake on hypothalamic inflammation in a free-choice diet-induced obesity rat model

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Belegri, Evita; Eggels, Leslie; Unmehopa, Unga A; Mul, Joram D; Boelen, Anita; la Fleur, Susanne E

2018-01-01

Consumption of fat and sugar induces hyperphagia and increases the prevalence of obesity and diabetes type 2. Low-grade inflammation in the hypothalamus, a key brain area involved in the regulation of energy homeostasis is shown to blunt signals of satiety after long term high fat diet. The fact

Creatine kinase activity in dogs with experimentally induced acute inflammation

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Dimitrinka Zapryanova

2013-01-01

Full Text Available The main purpose of this study was to investigate the effect of acute inflammation on total creatine kinase (CK activity in dogs. In these animals, CK is an enzyme found predominantly in skeletal muscle and significantly elevated serum activity is largely associated with muscle damage. Plasma increases in dogs are associated with cell membrane leakage and will therefore be seen in any condition associated with muscular inflammation. The study was induced in 15 mongrel male dogs (n=9 in experimental group and n=6 in control group at the age of two years and body weight 12-15 kg. The inflammation was reproduced by inoculation of 2 ml turpentine oil subcutaneously in lumbar region. The plasma activity of creatine kinase was evaluated at 0, 6, 24, 48, 72 hours after inoculation and on days 7, 14 and 21 by a kit from Hospitex Diagnostics. In the experimental group, the plasma concentrations of the CK-activity were increased at the 48th hour (97.48±6.92 U/L and remained significantly higher (p<0.05 at the 72 hour (97.43±2.93 U/L compared to the control group (77.08±5.27 U/L. The results of this study suggest that the evaluation of creatine kinase in dogs with experimentally induced acute inflammation has a limited diagnostic value. It was observed that the creatine kinase activity is slightly affected by the experimentally induced acute inflammation in dogs.

Contribution of neuroinflammation and immunity to brain aging and the mitigating effects of physical and cognitive interventions.

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Di Benedetto, Svetlana; Müller, Ludmila; Wenger, Elisabeth; Düzel, Sandra; Pawelec, Graham

2017-04-01

It is widely accepted that the brain and the immune system continuously interact during normal as well as pathological functioning. Human aging is commonly accompanied by low-grade inflammation in both the immune and central nervous systems, thought to contribute to many age-related diseases. This review of the current literature focuses first on the normal neuroimmune interactions occurring in the brain, which promote learning, memory and neuroplasticity. Further, we discuss the protective and dynamic role of barriers to neuroimmune interactions, which have become clearer with the recent discovery of the meningeal lymphatic system. Next, we consider age-related changes of the immune system and possible deleterious influences of immunosenescence and low-grade inflammation (inflammaging) on neurodegenerative processes in the normally aging brain. We survey the major immunomodulators and neuroregulators in the aging brain and their highly tuned dynamic and reciprocal interactions. Finally, we consider our current understanding of how physical activity, as well as a combination of physical and cognitive interventions, may mediate anti-inflammatory effects and thus positively impact brain aging. Copyright © 2017 Elsevier Ltd. All rights reserved.

Characterization and pharmacological modulation of intestinal inflammation induced by ionizing radiation; Caracterisation et modulation pharmacologique de l'inflammation intestinale induite par les rayonnements ionisants

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Gremy, O

2006-12-15

The use of radiation therapy to treat abdominal and pelvic malignancies inevitably involves exposure of healthy intestinal tissues which are very radiosensitive. As a result, most patients experience symptoms such as abdominal pain, nausea and diarrhea. Such symptoms are associated with acute damage to intestine mucosa including radio-induced inflammatory processes. With a rat model of colorectal fractionated radiation, we have shown a gradual development of a colonic inflammation during radiation planning, without evident tissue injury. This radio-induced inflammation is characterized not only by the sur expressions of pro-inflammatory cytokines and chemokines, a NF-kB activation, but also by a repression of anti-inflammatory cytokines and the nuclear receptors PPARa and RXRa, both involved in inflammation control. This early inflammation is associated with a discreet neutrophil recruitment and a macrophage accumulation. Macrophages are still abnormally numerous in tissue 27 weeks after the last day of irradiation. Inflammatory process is the most often related to a specific immune profile, either a type Th1 leading to a cellular immune response, or a type Th2 for humoral immunity. According to our studies, a unique abdominal radiation in the rat induces an ileum inflammation and an immune imbalance resulting in a Th2-type profile. Inhibiting this profile is important as its persistence promotes chronic inflammation, predisposition to bacterial infections and fibrosis which is the main delayed side-effect of radiotherapy. The treatment of rats with an immuno-modulator compound, the caffeic acid phenethyl ester (C.A.P.E.), have the potential to both reduce ileal mucosal inflammation and inhibit the radio-induced Th2 status. In order to search new therapeutic molecular target, we has been interested in the PPARg nuclear receptor involved in the maintenance of colon mucosal integrity. In our abdominal irradiation model, we have demonstrated that the prophylactic

Air pollution and detrimental effects on children's brain. The need for a multidisciplinary approach to the issue complexity and challenges.

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Calderón-Garcidueñas, Lilian; Torres-Jardón, Ricardo; Kulesza, Randy J; Park, Su-Bin; D'Angiulli, Amedeo

2014-01-01

Millions of children in polluted cities are showing brain detrimental effects. Urban children exhibit brain structural and volumetric abnormalities, systemic inflammation, olfactory, auditory, vestibular and cognitive deficits v low-pollution controls. Neuroinflammation and blood-brain-barrier (BBB) breakdown target the olfactory bulb, prefrontal cortex and brainstem, but are diffusely present throughout the brain. Urban adolescent Apolipoprotein E4 carriers significantly accelerate Alzheimer pathology. Neurocognitive effects of air pollution are substantial, apparent across all populations, and potentially clinically relevant as early evidence of evolving neurodegenerative changes. The diffuse nature of the neuroinflammation and neurodegeneration forces to employ a weight of evidence approach incorporating current clinical, cognitive, neurophysiological, radiological and epidemiological research. Pediatric air pollution research requires extensive multidisciplinary collaborations to accomplish a critical goal: to protect exposed children through multidimensional interventions having both broad impact and reach. Protecting children and teens from neural effects of air pollution should be of pressing importance for public health.

A PET study on brain control of micturition in humans

NARCIS (Netherlands)

Blok, BFM; Willemsen, ATM; Holstege, G

Although the brain plays a crucial role in the control of micturition, little is known about the structures involved. Identification of these areas is important because their dysfunction is thought to cause urge incontinence, a major problem in the elderly. In the cat, three areas in the brainstem

Evidence that the EphA2 receptor exacerbates ischemic brain injury.

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John Thundyil

Full Text Available Ephrin (Eph signaling within the central nervous system is known to modulate axon guidance, synaptic plasticity, and to promote long-term potentiation. We investigated the potential involvement of EphA2 receptors in ischemic stroke-induced brain inflammation in a mouse model of focal stroke. Cerebral ischemia was induced in male C57Bl6/J wild-type (WT and EphA2-deficient (EphA2(-/- mice by middle cerebral artery occlusion (MCAO; 60 min, followed by reperfusion (24 or 72 h. Brain infarction was measured using triphenyltetrazolium chloride staining. Neurological deficit scores and brain infarct volumes were significantly less in EphA2(-/- mice compared with WT controls. This protection by EphA2 deletion was associated with a comparative decrease in brain edema, blood-brain barrier damage, MMP-9 expression and leukocyte infiltration, and higher expression levels of the tight junction protein, zona occludens-1. Moreover, EphA2(-/- brains had significantly lower levels of the pro-apoptotic proteins, cleaved caspase-3 and BAX, and higher levels of the anti-apoptotic protein, Bcl-2 as compared to WT group. We confirmed that isolated WT cortical neurons express the EphA2 receptor and its ligands (ephrin-A1-A3. Furthermore, expression of all four proteins was increased in WT primary cortical neurons following 24 h of glucose deprivation, and in the brains of WT mice following stroke. Glucose deprivation induced less cell death in primary neurons from EphA2(-/- compared with WT mice. In conclusion, our data provide the first evidence that the EphA2 receptor directly contributes to blood-brain barrier damage and neuronal death following ischemic stroke.

Berberine Ameliorates Diabetes-Associated Cognitive Decline through Modulation of Aberrant Inflammation Response and Insulin Signaling Pathway in DM Rats

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Qingjie Chen

2017-06-01

Full Text Available Background: Memory-impairment was one of the common characteristics in patients with diabetes mellitus. The release of chronic inflammation mediators and insulin resistance in diabetic brain gave rise to the generation of toxic factor Aβ42 which was the marker of Alzheimer’s disease. In addition, the impairment of memory in diabetes mellitus was also correlated predominantly with uptake/metabolism of glucose in medial prefrontal cortex (mPFC. Previously, anti-inflammation and hypoglycemic effects of berberine (BBr have been described in peripheral tissues. For better understanding the effects of BBr on cognitive action in diabetics, we investigated the functions of BBr involved in anti-inflammation and ameliorating insulin resistance in prefrontal cortex of diabetic rats.Methods: Intragastric administration of BBr (187.5 mg/Kg/d was used in diabetic rats. Fear-condition assay was applied for cognitive assessment, and relative protein expressions were detected by western-blot. The glucose uptake in prefrontal cortex of diabetic rats was tested by Positron-Emission Tomography imaging. The levels of inflammation mediators were determined by commercial ELISA kits.Results: The inflammation mediator release and insulin resistance in the mPFC of diabetic rats was inhibited by BBr. The activation of PI3K/Akt/mTOR and MAPK signaling pathway, as well as two novel isoforms PKCη and PKC and the translocation of NF-κB in neuron were also down-regulated by BBr; furthermore, the neuron specific glucose transporter GLUT3 was remarkably augmented by 2–3 times when compared with diabetic group; meanwhile, BBr also promoted glucose uptake in the brain. Additionally BBr decreased the expressions of amyloid precursor protein and BACE-1, and the production of oligomeric Aβ42. Finally, it accelerates the reinforcement of the information and ameliorates cognitive impairment.Conclusion: BBr inhibited the activation of inflammation pathway and insulin resistance

Effect of ovariectomy on inflammation induced by intermittent hypoxia in a mouse model of sleep apnea.

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Torres, Marta; Palomer, Xavier; Montserrat, Josep M; Vázquez-Carrera, Manel; Farré, Ramon

2014-10-01

Patient data report marked gender and pre-vs-postmenopausal differences in obstructive sleep apnea (OSA). However, no experimental data are available on how sexual hormones modulate OSA consequences. Here we report novel results on estrogen-modulated heart and brain inflammation in female mice subjected to intermittent hypoxia, a major injurious challenge in OSA. C57BL/6J (14-week old) intact and ovariectomized mice (n=6 each) were subjected to intermittent hypoxia (20 s at 5% and 40s at 21%, 60 cycles/h; 6 h/day). Identical intact and ovariectomized groups breathing room air were controls. After 30 days, the gene expressions of interleukins 6 and 8 (IL-6, IL-8) in the brain and heart tissues were measured. Whereas, compared with normoxia, intermittent hypoxia considerably increased IL-6 and IL-8 gene expressions in intact females, no change was found in ovariectomized mice when comparing normoxia and intermittent hypoxia. These data suggest that estrogens modulate the inflammatory effects of intermittent hypoxia and point to further studies on the role played by sex hormones in OSA. Copyright © 2014 Elsevier B.V. All rights reserved.

Smaller brain size likely in young adults (<40 years old) with depressive symptoms compared to healthy controls. A retrospective study

International Nuclear Information System (INIS)

Adachi, Michito; Sato, Takamichi; Kawaguchi, Etsuko; Shibata, Akiko

2011-01-01

The aim of this study was to determine whether the brain size of young patients with depressive symptoms is smaller than that of healthy controls using magnetic resonance imaging (MRI). We retrospectively evaluated brain size by calculating the ratio of the brain area to that of the skull (the brain-to-skull ratio) on routine MRI scans including the splenium of the corpus callosum obtained from 19 patients <40 years old with depressive symptoms in 2009. The controls were 12 healthy individuals <40 years old who underwent MRI for medical examinations. The mean brain-to-skull ratio of the control group was 0.850±0.022 (range 0.822-0.889), and that of the patient group was 0.819±0.041 (range 0.756-0.878). An unpaired t-test showed a significant difference in the brain-to-skull ratios between these groups (P=0.011). In particular, in 7 of the 19 patients with longer duration of illness and more severe symptoms, the brain-to-skull ratio was 89%-92% of the mean ratio of the control group. The brain size of young patients with depressive symptoms appears to be smaller than that of healthy controls. (author)

Early post-natal exposure to intermittent hypoxia in rodents is pro-inflammatory, impairs white matter integrity and alters brain metabolism

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Darnall, Robert A.; Chen, Xi; Nemani, Krishnamurthy V.; Sirieix, Chrystelle M.; Gimi, Barjor; Knoblach, Susan; McEntire, Betty L.; Hunt, Carl E.

2017-01-01

Background Preterm infants are frequently exposed to intermittent hypoxia (IH) associated with apnea and periodic breathing that may result in inflammation and brain injury that later manifests as cognitive and executive function deficits. We used a rodent model to determine whether early postnatal exposure to IH would result in inflammation and brain injury. Methods Rat pups were exposed to IH from P2–P12. Control animals were exposed to room air. Cytokines were analyzed in plasma and brain tissue at P13 and P18. At P20–P22, diffusion tensor imaging (DTI) and magnetic resonance spectroscopy (MRS) were performed. Results Pups exposed to IH had increased plasma Gro/CXCL1 and cerebellar IFN-γ and IL-1β at P13, and brainstem enolase at P18. DTI showed a decrease in FA and AD in the corpus callosum (CC) and cingulate gyrus and an increase in RD in the CC. MRS revealed decreases in NAA/Cho, Cr, Tau/Cr and Gly/Cr and increases in TCho and GPC in the brainstem and decreases in NAA/Cho in the hippocampus. Conclusions We conclude that early postnatal exposure to IH, similar in magnitude experienced in human preterm infants, is associated with evidence for pro-inflammatory changes, decreases in white matter integrity, and metabolic changes consistent with hypoxia. PMID:28388601

Neonatal CNS infection and inflammation caused by Ureaplasma species: rare or relevant?

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Glaser, Kirsten; Speer, Christian P

2015-02-01

Colonization with Ureaplasma species has been associated with adverse pregnancy outcome, and perinatal transmission has been implicated in the development of bronchopulmonary dysplasia in preterm neonates. Little is known about Ureaplasma-mediated infection and inflammation of the CNS in neonates. Controversy remains concerning its incidence and implication in the pathogenesis of neonatal brain injury. In vivo and in vitro data are limited. Despite improving care options for extremely immature preterm infants, relevant complications remain. Systematic knowledge of ureaplasmal infection may be of great benefit. This review aims to summarize pathogenic mechanisms, clinical data and diagnostic pitfalls. Studies in preterm and term neonates are critically discussed with regard to their limitations. Clinical questions concerning therapy or prophylaxis are posed. We conclude that ureaplasmas may be true pathogens, especially in preterm neonates, and may cause CNS inflammation in a complex interplay of host susceptibility, serovar pathogenicity and gestational age-dependent CNS vulnerability.

Brain Ceramide Metabolism in the Control of Energy Balance

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Céline Cruciani-Guglielmacci

2017-10-01

Full Text Available The regulation of energy balance by the central nervous system (CNS is a key actor of energy homeostasis in mammals, and deregulations of the fine mechanisms of nutrient sensing in the brain could lead to several metabolic diseases such as obesity and type 2 diabetes (T2D. Indeed, while neuronal activity primarily relies on glucose (lactate, pyruvate, the brain expresses at high level enzymes responsible for the transport, utilization and storage of lipids. It has been demonstrated that discrete neuronal networks in the hypothalamus have the ability to detect variation of circulating long chain fatty acids (FA to regulate food intake and peripheral glucose metabolism. During a chronic lipid excess situation, this physiological lipid sensing is impaired contributing to type 2 diabetes in predisposed subjects. Recently, different studies suggested that ceramides levels could be involved in the regulation of energy balance in both hypothalamic and extra-hypothalamic areas. Moreover, under lipotoxic conditions, these ceramides could play a role in the dysregulation of glucose homeostasis. In this review we aimed at describing the potential role of ceramides metabolism in the brain in the physiological and pathophysiological control of energy balance.

Effect of acute moderate exercise on induced inflammation and arterial function in older adults.

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Ranadive, Sushant Mohan; Kappus, Rebecca Marie; Cook, Marc D; Yan, Huimin; Lane, Abbi Danielle; Woods, Jeffrey A; Wilund, Kenneth R; Iwamoto, Gary; Vanar, Vishwas; Tandon, Rudhir; Fernhall, Bo

2014-04-01

Acute inflammation reduces flow-mediated vasodilatation and increases arterial stiffness in young healthy individuals. However, this response has not been studied in older adults. The aim of this study, therefore, was to evaluate the effect of acute induced systemic inflammation on endothelial function and wave reflection in older adults. Furthermore, an acute bout of moderate-intensity aerobic exercise can be anti-inflammatory. Taken together, we tested the hypothesis that acute moderate-intensity endurance exercise, immediately preceding induced inflammation, would be protective against the negative effects of acute systemic inflammation on vascular function. Fifty-nine healthy volunteers between 55 and 75 years of age were randomized to an exercise or a control group. Both groups received a vaccine (induced inflammation) and sham (saline) injection in a counterbalanced crossover design. Inflammatory markers, endothelial function (flow-mediated vasodilatation) and measures of wave reflection and arterial stiffness were evaluated at baseline and at 24 and 48 h after injections. There were no significant differences in endothelial function and arterial stiffness between the exercise and control group after induced inflammation. The groups were then analysed together, and we found significant differences in the inflammatory markers 24 and 48 h after induction of acute inflammation compared with sham injection. However, flow-mediated vasodilatation, augmentation index normalized for heart rate (AIx75) and β-stiffness did not change significantly. Our results suggest that acute inflammation induced by influenza vaccination did not affect endothelial function in older adults.

Role of Peroxisome Proliferator-Activated Receptors in Inflammation Control

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Jihan Youssef

2004-01-01

Full Text Available Peroxisome proliferator-activated receptors (PPARs were discovered over a decade ago, and were classified as orphan members of the nuclear receptor superfamily. To date, three PPAR subtypes have been discovered and characterized (PPARα, β/δ, γ. Different PPAR subtypes have been shown to play crucial roles in important diseases and conditions such as obesity, diabetes, atherosclerosis, cancer, and fertility. Among the most studied roles of PPARs is their involvement in inflammatory processes. Numerous studies have revealed that agonists of PPARα and PPARγ exert anti-inflammatory effects both in vitro and in vivo. Using the carrageenan-induced paw edema model of inflammation, a recent study in our laboratories showed that these agonists hinder the initiation phase, but not the late phase of the inflammatory process. Furthermore, in the same experimental model, we recently also observed that activation of PPARδ exerted an anti-inflammatory effect. Despite the fact that exclusive dependence of these effects on PPARs has been questioned, the bulk of evidence suggests that all three PPAR subtypes, PPARα,δ,γ, play a significant role in controlling inflammatory responses. Whether these subtypes act via a common mechanism or are independent of each other remains to be elucidated. However, due to the intensity of research efforts in this area, it is anticipated that these efforts will result in the development of PPAR ligands as therapeutic agents for the treatment of inflammatory diseases.

Brain-specific transcriptional regulator T-brain-1 controls brain wiring and neuronal activity in autism spectrum disorders

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Tzyy-Nan eHuang

2015-11-01

Full Text Available T-brain-1 (TBR1 is a brain-specific T-box transcription factor. In 1995, Tbr1 was first identified from a subtractive hybridization that compared mouse embryonic and adult telencephalons. Previous studies of Tbr1–/– mice have indicated critical roles for TBR1 in the development of the cerebral cortex, amygdala and olfactory bulb. Neuronal migration and axonal projection are two important developmental features controlled by TBR1. Recently, recurrent de novo disruptive mutations in the TBR1 gene have been found in patients with autism spectrum disorders (ASDs. Human genetic studies have identified TBR1 as a high-confidence risk factor for ASDs. Because only one allele of the TBR1 gene is mutated in these patients, Tbr1+/– mice serve as a good genetic mouse model to explore the mechanism by which de novo TBR1 mutation leads to ASDs. Although neuronal migration and axonal projection defects of cerebral cortex are the most prominent phenotypes in Tbr1–/– mice, these features are not found in Tbr1+/– mice. Instead, inter- and intra-amygdalar axonal projections and NMDAR expression and activity in amygdala are particularly susceptible to Tbr1 haploinsufficiency. The studies indicated that both abnormal brain wiring (abnormal amygdalar connections and excitation/inhibition imbalance (NMDAR hypoactivity, two prominent models for ASD etiology, are present in Tbr1+/– mice. Moreover, calcium/calmodulin-dependent serine protein kinase (CASK was found to interact with TBR1. The CASK-TBR1 complex had been shown to directly bind the promoter of the Grin2b gene, which is also known as Nmdar2b, and upregulate Grin2b expression. This molecular function of TBR1 provides an explanation for NMDAR hypoactivity in Tbr1+/– mice. In addition to Grin2b, cell adhesion molecules－including Ntng1, Cdh8 and Cntn2－are also regulated by TBR1 to control axonal projections of amygdala. Taken together, the studies of Tbr1 provide an integrated picture of ASD

[Inhibition of glycogen synthase kinase 3b activity regulates Toll-like receptor 4-mediated liver inflammation].

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Ren, Feng; Zhang, Hai-yan; Piao, Zheng-fu; Zheng, Su-jun; Chen, Yu; Chen, De-xi; Duan, Zhong-ping

2012-09-01

To determine the mechanism underlying the therapeutic activities of glycogen synthase kinase 3b (GSK3b) against hepatic ischemia-reperfusion (H-IR) injury by investigating the inhibitive effects of GSK3b on inflammation mediated by Toll-like receptor 4 (TLR4). C57BL/6 male mice were subjected to 90 min of warm liver cephalad lobe ischemia, followed by reperfusion for various lengths of time. The mice were divided into three groups: the H-IR untreated model (control group), and the H-IR inflammation-induced models that received an intraperitoneal injection of purified lipopolysaccharide (LPS) endotoxin alone (inflammation group) or with pretreatment of the SB216763 GSK3b-specific inhibitor (intervention group). To create a parallel isolated cell system for detailed investigations of macrophages, marrow-derived stem cells were isolated from femurs of the H-IR control group of mice and used to derive primary macrophages. The cells were then divided into the same three groups as the whole mouse system: control, LPS-induced inflammation model, and inflammation model with SB216763 intervention. Differential expressions of inflammation-related proteins and genes were detected by Western blotting and real-time quantitative PCR, respectively. The phosphorylation levels of ERK, JNK and p38 MAPK were induced in liver at 1 h after reperfusion, but then steadily decreased and returned to baseline levels by 4 h after reperfusion. In addition, the phosphorylation levels of ERK and JNK were induced in macrophages at 15 min after LPS stimulation, while the phosphorylation level of p38 MAPK was induced at 1 h; SB216763 pretreatment suppressed the LPS-stimulated ERK, JNK and p38 phosphorylation in macrophages. In the mouse model, GSK3b activity was found to promote the gene expression of anti-inflammatory cytokine IL-10 (control: 0.21 ± 0.08, inflammation: 0.83 ± 0.21, intervention: 1.76 ± 0.67; F = 3.16, P = 0.027) but to significantly inhibit the gene expression of pro

Incidence of adult brain cancers is higher in countries where the protozoan parasite Toxoplasma gondii is common

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Thomas, Frédéric; Lafferty, Kevin D.; Brodeur, Jacques; Elguero, Eric; Gauthier-Clerc, Michel; Missé, Dorothée

2011-01-01

We explored associations between the common protozoan parasite Toxoplasma gondii and brain cancers in human populations. We predicted that T. gondii could increase the risk of brain cancer because it is a long-lived parasite that encysts in the brain, where it provokes inflammation and inhibits apoptosis. We used a medical geography approach based on the national incidence of brain cancers and seroprevalence of T. gondii. We corrected reports of incidence for national gross domestic product b...

Leukemia and brain tumors in Norwegian railway workers, a nested case-control study.

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Tynes, T; Jynge, H; Vistnes, A I

1994-04-01

In an attempt to assess whether exposure to electromagnetic fields on Norwegian railways induces brain tumors or leukemia, the authors conducted a nested case-control study of railway workers based on incident cases from the Cancer Registry of Norway in a cohort of 13,030 male Norwegian railway workers who had worked on either electric or non-electric railways. The cohort comprised railway line, outdoor station, and electricity workers. The case series comprised 39 men with brain tumors and 52 men with leukemia (follow-up, 1958-1990). Each case was matched on age with four or five controls selected from the same cohort. The exposure of each study subject to electric and magnetic fields was evaluated from cumulative exposure measures based on present measurements and historical data. Limited information on potential confounders such as creosote, solvents, and herbicides was also collected; information on whether the subject had smoked was obtained by interviews with the subjects or work colleagues. The case-control analysis showed that men employed on electric railways, compared with non-electric ones, had an odds ratio for leukemia of 0.70 (adjusted for smoking) and an odds ratio for brain tumor of 0.87. No significant trend was shown for exposure to either magnetic or electric fields. These results do not support an association between exposure to 16 2/3-Hertz electric or magnetic fields and the risk for leukemia or brain tumors.

Brain-Heart Interaction: Cardiac Complications After Stroke.

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Chen, Zhili; Venkat, Poornima; Seyfried, Don; Chopp, Michael; Yan, Tao; Chen, Jieli

2017-08-04

Neurocardiology is an emerging specialty that addresses the interaction between the brain and the heart, that is, the effects of cardiac injury on the brain and the effects of brain injury on the heart. This review article focuses on cardiac dysfunction in the setting of stroke such as ischemic stroke, brain hemorrhage, and subarachnoid hemorrhage. The majority of post-stroke deaths are attributed to neurological damage, and cardiovascular complications are the second leading cause of post-stroke mortality. Accumulating clinical and experimental evidence suggests a causal relationship between brain damage and heart dysfunction. Thus, it is important to determine whether cardiac dysfunction is triggered by stroke, is an unrelated complication, or is the underlying cause of stroke. Stroke-induced cardiac damage may lead to fatality or potentially lifelong cardiac problems (such as heart failure), or to mild and recoverable damage such as neurogenic stress cardiomyopathy and Takotsubo cardiomyopathy. The role of location and lateralization of brain lesions after stroke in brain-heart interaction; clinical biomarkers and manifestations of cardiac complications; and underlying mechanisms of brain-heart interaction after stroke, such as the hypothalamic-pituitary-adrenal axis; catecholamine surge; sympathetic and parasympathetic regulation; microvesicles; microRNAs; gut microbiome, immunoresponse, and systemic inflammation, are discussed. © 2017 American Heart Association, Inc.

Elevated Ictal Brain Network Ictogenicity Enables Prediction of Optimal Seizure Control

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Marinho A. Lopes

2018-03-01

Full Text Available Recent studies have shown that mathematical models can be used to analyze brain networks by quantifying how likely they are to generate seizures. In particular, we have introduced the quantity termed brain network ictogenicity (BNI, which was demonstrated to have the capability of differentiating between functional connectivity (FC of healthy individuals and those with epilepsy. Furthermore, BNI has also been used to quantify and predict the outcome of epilepsy surgery based on FC extracted from pre-operative ictal intracranial electroencephalography (iEEG. This modeling framework is based on the assumption that the inferred FC provides an appropriate representation of an ictogenic network, i.e., a brain network responsible for the generation of seizures. However, FC networks have been shown to change their topology depending on the state of the brain. For example, topologies during seizure are different to those pre- and post-seizure. We therefore sought to understand how these changes affect BNI. We studied peri-ictal iEEG recordings from a cohort of 16 epilepsy patients who underwent surgery and found that, on average, ictal FC yield higher BNI relative to pre- and post-ictal FC. However, elevated ictal BNI was not observed in every individual, rather it was typically observed in those who had good post-operative seizure control. We therefore hypothesize that elevated ictal BNI is indicative of an ictogenic network being appropriately represented in the FC. We evidence this by demonstrating superior model predictions for post-operative seizure control in patients with elevated ictal BNI.

Autoimmunity/inflammation in a monogenic primary immunodeficiency cohort.

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Rae, William; Ward, Daniel; Mattocks, Christopher J; Gao, Yifang; Pengelly, Reuben J; Patel, Sanjay V; Ennis, Sarah; Faust, Saul N; Williams, Anthony P

2017-09-01

Primary immunodeficiencies (PIDs) are rare inborn errors of immunity that have a heterogeneous phenotype that can include severe susceptibility to life-threatening infections from multiple pathogens, unique sensitivity to a single pathogen, autoimmune/inflammatory (AI/I) disease, allergies and/or malignancy. We present a diverse cohort of monogenic PID patients with and without AI/I diseases who underwent clinical, genetic and immunological phenotyping. Novel pathogenic variants were identified in IKBKG , CTLA4 , NFKB1 , GATA2 , CD40LG and TAZ as well as previously reported pathogenic variants in STAT3 , PIK3CD , STAT1 , NFKB2 and STXBP2 . AI/I manifestations were frequently encountered in PIDs, including at presentation. Autoimmunity/inflammation was multisystem in those effected, and regulatory T cell (Treg) percentages were significantly decreased compared with those without AI/I manifestations. Prednisolone was used as the first-line immunosuppressive agent in all cases, however steroid monotherapy failed long-term control of autoimmunity/inflammation in the majority of cases and additional immunosuppression was required. Patients with multisystem autoimmunity/inflammation should be investigated for an underlying PID, and in those with PID early assessment of Tregs may help to assess the risk of autoimmunity/inflammation.

The NALP3/Cryopyrin-Inflammasome Complex is Expressed in LPS-Induced Ocular Inflammation

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José F. González-Benítez

2008-01-01

Full Text Available In the inflammosome complex, NALP3 or NALP1 binds to ASC and activates caspase-1 which induces IL-1β. In murine LPS-induced ocular inflammation, the production of IL-1β is increased. We suggest that NALP3- or NALP1-inflammasome complex can be participating in the LPS-induced ocular inflammation. In this work, eye, brain, testis, heart, spleen, and lung were obtained from C3H/HeN mice treated with LPS for 3 to 48 hours, and the expression of NALP1b, NALP3, ASC, caspase-1, IL-1β, and IL-18 was determined. Infiltrated leukocytes producing IL-1β in the anterior chamber were found at 12-hour posttreatment. A high upregulated expression of NALP3, ASC, caspase-1, IL-1β, and IL-18 was found at the same time when infiltrated leukocytes were observed. NALP1b was not detected in the eye of treated mice. NALP3 was also overexpressed in heart and lung. These results suggest that NALP3-, but not NALP1-inflammosome complex, is participating in the murine LPS-induced ocular inflammation.

Characterization and pharmacological modulation of intestinal inflammation induced by ionizing radiation; Caracterisation et modulation pharmacologique de l'inflammation intestinale induite par les rayonnements ionisants

Energy Technology Data Exchange (ETDEWEB)

Gremy, O

2006-12-15

The use of radiation therapy to treat abdominal and pelvic malignancies inevitably involves exposure of healthy intestinal tissues which are very radiosensitive. As a result, most patients experience symptoms such as abdominal pain, nausea and diarrhea. Such symptoms are associated with acute damage to intestine mucosa including radio-induced inflammatory processes. With a rat model of colorectal fractionated radiation, we have shown a gradual development of a colonic inflammation during radiation planning, without evident tissue injury. This radio-induced inflammation is characterized not only by the sur expressions of pro-inflammatory cytokines and chemokines, a NF-kB activation, but also by a repression of anti-inflammatory cytokines and the nuclear receptors PPARa and RXRa, both involved in inflammation control. This early inflammation is associated with a discreet neutrophil recruitment and a macrophage accumulation. Macrophages are still abnormally numerous in tissue 27 weeks after the last day of irradiation. Inflammatory process is the most often related to a specific immune profile, either a type Th1 leading to a cellular immune response, or a type Th2 for humoral immunity. According to our studies, a unique abdominal radiation in the rat induces an ileum inflammation and an immune imbalance resulting in a Th2-type profile. Inhibiting this profile is important as its persistence promotes chronic inflammation, predisposition to bacterial infections and fibrosis which is the main delayed side-effect of radiotherapy. The treatment of rats with an immuno-modulator compound, the caffeic acid phenethyl ester (C.A.P.E.), have the potential to both reduce ileal mucosal inflammation and inhibit the radio-induced Th2 status. In order to search new therapeutic molecular target, we has been interested in the PPARg nuclear receptor involved in the maintenance of colon mucosal integrity. In our abdominal irradiation model, we have demonstrated that the prophylactic

Brain Diseases

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The brain is the control center of the body. It controls thoughts, memory, speech, and movement. It regulates the function of many organs. When the brain is healthy, it works quickly and automatically. However, ...

Brain-Computer Interface application: auditory serial interface to control a two-class motor-imagery-based wheelchair.

Science.gov (United States)

Ron-Angevin, Ricardo; Velasco-Álvarez, Francisco; Fernández-Rodríguez, Álvaro; Díaz-Estrella, Antonio; Blanca-Mena, María José; Vizcaíno-Martín, Francisco Javier

2017-05-30

Certain diseases affect brain areas that control the movements of the patients' body, thereby limiting their autonomy and communication capacity. Research in the field of Brain-Computer Interfaces aims to provide patients with an alternative communication channel not based on muscular activity, but on the processing of brain signals. Through these systems, subjects can control external devices such as spellers to communicate, robotic prostheses to restore limb movements, or domotic systems. The present work focus on the non-muscular control of a robotic wheelchair. A proposal to control a wheelchair through a Brain-Computer Interface based on the discrimination of only two mental tasks is presented in this study. The wheelchair displacement is performed with discrete movements. The control signals used are sensorimotor rhythms modulated through a right-hand motor imagery task or mental idle state. The peculiarity of the control system is that it is based on a serial auditory interface that provides the user with four navigation commands. The use of two mental tasks to select commands may facilitate control and reduce error rates compared to other endogenous control systems for wheelchairs. Seventeen subjects initially participated in the study; nine of them completed the three sessions of the proposed protocol. After the first calibration session, seven subjects were discarded due to a low control of their electroencephalographic signals; nine out of ten subjects controlled a virtual wheelchair during the second session; these same nine subjects achieved a medium accuracy level above 0.83 on the real wheelchair control session. The results suggest that more extensive training with the proposed control system can be an effective and safe option that will allow the displacement of a wheelchair in a controlled environment for potential users suffering from some types of motor neuron diseases.

Brain functional plasticity associated with the emergence of expertise in extreme language control.

Science.gov (United States)

Hervais-Adelman, Alexis; Moser-Mercer, Barbara; Golestani, Narly

2015-07-01

We used functional magnetic resonance imaging (fMRI) to longitudinally examine brain plasticity arising from long-term, intensive simultaneous interpretation training. Simultaneous interpretation is a bilingual task with heavy executive control demands. We compared brain responses observed during simultaneous interpretation with those observed during simultaneous speech repetition (shadowing) in a group of trainee simultaneous interpreters, at the beginning and at the end of their professional training program. Age, sex and language-proficiency matched controls were scanned at similar intervals. Using multivariate pattern classification, we found distributed patterns of changes in functional responses from the first to second scan that distinguished the interpreters from the controls. We also found reduced recruitment of the right caudate nucleus during simultaneous interpretation as a result of training. Such practice-related change is consistent with decreased demands on multilingual language control as the task becomes more automatized with practice. These results demonstrate the impact of simultaneous interpretation training on the brain functional response in a cerebral structure that is not specifically linguistic, but that is known to be involved in learning, in motor control, and in a variety of domain-general executive functions. Along with results of recent studies showing functional and structural adaptations in the caudate nuclei of experts in a broad range of domains, our results underline the importance of this structure as a central node in expertise-related networks. Copyright © 2015 Elsevier Inc. All rights reserved.

High-protein diet improves sensitivity to cholecystokinin and shifts the cecal microbiome without altering brain inflammation in diet-induced obesity in rats.

Science.gov (United States)

Wang, Lixin; Jacobs, Jonathan P; Lagishetty, Venu; Yuan, Pu-Qing; Wu, Shuping V; Million, Mulugeta; Reeve, Joseph R; Pisegna, Joseph R; Taché, Yvette

2017-10-01

High-protein diet (HPD) curtails obesity and/or fat mass, but it is unknown whether it reverses neuroinflammation or alters glucose levels, CCK sensitivity, and gut microbiome in rats fed a Western diet (WD)-induced obesity (DIO). Male rats fed a WD (high fat and sugar) for 12 wk were switched to a HPD for 6 wk. Body composition, food intake, meal pattern, sensitivity to intraperitoneal CCK-8S, blood glucose, brain signaling, and cecal microbiota were assessed. When compared with a normal diet, WD increased body weight (9.3%) and fat mass (73.4%). CCK-8S (1.8 or 5.2 nmol/kg) did not alter food intake and meal pattern in DIO rats. Switching to a HPD for 6 wk reduced fat mass (15.7%) with a nonsignificantly reduced body weight gain, normalized blood glucose, and decreased feeding after CCK-8S. DIO rats on the WD or switched to a HPD showed comparable microbial diversity. However, in HPD versus WD rats, there was enrichment of 114 operational taxonomic units (OTUs) and depletion of 188 OTUs. Of those, Akkermansia muciniphila (enriched on a HPD), an unclassified Clostridiales, a member of the RF39 order, and a Phascolarctobacterium were significantly associated with fat mass. The WD increased cytokine expression in the hypothalamus and dorsal medulla that was unchanged by switching to HPD. These data indicate that HPD reduces body fat and restores glucose homeostasis and CCK sensitivity, while not modifying brain inflammation. In addition, expansion of cecal Akkermansia muciniphila correlated to fat mass loss may represent a potential peripheral mechanism of HPD beneficial effects.

Chapter 8 Military Personnel With Traumatic Brain Injuries and Insomnia Have Reductions in PTSD and Improved Perceived Health Following Sleep Restoration: A Relationship Moderated by Inflammation.

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Barr, Taura; Livingston, Whitney; Guardado, Pedro; Baxter, Tristin; Mysliwiec, Vincent; Gill, Jessica

2015-01-01

Up to one-third of deployed military personnel sustain a traumatic brain injury (TBI). TBIs and the stress of deployment contribute to the vulnerability for chronic sleep disturbance, resulting in high rates of insomnia diagnoses as well as symptoms of posttraumatic stress disorder (PTSD), depression, and declines in health-related quality of life (HRQOL). Inflammation is associated with insomnia; however, the impact of sleep changes on comorbid symptoms and inflammation in this population is unknown. In this study, we examined the relationship between reported sleep changes and the provision of the standard of care, which could include one or more of the following: cognitive behavioral therapy (CBT), medications, and continuous positive airway pressure (CPAP). We compared the following: (a) the group with a decrease in the Pittsburgh Sleep Quality Index (PSQI; restorative sleep) and (b) the group with no change or increase in PSQI (no change). Independent t tests and chi-square tests were used to compare the groups on demographic and clinical characteristics, and mixed between-within subjects analysis of variance tests were used to determine the effect of group differences on changes in comorbid symptoms. Linear regression models were used to examine the role of inflammation in changes in symptoms and HRQOL. The sample included 70 recently deployed military personnel with TBI, seeking care for sleep disturbances. Thirty-seven participants reported restorative sleep and 33 reported no sleep changes or worse sleep. The two groups did not differ in demographic characteristics or clinical symptoms at baseline. The TBI+restored sleep group had significant reductions in PTSD and depression over the 3-month period, whereas the TBI+no change group had a slight increase in both PTSD and depression. The TBI+restored sleep group also had significant changes in HRQOL, including the following HRQOL subcomponents: physical functioning, role limitations in physical health

Sensorless speed control of switched reluctance motor using brain emotional learning based intelligent controller

International Nuclear Information System (INIS)

Dehkordi, Behzad Mirzaeian; Parsapoor, Amir; Moallem, Mehdi; Lucas, Caro

2011-01-01

In this paper, a brain emotional learning based intelligent controller (BELBIC) is developed to control the switched reluctance motor (SRM) speed. Like other intelligent controllers, BELBIC is model free and is suitable to control nonlinear systems. Motor parameter changes, operating point changes, measurement noise, open circuit fault in one phase and asymmetric phases in SRM are also simulated to show the robustness and superior performance of BELBIC. To compare the BELBIC performance with other intelligent controllers, Fuzzy Logic Controller (FLC) is developed. System responses with BELBIC and FLC are compared. Furthermore, by eliminating the position sensor, a method is introduced to estimate the rotor position. This method is based on Adaptive Neuro Fuzzy Inference System (ANFIS). The estimator inputs are four phase flux linkages. Suggested rotor position estimator is simulated in different conditions. Simulation results confirm the accurate rotor position estimation in different loads and speeds.

Sensorless speed control of switched reluctance motor using brain emotional learning based intelligent controller

Energy Technology Data Exchange (ETDEWEB)

Dehkordi, Behzad Mirzaeian, E-mail: mirzaeian@eng.ui.ac.i [Department of Electrical Engineering, Faculty of Engineering, University of Isfahan, Hezar-Jerib St., Postal code 8174673441, Isfahan (Iran, Islamic Republic of); Parsapoor, Amir, E-mail: amirparsapoor@yahoo.co [Department of Electrical Engineering, Faculty of Engineering, University of Isfahan, Hezar-Jerib St., Postal code 8174673441, Isfahan (Iran, Islamic Republic of); Moallem, Mehdi, E-mail: moallem@cc.iut.ac.i [Department of Electrical Engineering, Isfahan University of Technology, Isfahan (Iran, Islamic Republic of); Lucas, Caro, E-mail: lucas@ut.ac.i [Centre of Excellence for Control and Intelligent Processing, Electrical and Computer Engineering Faculty, College of Engineering, University of Tehran, Tehran (Iran, Islamic Republic of)

2011-01-15

In this paper, a brain emotional learning based intelligent controller (BELBIC) is developed to control the switched reluctance motor (SRM) speed. Like other intelligent controllers, BELBIC is model free and is suitable to control nonlinear systems. Motor parameter changes, operating point changes, measurement noise, open circuit fault in one phase and asymmetric phases in SRM are also simulated to show the robustness and superior performance of BELBIC. To compare the BELBIC performance with other intelligent controllers, Fuzzy Logic Controller (FLC) is developed. System responses with BELBIC and FLC are compared. Furthermore, by eliminating the position sensor, a method is introduced to estimate the rotor position. This method is based on Adaptive Neuro Fuzzy Inference System (ANFIS). The estimator inputs are four phase flux linkages. Suggested rotor position estimator is simulated in different conditions. Simulation results confirm the accurate rotor position estimation in different loads and speeds.

Enhanced attenuation of meningeal inflammation and brain edema by concomitant administration of anti-CD18 monoclonal antibodies and dexamethasone in experimental Haemophilus meningitis.

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Sáez-Llorens, X; Jafari, H S; Severien, C; Parras, F; Olsen, K D; Hansen, E J; Singer, I I; McCracken, G H

1991-12-01

Antiinflammatory therapy has been shown to reduce the adverse pathophysiological consequences that occur in bacterial meningitis and to improve outcome from disease. In the present study, modulation of two principal steps of the meningeal inflammatory cascade was accomplished by concomitant administration of dexamethasone to diminish overproduction of cytokines in response to a bacterial stimulus and of a monoclonal antibody directed against adhesion-promoting receptors on leukocytes to inhibit recruitment of white blood cells into the subarachnoid space. Dexamethasone and antibody therapy produced a marked attenuation of all indices of meningeal inflammation and reduction of brain water accumulation after H. influenzae-induced meningitis in rabbits compared with results of each agent given alone and of untreated animals. In addition, the enhanced host's meningeal inflammatory reaction that follows antibiotic-induced bacterial lysis was profoundly ameliorated when dual therapy was administered without affecting clearance rates of bacteria from cerebrospinal fluid and vascular compartments. The combination of both therapeutic approaches may offer a promising mode of treatment to improve further the outcome from bacterial meningitis.

Towards brain-activity-controlled information retrieval: Decoding image relevance from MEG signals.

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Kauppi, Jukka-Pekka; Kandemir, Melih; Saarinen, Veli-Matti; Hirvenkari, Lotta; Parkkonen, Lauri; Klami, Arto; Hari, Riitta; Kaski, Samuel

2015-05-15

We hypothesize that brain activity can be used to control future information retrieval systems. To this end, we conducted a feasibility study on predicting the relevance of visual objects from brain activity. We analyze both magnetoencephalographic (MEG) and gaze signals from nine subjects who were viewing image collages, a subset of which was relevant to a predetermined task. We report three findings: i) the relevance of an image a subject looks at can be decoded from MEG signals with performance significantly better than chance, ii) fusion of gaze-based and MEG-based classifiers significantly improves the prediction performance compared to using either signal alone, and iii) non-linear classification of the MEG signals using Gaussian process classifiers outperforms linear classification. These findings break new ground for building brain-activity-based interactive image retrieval systems, as well as for systems utilizing feedback both from brain activity and eye movements. Copyright © 2015 Elsevier Inc. All rights reserved.

Evidence from intrinsic activity that asymmetry of the human brain is controlled by multiple factors

OpenAIRE

Liu, Hesheng; Stufflebeam, Steven M.; Sepulcre, Jorge; Hedden, Trey; Buckner, Randy L.

2009-01-01

Cerebral lateralization is a fundamental property of the human brain and a marker of successful development. Here we provide evidence that multiple mechanisms control asymmetry for distinct brain systems. Using intrinsic activity to measure asymmetry in 300 adults, we mapped the most strongly lateralized brain regions. Both men and women showed strong asymmetries with a significant, but small, group difference. Factor analysis on the asymmetric regions revealed 4 separate factors that each ac...

Neuroprotective Effect of Dexmedetomidine on Hyperoxia-Induced Toxicity in the Neonatal Rat Brain

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Marco Sifringer

2015-01-01

Full Text Available Dexmedetomidine is a highly selective agonist of α2-receptors with sedative, anxiolytic, analgesic, and anesthetic properties. Neuroprotective effects of dexmedetomidine have been reported in various brain injury models. In the present study, we investigated the effects of dexmedetomidine on neurodegeneration, oxidative stress markers, and inflammation following the induction of hyperoxia in neonatal rats. Six-day-old Wistar rats received different concentrations of dexmedetomidine (1, 5, or 10 µg/kg bodyweight and were exposed to 80% oxygen for 24 h. Sex-matched littermates kept in room air and injected with normal saline or dexmedetomidine served as controls. Dexmedetomidine pretreatment significantly reduced hyperoxia-induced neurodegeneration in different brain regions of the neonatal rat. In addition, dexmedetomidine restored the reduced/oxidized glutathione ratio and attenuated the levels of malondialdehyde, a marker of lipid peroxidation, after exposure to high oxygen concentration. Moreover, administration of dexmedetomidine induced downregulation of IL-1β on mRNA and protein level in the developing rat brain. Dexmedetomidine provides protections against toxic oxygen induced neonatal brain injury which is likely associated with oxidative stress signaling and inflammatory cytokines. Our results suggest that dexmedetomidine may have a therapeutic potential since oxygen administration to neonates is sometimes inevitable.

Helicobacter pylori coinfection is a confounder, modulating mucosal inflammation in oral submucous fibrosis

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Rajendran R

2009-01-01

Full Text Available The oral cavity has been considered a potential reservoir for Helicobacter pylori (H pylori , from where the organism causes recurrent gastric infections. Aim: With this case-control study we tried to evaluate the role of H pylori in the etiology of mucosal inflammation, a condition that compounds the morbid state associated with oral submucous fibrosis (OSF. Materials and Methods : Subjects ( n = 150 were selected following institutional regulations on sample collection and grouped into test cases and positive and negative controls based on the presence of mucosal fibrosis and inflammation. The negative controls had none of the clinical signs. All patients underwent an oral examination as well as tests to assess oral hygiene/periodontal disease status; a rapid urease test (RUT of plaque samples was also done to estimate the H pylori bacterial load. We used univariate and mutivariate logistic regression for statistical analysis of the data and calculated the odds ratios to assess the risk posed by the different variables. Results : The RUT results differed significantly between the groups, reflecting the variations in the bacterial loads in each category. The test was positive in 52% in the positive controls (where nonspecific inflammation of oral mucosa was seen unassociated with fibrosis, in 46% of the test cases, and in 18% of the negative controls (healthy volunteers (χ2 = 13.887; P < 0.01. A positive correlation was seen between the oral hygiene/periodontal disease indices and RUT reactivity in all the three groups. Conclusions: The contribution of the H pylori in dental plaque to mucosal inflammation and periodontal disease was significant. Logistic regression analysis showed gastrointestinal disease and poor oral hygiene as being the greatest risk factors for bacterial colonization, irrespective of the subject groups. A positive correlation exists between RUT reactivity and the frequency of mucosal inflammation.

Brain responses to sound intensity changes dissociate depressed participants and healthy controls.

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Ruohonen, Elisa M; Astikainen, Piia

2017-07-01

Depression is associated with bias in emotional information processing, but less is known about the processing of neutral sensory stimuli. Of particular interest is processing of sound intensity which is suggested to indicate central serotonergic function. We tested weather event-related brain potentials (ERPs) to occasional changes in sound intensity can dissociate first-episode depressed, recurrent depressed and healthy control participants. The first-episode depressed showed larger N1 amplitude to deviant sounds compared to recurrent depression group and control participants. In addition, both depression groups, but not the control group, showed larger N1 amplitude to deviant than standard sounds. Whether these manifestations of sensory over-excitability in depression are directly related to the serotonergic neurotransmission requires further research. The method based on ERPs to sound intensity change is fast and low-cost way to objectively measure brain activation and holds promise as a future diagnostic tool. Copyright © 2017 Elsevier B.V. All rights reserved.

Preliminary application of SPECT three dimensional brain imaging in normal controls and patients with cerebral infarction

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Zhaosheng, Luan; Pengyong,; Xiqin, Sun; Wei, Wang; Huisheng, Liu; Wen, Zhou [88 Hospital PLA, Taian, SD (China). Dept. of Nuclear Medicine

1992-11-01

10 normal controls and 32 cerebral infarction patients were examined with SPECT three-dimensional (3D) and sectional imaging. The result shows that 3D brain imaging has significant value in the diagnosis of cerebral infarction. 3D brain imaging is superior to sectional imaging in determining the location and size of superficial lesions. For the diagnosis of deep lesions, it is better to combine 3D brain imaging with sectional imaging. The methodology of 3D brain imaging is also discussed.

Preliminary application of SPECT three dimensional brain imaging in normal controls and patients with cerebral infarction

International Nuclear Information System (INIS)

Luan Zhaosheng; Pengyong; Sun Xiqin; Wang Wei; Liu Huisheng; Zhou Wen

1992-01-01

10 normal controls and 32 cerebral infarction patients were examined with SPECT three-dimensional (3D) and sectional imaging. The result shows that 3D brain imaging has significant value in the diagnosis of cerebral infarction. 3D brain imaging is superior to sectional imaging in determining the location and size of superficial lesions. For the diagnosis of deep lesions, it is better to combine 3D brain imaging with sectional imaging. The methodology of 3D brain imaging is also discussed

Human brain expansion during evolution is independent of fire control and cooking

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Alianda Maira Cornélio

2016-04-01

Full Text Available What makes humans unique? This question has fascinated scientists and philosophers for centuries and it is still a matter of intense debate. Nowadays, human brain expansion during evolution has been acknowledged to explain our empowered cognitive capabilities. The drivers for such accelerated expansion remain, however, largely unknown. In this sense, studies have suggested that the cooking of food could be a pre-requisite for the expansion of brain size in early hominins. However, this appealing hypothesis is only supported by a mathematical model suggesting that the increasing number of neurons in the brain would constrain body size among primates due to a limited amount of calories obtained from diets. Here, we show, by using a similar mathematical model, that a tradeoff between body mass and the number of brain neurons imposed by dietary constraints during hominin evolution is unlikely. Instead, the predictable number of neurons in the hominin brain varies much more in function of foraging efficiency than body mass. We also review archeological data to show that the expansion of the brain volume in the hominin lineage is described by a linear function independent of evidences of fire control, and therefore, thermal processing of food does not account for this phenomenon. Finally, we report experiments in mice showing that thermal processing of meat does not increase its caloric availability in mice. Altogether, our data indicate that cooking is neither sufficient nor necessary to explain hominin brain expansion.

Human Brain Expansion during Evolution Is Independent of Fire Control and Cooking.

Science.gov (United States)

Cornélio, Alianda M; de Bittencourt-Navarrete, Ruben E; de Bittencourt Brum, Ricardo; Queiroz, Claudio M; Costa, Marcos R

2016-01-01

What makes humans unique? This question has fascinated scientists and philosophers for centuries and it is still a matter of intense debate. Nowadays, human brain expansion during evolution has been acknowledged to explain our empowered cognitive capabilities. The drivers for such accelerated expansion remain, however, largely unknown. In this sense, studies have suggested that the cooking of food could be a pre-requisite for the expansion of brain size in early hominins. However, this appealing hypothesis is only supported by a mathematical model suggesting that the increasing number of neurons in the brain would constrain body size among primates due to a limited amount of calories obtained from diets. Here, we show, by using a similar mathematical model, that a tradeoff between body mass and the number of brain neurons imposed by dietary constraints during hominin evolution is unlikely. Instead, the predictable number of neurons in the hominin brain varies much more in function of foraging efficiency than body mass. We also review archeological data to show that the expansion of the brain volume in the hominin lineage is described by a linear function independent of evidence of fire control, and therefore, thermal processing of food does not account for this phenomenon. Finally, we report experiments in mice showing that thermal processing of meat does not increase its caloric availability in mice. Altogether, our data indicate that cooking is neither sufficient nor necessary to explain hominin brain expansion.

Inflammable materials stores

International Nuclear Information System (INIS)

Nandagopan, V.

2017-01-01

A new Inflammable Materials Stores has been constructed by A and SED, BARC near Gamma Field for storage of inflammable materials falling into Petroleum Class ‘A’ ‘B’ and “C” mainly comprising of oils and lubricants, Chemicals like Acetone, Petroleum Ether etc. which are regularly procured by Central Stores Unit (CSU) for issue to the various divisions of BARC. The design of the shed done by A and SED, BARC was duly got approved from Petroleum and Explosive Safety Organization (PESO) which is a mandatory requirement before commencement of the construction. The design had taken into account various safety factors which is ideally required for an inflammable materials stores

Association of cord blood chemokines and other biomarkers with neonatal complications following intrauterine inflammation.

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Yoshikazu Otsubo

Full Text Available Intrauterine inflammation has been associated with preterm birth and neonatal complications. Few reports have comprehensively investigated multiple cytokine profiles in cord blood and precisely identified surrogate markers for intrauterine inflammation.To identify the cytokines and surrogate markers associated with intrauterine inflammation and subsequent neonatal complications.We analyzed cord blood samples from 135 patients admitted to the neonatal intensive care unit at Sasebo City General Hospital. We retrospectively determined the associations between the presence of neonatal complications and cord blood cytokines, prenatal factors, and laboratory data at birth. A total of 27 cytokines in the cord blood were measured using a bead-based array sandwich immunoassay.Both Th1 and Th2 cytokine levels were low, whereas the levels of growth factors and chemokines were high. In particular, chemokines IL-8, MCP-1, and MIP-1α were significantly higher in very premature neonates when compared with more mature neonates. In addition, some have been shown to be associated with multiple neonatal complications, including patent ductus arteriosus (PDA, respiratory distress syndrome (RDS, and chronic lung disease (CLD. Similarly, the levels of N-terminal pro-brain natriuretic peptide, nucleated RBC, and urinary β2-microglobulin were associated with these complications and chemokine levels.Our results suggest the association of inflammatory chemokines IL-8, MCP-1, and MIP-1α with intrauterine inflammation, premature birth, and neonatal complications in these perinatal subjects. Furthermore, the association of the aforementioned biomarkers with PDA, RDS, and CLD may help establish early diagnostic measures to predict such neonatal complications following intrauterine inflammation.

Soft brain-machine interfaces for assistive robotics: A novel control approach.

Science.gov (United States)

Schiatti, Lucia; Tessadori, Jacopo; Barresi, Giacinto; Mattos, Leonardo S; Ajoudani, Arash

2017-07-01

Robotic systems offer the possibility of improving the life quality of people with severe motor disabilities, enhancing the individual's degree of independence and interaction with the external environment. In this direction, the operator's residual functions must be exploited for the control of the robot movements and the underlying dynamic interaction through intuitive and effective human-robot interfaces. Towards this end, this work aims at exploring the potential of a novel Soft Brain-Machine Interface (BMI), suitable for dynamic execution of remote manipulation tasks for a wide range of patients. The interface is composed of an eye-tracking system, for an intuitive and reliable control of a robotic arm system's trajectories, and a Brain-Computer Interface (BCI) unit, for the control of the robot Cartesian stiffness, which determines the interaction forces between the robot and environment. The latter control is achieved by estimating in real-time a unidimensional index from user's electroencephalographic (EEG) signals, which provides the probability of a neutral or active state. This estimated state is then translated into a stiffness value for the robotic arm, allowing a reliable modulation of the robot's impedance. A preliminary evaluation of this hybrid interface concept provided evidence on the effective execution of tasks with dynamic uncertainties, demonstrating the great potential of this control method in BMI applications for self-service and clinical care.

Radiosurgery without whole brain radiotherapy in melanoma brain metastases

International Nuclear Information System (INIS)

Grob, J.J.; Regis, J.; Laurans, R.; Delaunay, M.; Wolkenstein, P.; Paul, K.; Souteyrand, P.; Koeppel, M.C.; Murraciole, X.; Perragut, J.C.; Bonerandi, J.J.

1998-01-01

To evaluate the effectiveness of radiosurgery without whole brain radiotherapy in the palliative treatment of melanoma brain metastases, we retrospectively assessed the results in 35 patients: 4 with a solitary brain metastasis, 13 with a single brain metastasis and metastases elsewhere and 18 with multiple brain metastases. The local control rate was 98.2% (55/56 metastases) at 3 months. Median survival was 22 months in patients with a solitary brain metastasis, 7.5 months in patients with a single brain metastasis and metastases elsewhere, and 4 months in patients with multiple brain metastases. Complications were unusual and surgery was required in 2 of 35 patients. These results show for the first time that melanoma patients with a unique brain metastasis with or without metastases elsewhere clearly benefit from tumour control easily obtained by radiosurgery. Although the comparison of radiosurgery with surgery and/or whole brain radiotherapy cannot be adequately addressed, radiosurgery alone seems to provide similar results with lower morbidity and impact on quality of life. (Copyright (c) 1998 Elsevier Science B.V., Amsterdam. All rights reserved.)

Brain versus Machine Control.

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Jose M Carmena

2004-12-01

Full Text Available Dr. Octopus, the villain of the movie "Spiderman 2", is a fusion of man and machine. Neuroscientist Jose Carmena examines the facts behind this fictional account of a brain- machine interface

Modulation of lung inflammation by vessel dilator in a mouse model of allergic asthma

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Cormier Stephania A

2009-07-01

Full Text Available Abstract Background Atrial natriuretic peptide (ANP and its receptor, NPRA, have been extensively studied in terms of cardiovascular effects. We have found that the ANP-NPRA signaling pathway is also involved in airway allergic inflammation and asthma. ANP, a C-terminal peptide (amino acid 99–126 of pro-atrial natriuretic factor (proANF and a recombinant peptide, NP73-102 (amino acid 73–102 of proANF have been reported to induce bronchoprotective effects in a mouse model of allergic asthma. In this report, we evaluated the effects of vessel dilator (VD, another N-terminal natriuretic peptide covering amino acids 31–67 of proANF, on acute lung inflammation in a mouse model of allergic asthma. Methods A549 cells were transfected with pVD or the pVAX1 control plasmid and cells were collected 24 hrs after transfection to analyze the effect of VD on inactivation of the extracellular-signal regulated receptor kinase (ERK1/2 through western blot. Luciferase assay, western blot and RT-PCR were also performed to analyze the effect of VD on NPRA expression. For determination of VD's attenuation of lung inflammation, BALB/c mice were sensitized and challenged with ovalbumin and then treated intranasally with chitosan nanoparticles containing pVD. Parameters of airway inflammation, such as airway hyperreactivity, proinflammatory cytokine levels, eosinophil recruitment and lung histopathology were compared with control mice receiving nanoparticles containing pVAX1 control plasmid. Results pVD nanoparticles inactivated ERK1/2 and downregulated NPRA expression in vitro, and intranasal treatment with pVD nanoparticles protected mice from airway inflammation. Conclusion VD's modulation of airway inflammation may result from its inactivation of ERK1/2 and downregulation of NPRA expression. Chitosan nanoparticles containing pVD may be therapeutically effective in preventing allergic airway inflammation.

Toll-like receptors and cytokines in the brain and in spleen of dogs with visceral leishmaniosis.

Science.gov (United States)

Grano, Fernanda G; Dos S Silva, José Eduardo; Melo, Guilherme D; de Souza, Milena S; Lima, Valéria M F; Machado, Gisele F

2018-04-15

Visceral leishmaniosis (VL) is a multisystem disease that affects domestic dogs and can have several clinical manifestations, including some rare reports of neurological clinical signs, or it may remain asymptomatic, depending on the individual immune response against the Leishmania parasite. VL involves immune system sensors, such as the Toll-like receptors (TLRs), that are related to innate immunity and inflammation. Previously, we have reported the presence of brain inflammation in infected dogs. Here, we investigated the gene expression profile of TLRs 1-10 in the brain and the spleen of infected dogs, along with the production of proinflammatory cytokines (TNF-α, IFN-γ, IL-1β and IL-6) with the aim of explaining the origin of brain inflammation. The gene expression of TLRs has varied according to the tissue evaluated. In the brain, TLR-4 was only up-regulated in a small subpopulation of infected dogs, while in the spleen, we detected an increase in TLR-5 and TLR-9 transcripts, as well as a reduction in TLRs 2-4 and TLR-10. All cytokines except IL-6 were detected in infected dogs. Moreover, we detected Leishmania DNA in all infected dogs in both tissues evaluated. In the histopathological analysis, we observed a predominance of lymphoplasmacytic infiltrate, mainly in leptomeninges and choroid plexuses, ranging from mild to intense. This study provides the first insight into the TLRs profile in the brain and the spleen during canine VL and provides support to confirm the involvement of sensors of the innate immune system sensors against L. infantum parasites. Copyright © 2018 Elsevier B.V. All rights reserved.

Traumatic Brain Injury Increases Cortical Glutamate Network Activity by Compromising GABAergic Control.

Science.gov (United States)

Cantu, David; Walker, Kendall; Andresen, Lauren; Taylor-Weiner, Amaro; Hampton, David; Tesco, Giuseppina; Dulla, Chris G

2015-08-01

Traumatic brain injury (TBI) is a major risk factor for developing pharmaco-resistant epilepsy. Although disruptions in brain circuitry are associated with TBI, the precise mechanisms by which brain injury leads to epileptiform network activity is unknown. Using controlled cortical impact (CCI) as a model of TBI, we examined how cortical excitability and glutamatergic signaling was altered following injury. We optically mapped cortical glutamate signaling using FRET-based glutamate biosensors, while simultaneously recording cortical field potentials in acute brain slices 2-4 weeks following CCI. Cortical electrical stimulation evoked polyphasic, epileptiform field potentials and disrupted the input-output relationship in deep layers of CCI-injured cortex. High-speed glutamate biosensor imaging showed that glutamate signaling was significantly increased in the injured cortex. Elevated glutamate responses correlated with epileptiform activity, were highest directly adjacent to the injury, and spread via deep cortical layers. Immunoreactivity for markers of GABAergic interneurons were significantly decreased throughout CCI cortex. Lastly, spontaneous inhibitory postsynaptic current frequency decreased and spontaneous excitatory postsynaptic current increased after CCI injury. Our results suggest that specific cortical neuronal microcircuits may initiate and facilitate the spread of epileptiform activity following TBI. Increased glutamatergic signaling due to loss of GABAergic control may provide a mechanism by which TBI can give rise to post-traumatic epilepsy. © The Author 2014. Published by Oxford University Press. All rights reserved. For Permissions, please e-mail: journals.permissions@oup.com.

Role of Smooth Muscle in Intestinal Inflammation

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Stephen M Collins

1996-01-01

Full Text Available The notion that smooth muscle function is altered in inflammation is prompted by clinical observations of altered motility in patients with inflammatory bowel disease (IBD. While altered motility may reflect inflammation-induced changes in intrinsic or extrinsic nerves to the gut, changes in gut hormone release and changes in muscle function, recent studies have provided in vitro evidence of altered muscle contractility in muscle resected from patients with ulcerative colitis or Crohn’s disease. In addition, the observation that smooth muscle cells are more numerous and prominent in the strictured bowel of IBD patients compared with controls suggests that inflammation may alter the growth of intestinal smooth muscle. Thus, inflammation is associated with changes in smooth muscle growth and contractility that, in turn, contribute to important symptoms of IBD including diarrhea (from altered motility and pain (via either altered motility or stricture formation. The involvement of smooth muscle in this context may be as an innocent bystander, where cells and products of the inflammatory process induce alterations in muscle contractility and growth. However, it is likely that intestinal muscle cells play a more active role in the inflammatory process via the elaboration of mediators and trophic factors, including cytokines, and via the production of collagen. The concept of muscle cells as active participants in the intestinal inflammatory process is a new concept that is under intense study. This report summarizes current knowledge as it relates to these two aspects of altered muscle function (growth and contractility in the inflamed intestine, and will focus on mechanisms underlying these changes, based on data obtained from animal models of intestinal inflammation.

Inflammatory-induced hibernation in the fetus: priming of fetal sheep metabolism correlates with developmental brain injury.

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Matthias Keller

Full Text Available Prenatal inflammation is considered an important factor contributing to preterm birth and neonatal mortality and morbidity. The impact of prenatal inflammation on fetal bioenergetic status and the correlation of specific metabolites to inflammatory-induced developmental brain injury are unknown. We used a global metabolomics approach to examine plasma metabolites differentially regulated by intrauterine inflammation. Preterm-equivalent sheep fetuses were randomized to i.v. bolus infusion of either saline-vehicle or LPS. Blood samples were collected at baseline 2 h, 6 h and daily up to 10 days for metabolite quantification. Animals were killed at 10 days after LPS injection, and brain injury was assessed by histopathology. We detected both acute and delayed effects of LPS on fetal metabolism, with a long-term down-regulation of fetal energy metabolism. Within the first 3 days after LPS, 121 metabolites were up-regulated or down-regulated. A transient phase (4-6 days, in which metabolite levels recovered to baseline, was followed by a second phase marked by an opposing down-regulation of energy metabolites, increased pO(2 and increased markers of inflammation and ADMA. The characteristics of the metabolite response to LPS in these two phases, defined as 2 h to 2 days and at 6-9 days, respectively, were strongly correlated with white and grey matter volumes at 10 days recovery. Based on these results we propose a novel concept of inflammatory-induced hibernation of the fetus. Inflammatory priming of fetal metabolism correlated with measures of brain injury, suggesting potential for future biomarker research and the identification of therapeutic targets.

Peripheral Tumor Necrosis Factor-Alpha (TNF-α) Modulates Amyloid Pathology by Regulating Blood-Derived Immune Cells and Glial Response in the Brain of AD/TNF Transgenic Mice.

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Paouri, Evi; Tzara, Ourania; Kartalou, Georgia-Ioanna; Zenelak, Sofia; Georgopoulos, Spiros

2017-05-17

Increasing evidence has suggested that systemic inflammation along with local brain inflammation can play a significant role in Alzheimer's disease (AD) pathogenesis. Identifying key molecules that regulate the crosstalk between the immune and the CNS can provide potential therapeutic targets. TNF-α is a proinflammatory cytokine implicated in the pathogenesis of systemic inflammatory and neurodegenerative diseases, such as rheumatoid arthritis (RA) and AD. Recent studies have reported that anti-TNF-α therapy or RA itself can modulate AD pathology, although the underlying mechanism is unclear. To investigate the role of peripheral TNF-α as a mediator of RA in the pathogenesis of AD, we generated double-transgenic 5XFAD/Tg197 AD/TNF mice that develop amyloid deposits and inflammatory arthritis induced by human TNF-α (huTNF-α) expression. We found that 5XFAD/Tg197 mice display decreased amyloid deposition, compromised neuronal integrity, and robust brain inflammation characterized by extensive gliosis and elevated blood-derived immune cell populations, including phagocytic macrophages and microglia. To evaluate the contribution of peripheral huTNF-α in the observed brain phenotype, we treated 5XFAD/Tg197 mice systemically with infliximab, an anti-huTNF-α antibody that does not penetrate the blood-brain barrier and prevents arthritis. Peripheral inhibition of huTNF-α increases amyloid deposition, rescues neuronal impairment, and suppresses gliosis and recruitment of blood-derived immune cells, without affecting brain huTNF-α levels. Our data report, for the first time, a distinctive role for peripheral TNF-α in the modulation of the amyloid phenotype in mice by regulating blood-derived and local brain inflammatory cell populations involved in β-amyloid clearance. SIGNIFICANCE STATEMENT Mounting evidence supports the active involvement of systemic inflammation, in addition to local brain inflammation, in Alzheimer's disease (AD) progression. TNF-α is a

Treatment of surgical brain injury by immune tolerance induced by intrathymic and hepatic portal vein injection of brain antigens.

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Yang, Weijian; Liu, Yong; Liu, Baolong; Tan, Huajun; Lu, Hao; Wang, Hong; Yan, Hua

2016-08-24

Surgical brain injury (SBI) defines complications induced by intracranial surgery, such as cerebral edema and other secondary injuries. In our study, intrathymic and hepatic portal vein injection of allogeneic myelin basic protein (MBP) or autogeneic brain cell suspensions were administered to a standard SBI model. Serum pro-inflammatory IL-2, anti-inflammatory IL-4 concentrations and the CD4(+)T/CD8(+)T ratio were measured at 1, 3, 7, 14 and 21 d after surgery to verify the establishment of immune tolerance. Furthermore, we confirmed neuroprotective effects by evaluating neurological scores at 1, 3, 7, 14 and 21 d after SBI. Anti-Fas ligand (FasL) immunohistochemistry and TUNEL assays of brain sections were tested at 21 d after surgery. Intrathymic injections of MBP or autogeneic brain cell suspensions functioned by both suppressing secondary inflammatory reactions and improving prognoses, whereas hepatic portal vein injections of autogeneic brain cell suspensions exerted a better effect than MBP. Intrathymic and hepatic portal vein injections of MBP had equal effects on reducing secondary inflammation and improving prognoses. Otherwise, hepatic portal vein injections of autogeneic brain cell suspensions had better outcomes than intrathymic injections of autogeneic brain cell suspensions. Moreover, the benefit of injecting antigens into the thymus was outweighed by hepatic portal vein injections.

Activation of bradykinin B2 receptor induced the inflammatory responses of cytosolic phospholipase A2 after the early traumatic brain injury.

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Chao, Honglu; Liu, Yinlong; Lin, Chao; Xu, Xiupeng; Li, Zheng; Bao, Zhongyuan; Fan, Liang; Tao, Chao; Zhao, Lin; Liu, Yan; Wang, Xiaoming; You, Yongping; Liu, Ning; Ji, Jing

2018-06-09

Phospholipase A 2 is a known aggravator of inflammation and deteriorates neurological outcomes after traumatic brain injury (TBI), however the exact inflammatory mechanisms remain unknown. This study investigated the role of bradykinin and its receptor, which are known initial mediators within inflammation activation, as well as the mechanisms of the cytosolic phospholipase A 2 (cPLA 2 )-related inflammatory responses after TBI. We found that cPLA 2 and bradykinin B2 receptor were upregulated after a TBI. Rats treated with the bradykinin B2 receptor inhibitor LF 16-0687 exhibited significantly less cPLA 2 expression and related inflammatory responses in the brain cortex after sustaining a controlled cortical impact (CCI) injury. Both the cPLA 2 inhibitor and the LF16-0687 improved CCI rat outcomes by decreasing neuron death and reducing brain edema. The following TBI model utilized both primary astrocytes and primary neurons in order to gain further understanding of the inflammation mechanisms of the B2 bradykinin receptor and the cPLA 2 in the central nervous system. There was a stronger reaction from the astrocytes as well as a protective effect of LF16-0687 after the stretch injury and bradykinin treatment. The protein kinase C pathway was thought to be involved in the B2 bradykinin receptor as well as the cPLA 2 -related inflammatory responses. Rottlerin, a Protein Kinase C (PKC) δ inhibitor, decreased the activity of the cPLA 2 activity post-injury, and LF16-0687 suppressed both the PKC pathway and the cPLA 2 activity within the astrocytes. These results indicated that the bradykinin B2 receptor-mediated pathway is involved in the cPLA 2 -related inflammatory response from the PKC pathway. Copyright © 2018. Published by Elsevier B.V.

Childhood brain tumours and use of mobile phones: comparison of a case–control study with incidence data

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Aydin Denis

2012-05-01

Full Text Available Abstract The first case–control study on mobile phone use and brain tumour risk among children and adolescents (CEFALO study has recently been published. In a commentary published in Environmental Health, Söderqvist and colleagues argued that CEFALO suggests an increased brain tumour risk in relation to wireless phone use. In this article, we respond and show why consistency checks of case–control study results with observed time trends of incidence rates are essential, given the well described limitations of case–control studies and the steep increase of mobile phone use among children and adolescents during the last decade. There is no plausible explanation of how a notably increased risk from use of wireless phones would correspond to the relatively stable incidence time trends for brain tumours among children and adolescents observed in the Nordic countries. Nevertheless, an increased risk restricted to heavy mobile phone use, to very early life exposure, or to rare subtypes of brain tumours may be compatible with stable incidence trends at this time and thus further monitoring of childhood brain tumour incidence rate time trends is warranted.

Pilot Study of 64CuCl2 for PET Imaging of Inflammation

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Lei Jiang

2018-02-01

Full Text Available Copper(II ion (Cu2+ is the essential element for numerous pathophysiological processes in vivo. Copper transporter 1 (CTR1 is mainly responsible for maintaining Cu2+ accumulation in cells, which has been found to be over-expressed in inflammatory tissues. Therefore, we explored the potential application of 64CuCl2 for PET imaging of inflammation through targeting CTR1. The animal models of H2O2 induced muscle inflammation and lipopolysaccaharide induced lung inflammation were successfully established, then imaged by small animal PET (PET/CT post-injection of 64CuCl2, and PET images were quantitatively analyzed. H&E and immunohistochemical (IHC staining and western blot experiments were performed for evaluating CTR1 levels in the inflammatory and control tissues. Both inflammatory muscle and lungs can be clearly imaged by PET. PET image quantitative analysis revealed that the inflammatory muscle and lungs showed significantly higher 64Cu accumulation than the controls, respectively (p < 0.05. Furthermore, IHC staining and western blot analysis demonstrated that compared with the controls, CTR1 expression was increased in both the inflammatory muscle and lungs, which was consistent with the levels of 64Cu2+ accumulation in these tissues. 64CuCl2 can be used as a novel, simple, and highly promising PET tracer for CTR1 targeted imaging of inflammation.

Executive and language control in the multilingual brain.

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Kong, Anthony Pak-Hin; Abutalebi, Jubin; Lam, Karen Sze-Yan; Weekes, Brendan

2014-01-01

Neuroimaging studies suggest that the neural network involved in language control may not be specific to bi-/multilingualism but is part of a domain-general executive control system. We report a trilingual case of a Cantonese (L1), English (L2), and Mandarin (L3) speaker, Dr. T, who sustained a brain injury at the age of 77 causing lesions in the left frontal lobe and in the left temporo-parietal areas resulting in fluent aphasia. Dr. T's executive functions were impaired according to a modified version of the Stroop color-word test and the Wisconsin Card Sorting Test performance was characterized by frequent perseveration errors. Dr. T demonstrated pathological language switching and mixing across her three languages. Code switching in Cantonese was more prominent in discourse production than confrontation naming. Our case suggests that voluntary control of spoken word production in trilingual speakers shares neural substrata in the frontobasal ganglia system with domain-general executive control mechanisms. One prediction is that lesions to such a system would give rise to both pathological switching and impairments of executive functions in trilingual speakers.

EXiO-A Brain-Controlled Lower Limb Exoskeleton for Rhesus Macaques.

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Vouga, Tristan; Zhuang, Katie Z; Olivier, Jeremy; Lebedev, Mikhail A; Nicolelis, Miguel A L; Bouri, Mohamed; Bleuler, Hannes

2017-02-01

Recent advances in the field of brain-machine interfaces (BMIs) have demonstrated enormous potential to shape the future of rehabilitation and prosthetic devices. Here, a lower-limb exoskeleton controlled by the intracortical activity of an awake behaving rhesus macaque is presented as a proof-of-concept for a locomotorBMI. A detailed description of the mechanical device, including its innovative features and first experimental results, is provided. During operation, BMI-decoded position and velocity are directly mapped onto the bipedal exoskeleton's motions, which then move the monkey's legs as the monkey remains physicallypassive. To meet the unique requirements of such an application, the exoskeleton's features include: high output torque with backdrivable actuation, size adjustability, and safe user-robot interface. In addition, a novel rope transmission is introduced and implemented. To test the performance of the exoskeleton, a mechanical assessment was conducted, which yielded quantifiable results for transparency, efficiency, stiffness, and tracking performance. Usage under both brain control and automated actuation demonstrates the device's capability to fulfill the demanding needs of this application. These results lay the groundwork for further advancement in BMI-controlled devices for primates including humans.

Using Ferumoxytol-Enhanced MRI to Measure Inflammation in Patients With Brain Tumors or Other Conditions of the CNS

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2017-08-30

Brain Injury; Central Nervous System Degenerative Disorder; Central Nervous System Infectious Disorder; Central Nervous System Vascular Malformation; Hemorrhagic Cerebrovascular Accident; Ischemic Cerebrovascular Accident; Primary Brain Neoplasm; Brain Cancer; Brain Tumors

Adipose Tissue Inflammation Induces B Cell Inflammation and Decreases B Cell Function in Aging

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Daniela Frasca

2017-08-01

Full Text Available Aging is the greatest risk factor for developing chronic diseases. Inflamm-aging, the age-related increase in low-grade chronic inflammation, may be a common link in age-related diseases. This review summarizes recent published data on potential cellular and molecular mechanisms of the age-related increase in inflammation, and how these contribute to decreased humoral immune responses in aged mice and humans. Briefly, we cover how aging and related inflammation decrease antibody responses in mice and humans, and how obesity contributes to the mechanisms for aging through increased inflammation. We also report data in the literature showing adipose tissue infiltration with immune cells and how these cells are recruited and contribute to local and systemic inflammation. We show that several types of immune cells infiltrate the adipose tissue and these include macrophages, neutrophils, NK cells, innate lymphoid cells, eosinophils, T cells, B1, and B2 cells. Our main focus is how the adipose tissue affects immune responses, in particular B cell responses and antibody production. The role of leptin in generating inflammation and decreased B cell responses is also discussed. We report data published by us and by other groups showing that the adipose tissue generates pro-inflammatory B cell subsets which induce pro-inflammatory T cells, promote insulin resistance, and secrete pathogenic autoimmune antibodies.

Ability of procalcitonin to discriminate infection from non-infective inflammation using two pleural disease settings.

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Fiona J McCann

Full Text Available Procalcitonin has been shown to be useful in separating infection from non-infective disorders. However, infection is often paralleled by tissue inflammation. Most studies supporting the use of procalcitonin were confounded by more significant inflammation in the infection group. Few studies have examined the usefulness of procalcitonin when adjusted for inflammation.Pleural inflammation underlies the development of most exudative effusions including pleural infection and malignancy. Pleurodesis, often used to treat effusions, involves provocation of intense aseptic pleural inflammation. We conducted a two-part proof-of-concept study to test the specificity of procalcitonin in differentiating infection using cohorts of patients with pleural effusions of infective and non-infective etiologies, as well as subjects undergoing pleurodesis.We measured the blood procalcitonin level (i in 248 patients with pleural infection or with non-infective pleural inflammation, matched for severity of systemic inflammation by C-reactive protein (CRP, age and gender; and (ii in patients before and 24-48 hours after induction of non-infective pleural inflammation (from talc pleurodesis.1 Procalcitonin was significantly higher in patients with pleural infection compared with controls with non-infective effusions (n = 32 each group that were case-matched for systemic inflammation as measured by CRP [median (25-75%IQR: 0.58 (0.35-1.50 vs 0.34 (0.31-0.42 µg/L respectively, p = 0.003]. 2 Talc pleurodesis provoked intense systemic inflammation, and raised serum CRP by 360% over baseline. However procalcitonin remained relatively unaffected (21% rise. 3 Procalcitonin and CRP levels did not correlate. In 214 patients with pleural infection, procalcitonin levels did not predict the survival or need for surgical intervention.Using a pleural model, this proof-of-principle study confirmed that procalcitonin is a biomarker specific for infection and is not affected by non

Computational Identification of Potential Multi-drug Combinations for Reduction of Microglial Inflammation in Alzheimer Disease

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Thomas J. Anastasio

2015-06-01

Full Text Available Like other neurodegenerative diseases, Alzheimer Disease (AD has a prominent inflammatory component mediated by brain microglia. Reducing microglial inflammation could potentially halt or at least slow the neurodegenerative process. A major challenge in the development of treatments targeting brain inflammation is the sheer complexity of the molecular mechanisms that determine whether microglia become inflammatory or take on a more neuroprotective phenotype. The process is highly multifactorial, raising the possibility that a multi-target/multi-drug strategy could be more effective than conventional monotherapy. This study takes a computational approach in finding combinations of approved drugs that are potentially more effective than single drugs in reducing microglial inflammation in AD. This novel approach exploits the distinct advantages of two different computer programming languages, one imperative and the other declarative. Existing programs written in both languages implement the same model of microglial behavior, and the input/output relationships of both programs agree with each other and with data on microglia over an extensive test battery. Here the imperative program is used efficiently to screen the model for the most efficacious combinations of 10 drugs, while the declarative program is used to analyze in detail the mechanisms of action of the most efficacious combinations. Of the 1024 possible drug combinations, the simulated screen identifies only 7 that are able to move simulated microglia at least 50% of the way from a neurotoxic to a neuroprotective phenotype. Subsequent analysis shows that of the 7 most efficacious combinations, 2 stand out as superior both in strength and reliability. The model offers many experimentally testable and therapeutically relevant predictions concerning effective drug combinations and their mechanisms of action.

Computational identification of potential multi-drug combinations for reduction of microglial inflammation in Alzheimer disease.

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Anastasio, Thomas J

2015-01-01

Like other neurodegenerative diseases, Alzheimer Disease (AD) has a prominent inflammatory component mediated by brain microglia. Reducing microglial inflammation could potentially halt or at least slow the neurodegenerative process. A major challenge in the development of treatments targeting brain inflammation is the sheer complexity of the molecular mechanisms that determine whether microglia become inflammatory or take on a more neuroprotective phenotype. The process is highly multifactorial, raising the possibility that a multi-target/multi-drug strategy could be more effective than conventional monotherapy. This study takes a computational approach in finding combinations of approved drugs that are potentially more effective than single drugs in reducing microglial inflammation in AD. This novel approach exploits the distinct advantages of two different computer programming languages, one imperative and the other declarative. Existing programs written in both languages implement the same model of microglial behavior, and the input/output relationships of both programs agree with each other and with data on microglia over an extensive test battery. Here the imperative program is used efficiently to screen the model for the most efficacious combinations of 10 drugs, while the declarative program is used to analyze in detail the mechanisms of action of the most efficacious combinations. Of the 1024 possible drug combinations, the simulated screen identifies only 7 that are able to move simulated microglia at least 50% of the way from a neurotoxic to a neuroprotective phenotype. Subsequent analysis shows that of the 7 most efficacious combinations, 2 stand out as superior both in strength and reliability. The model offers many experimentally testable and therapeutically relevant predictions concerning effective drug combinations and their mechanisms of action.

Experimental modelling of the consequences of brief late gestation asphyxia on newborn lamb behaviour and brain structure.

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Margie Castillo-Melendez

Full Text Available Brief but severe asphyxia in late gestation or at the time of birth may lead to neonatal hypoxic ischemic encephalopathy and is associated with long-term neurodevelopmental impairment. We undertook this study to examine the consequences of transient in utero asphyxia in late gestation fetal sheep, on the newborn lamb after birth. Surgery was undertaken at 125 days gestation for implantation of fetal catheters and placement of a silastic cuff around the umbilical cord. At 132 days gestation (0.89 term, the cuff was inflated to induce umbilical cord occlusion (UCO, or sham (control. Fetal arterial blood samples were collected for assessment of fetal wellbeing and the pregnancy continued until birth. At birth, behavioral milestones for newborn lambs were recorded over 24 h, after which the lambs were euthanased for brain collection and histopathology assessments. After birth, UCO lambs displayed significant latencies to (i use all four legs, (ii attain a standing position, (iii find the udder, and (iv successfully suckle--compared to control lambs. Brains of UCO lambs showed widespread pathologies including cell death, white matter disruption, intra-parenchymal hemorrhage and inflammation, which were not observed in full term control brains. UCO resulted in some preterm births, but comparison with age-matched preterm non-UCO control lambs showed that prematurity per se was not responsible for the behavioral delays and brain structural abnormalities resulting from the in utero asphyxia. These results demonstrate that a single, brief fetal asphyxic episode in late gestation results in significant grey and white matter disruption in the developing brain, and causes significant behavioral delay in newborn lambs. These data are consistent with clinical observations that antenatal asphyxia is causal in the development of neonatal encephalopathy and provide an experimental model to advance our understanding of neuroprotective therapies.

Ultrasound-controlled neuronavigator-guided brain surgery.

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Koivukangas, J; Louhisalmi, Y; Alakuijala, J; Oikarinen, J

1993-07-01

The development of a unique neurosurgical navigator is described and a preliminary series of seven cases of intracerebral lesions approached with the assistance of this neuronavigation system under ultrasound control is presented. The clinical series included five low-grade astrocytomas, one chronic intracerebral hematoma, and one porencephalic cyst. Management procedures included biopsy in all cases, drainage of the hematoma, and endoscopy and fenestration for the cyst. The features of the neuronavigation system are interactive reconstructions of preoperative computerized tomography and magnetic resonance imaging data, corresponding intraoperative ultrasound images, versatility of the interchangeable end-effector instruments, graphic presentation of instruments on the reconstructed images, and voice control of the system. The principle of a common axis in the reconstructed images served to align the navigational pointer, biopsy guide, endoscope guide, ultrasound transducer, and surgical microscope to the brain anatomy. Intraoperative ultrasound imaging helped to verify the accuracy of the neuronavigator and check the results of the procedures. The arm of the neuronavigation system served as a holder for instruments, such as the biopsy guide, endoscope guide, and ultrasound transducer, in addition to functioning as a navigational pointer. Also, the surgical microscope was aligned with the neuronavigator for inspection and biopsy of the hematoma capsule to rule out tumor etiology. Voice control freed the neurosurgeon from manual exercises during start-up and calibration of the system.

A Brain-Computer Interface (BCI) system to use arbitrary Windows applications by directly controlling mouse and keyboard.

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Spuler, Martin

2015-08-01

A Brain-Computer Interface (BCI) allows to control a computer by brain activity only, without the need for muscle control. In this paper, we present an EEG-based BCI system based on code-modulated visual evoked potentials (c-VEPs) that enables the user to work with arbitrary Windows applications. Other BCI systems, like the P300 speller or BCI-based browsers, allow control of one dedicated application designed for use with a BCI. In contrast, the system presented in this paper does not consist of one dedicated application, but enables the user to control mouse cursor and keyboard input on the level of the operating system, thereby making it possible to use arbitrary applications. As the c-VEP BCI method was shown to enable very fast communication speeds (writing more than 20 error-free characters per minute), the presented system is the next step in replacing the traditional mouse and keyboard and enabling complete brain-based control of a computer.

Attention, predictions and expectations, and their violation: attentional control in the human brain

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Vossel, Simone; Geng, Joy J.; Friston, Karl J.

2014-01-01

In the complex scenes of everyday life, our brains must select from among many competing inputs for perceptual synthesis—so that only the most relevant are fully processed and irrelevant (distracting) information is suppressed. At the same time, we must remain responsive to salient events outside our current focus of attention—and balancing these two processing modes is a fundamental task our brain constantly needs to solve.This Research Topic examines how attentional control is guided by sen...

Characterization and pharmacological modulation of intestinal inflammation induced by ionizing radiation

International Nuclear Information System (INIS)

Gremy, O.

2006-12-01

The use of radiation therapy to treat abdominal and pelvic malignancies inevitably involves exposure of healthy intestinal tissues which are very radiosensitive. As a result, most patients experience symptoms such as abdominal pain, nausea and diarrhea. Such symptoms are associated with acute damage to intestine mucosa including radio-induced inflammatory processes. With a rat model of colorectal fractionated radiation, we have shown a gradual development of a colonic inflammation during radiation planning, without evident tissue injury. This radio-induced inflammation is characterized not only by the sur expressions of pro-inflammatory cytokines and chemokines, a NF-kB activation, but also by a repression of anti-inflammatory cytokines and the nuclear receptors PPARa and RXRa, both involved in inflammation control. This early inflammation is associated with a discreet neutrophil recruitment and a macrophage accumulation. Macrophages are still abnormally numerous in tissue 27 weeks after the last day of irradiation. Inflammatory process is the most often related to a specific immune profile, either a type Th1 leading to a cellular immune response, or a type Th2 for humoral immunity. According to our studies, a unique abdominal radiation in the rat induces an ileum inflammation and an immune imbalance resulting in a Th2-type profile. Inhibiting this profile is important as its persistence promotes chronic inflammation, predisposition to bacterial infections and fibrosis which is the main delayed side-effect of radiotherapy. The treatment of rats with an immuno-modulator compound, the caffeic acid phenethyl ester (C.A.P.E.), have the potential to both reduce ileal mucosal inflammation and inhibit the radio-induced Th2 status. In order to search new therapeutic molecular target, we has been interested in the PPARg nuclear receptor involved in the maintenance of colon mucosal integrity. In our abdominal irradiation model, we have demonstrated that the prophylactic

Catechins decrease neurological severity score through apoptosis and neurotropic factor pathway in rat traumatic brain injury

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Retty Ratnawati

2017-08-01

Administration of catechins decreased NSS through inhibiting inflammation and apoptosis, as well as induced the neurotrophic factors in rat brain injury. Catechins may serve as a potential intervention for TBI.

Aging, not age-associated inflammation, determines blood pressure and endothelial responses to acute inflammation.