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Sample records for progressive neurovascular inflammatory

  1. Neurovascular development

    PubMed Central

    James, Jennifer M

    2009-01-01

    Neurovascular development in the central nervous system has a rich history and compelling significance. The developing central nervous system (CNS) does not produce vascular progenitor cells, and so ingression of blood vessels is required for continued CNS development and function. Classic studies provide elegant descriptions of formation of the vascular plexus that surrounds the embryonic brain and spinal cord, and the subsequent ingression of blood vessels into the neural tissue. Recent work has focused on the molecular pathways responsible for neurovascular cross-talk and development of the blood-brain barrier. Here we review neurovascular development in the central nervous system, with emphasis on the spinal cord. We discuss the historical work, the current status of our knowledge and unanswered questions. The importance of neurovascular development to diseases of the cerebral vasculature and the neural stem cell niche are discussed. PMID:19363295

  2. [Progressive Multifocal Leukoencephalopathy with Inflammatory Reactions].

    PubMed

    Shishido-Hara, Yukiko; Uchihara, Toshiki; Sanjo, Nobuo

    2016-04-01

    Progressive multifocal leukoencephalopathy (PML) is a demyelinating disorder caused by reactivation of the JC virus associated with impaired host immunity. However, PML may occur even without an evident cause of immunosuppression. In such cases, JC virus DNA in cerebrospinal fluid (CSF) may not be detectable with polymerase chain reactions (PCR), and a brain biopsy may be performed. Pathology may exhibit marked inflammatory reactions around the JC virus-infected cells, although typical intranuclear viral inclusions would rarely be seen. Atypical inflammation in patients with PML likely an indication of the host's immune-response against the virus. this is usually observed in those with relatively-mild immunosuppression with favorable prognosis. Here, we describe cases of PML that exhibited inflammatory reactions; a recent topic, PML with immune reconstruction inflammatory syndrome (IRIS), will also be discussed. PMID:27056866

  3. Chronic progressive external ophthalmoplegia with inflammatory myopathy.

    PubMed

    Chen, Ting; Pu, Chuanqiang; Shi, Qiang; Wang, Qian; Cong, Lu; Liu, Jiexiao; Luo, Hongyu; Fei, Lingna; Tang, Wei; Yu, Shanshan

    2014-01-01

    Chronic progressive external ophthalmoplegia is one of mitochondrial disorders, characterized by ptosis, limitation of eye movement, variably severe bulbar muscle weakness and proximal limb weakness. Chronic progressive external ophthalmoplegia complicated with acquired disease is extremely rare. We report a 44 years old male patient with more than 20 years of chronic progressive bilateral ptosis and limitation of eye movements manifested dysarthria, dysphagia and neck muscle weakness for 3 years. The first muscle biopsy showed red-ragged fibers and cytochrome c oxidase negative fibers as well as inflammatory cells infiltration. Electron microscopy revealed paracrystalline inclusions. Mitochondrial genetic analysis demonstrated a large-scale mtDNA deletion of m.8470_13446del4977. The patient was treated with prednisone. In a three-year follow-up study, the second biopsy was performed. Before the treatment, except bilateral ptosis and external ophthalmopelgia, this patient presented bulbar muscle weakness and neck muscle weakness. After treated with prednisone, the symptoms of dysphagia, dysarthria and neck muscle weakness were significantly improved, and the second biopsy showed only mitochondrial myopathy pathology but the inflammations disappeared. Here, we report a patient with chronic progressive external ophthalmoplegia complicated with inflammatory myopathy and after treated with prednisone as myositis, he had a significant therapeutic effect. PMID:25674260

  4. [Progress in PDE4 targeted therapy for inflammatory diseases].

    PubMed

    Song, Shun-de; Tang, Hui-fang

    2014-05-01

    cAMP-specific phosphodiesterase type 4 (PDE4) is one of the hot targets for treatment of inflammatory diseases. PDE4 inhibitors can suppress inflammation by increasing the concentration of cAMP in inflammatory cells. The efficacy and safety evaluations of several PDE4 inhibitors are currently carried on in clinical trials, for example GSK256066 in asthma, roflumilast and GSK256066 in chronic obstructive pulmonary disease, tetomilast in inflammatory bowel disease, and apremilast in dermatitis and arthritis etc. This article reviews the recent progress on PDE4-targeted therapy for inflammatory diseases. PMID:24998661

  5. Progress in inflammatory neuropathy -the legacy of Dr Jack Griffin.

    PubMed

    Feldman, Eva L; Hughes, Richard A C; Willison, Hugh J

    2015-11-01

    The past quarter of a century has brought incredible advances in our understanding of inflammatory neuropathies, and the insights into Guillain-Barré syndrome (GBS) began in the 1990s with the seminal work of Dr Jack Griffin and his colleagues. In this essay, we provide a tribute to Jack, and review the recent progress in a field that he termed his personal favourite. In particular, we discuss the new developments in our understanding and diagnosis of inflammatory neuropathies, the recent emergence of the node of Ranvier and the paranode as sites of intensive investigation, and the mechanistic evidence that is providing a platform for therapeutic development studies. PMID:26458287

  6. Anti-inflammatory agents from plants: progress and potential.

    PubMed

    Recio, M C; Andujar, I; Rios, J L

    2012-01-01

    The identification of substances that can promote the resolution of inflammation in a way that is homeostatic, modulatory, efficient, and well-tolerated by the body is of fundamental importance. Traditional medicines have long provided front-line pharmacotherapy for many millions of people worldwide. Medicinal extracts are a rich source of therapeutic leads for the pharmaceutical industry. The use of medicinal plant therapies to treat chronic illness, including rheumatoid arthritis (RA) and inflammatory bowel disease (IBD), is thus widespread and on the rise.The aim of this review is to present recent progress in clinical anti-inflammatory studies of plant extracts and compound leads such as green tea polyphenols, curcumin, resveratrol, boswellic acid, and cucurbitacins, among others, against chronic inflammatory diseases, mainly RA and IBD. In this context, the present paper also highlights the most promising experimental data on those plant extracts and pure compounds active in animal models of the aforementioned diseases. PMID:22414101

  7. Chronic Inflammatory Diseases: Progress and Prospect with Herbal Medicine.

    PubMed

    Ghosh, Nilanjan; Ali, Asif; Ghosh, Rituparna; Das, Shaileyee; Mandal, Subhash C; Pal, Mahadeb

    2016-01-01

    Diseases associated with chronic inflammatory pathology claim a major share of worldwide deaths each year. A principal reason behind the huge number of casualties is associated with mild or unnoticed symptoms for long period of time since the outset, and that specific treatment options for these diseases have not yet emerged. Current anti-inflammatory drugs essentially have become ineffective for long term protection from these diseases as they also interfere with essential cellular pathways and associated toxicities. Notably, recent studies with a number of phytochemicals have shown promising results. These compounds isolated from various medicinal plants express their anti-inflammatory activities by down regulating expression of several crucial pro-inflammatory mediators. These are mostly antioxidants; inhibit induction of key transcription factors like nuclear factor kappa B (NF-κB) that are responsible for expression of proinflammatory mediators, and other growth regulators. Definitely, some of these compounds have the potential to be developed into new therapeutic agents to better control inflammation associated diseases in near future. This review summarizes recent findings on the molecular mechanisms through which various inflammatory activities are linked to disease progression and a group of natural products that have shown promise in controlling these processes. PMID:26561064

  8. Immunologic and inflammatory mechanisms that drive asthma progression to remodeling

    PubMed Central

    Broide, David H.

    2008-01-01

    Although histologic features of airway remodeling have been well characterized in asthma, the immunologic and inflammatory mechanisms that drive progression of asthma to remodeling are still incompletely understood. Conceptually, airway remodeling may be due to persistent inflammation and/or aberrant tissue repair mechanisms. It is likely that several immune and inflammatory cell types and mediators are involved in mediating airway remodeling. In addition, different features of airway remodeling are likely mediated by different inflammatory pathways. Several important candidate mediators of remodeling have been identified including TGF-β and Th2 cytokines (including IL-5 and IL-13), as well as VEGF, ADAM-33, and MMP-9. Mouse models of airway remodeling have provided important insight into potential mechanisms by which TGF-β activation of the Smad 2/3 signaling pathway may contribute to airway remodeling. Human studies have demonstrated that anti-IL-5 reduces levels of airway eosinophils expressing TGF-β, as well as levels of airway remodeling as assessed by bronchial biopsies. Further such studies confirming these observations, as well as alternate studies targeting additional individual cell types, cytokines, and mediators are needed in human subjects with asthma to determine the role of candidate mediators of inflammation on the development and progression of airway remodeling. PMID:18328887

  9. Neurovascular Unit in Chronic Pain

    PubMed Central

    Radu, Beatrice Mihaela; Bramanti, Placido; Osculati, Francesco; Flonta, Maria-Luisa; Radu, Mihai; Bertini, Giuseppe; Fabene, Paolo Francesco

    2013-01-01

    Chronic pain is a debilitating condition with major socioeconomic impact, whose neurobiological basis is still not clear. An involvement of the neurovascular unit (NVU) has been recently proposed. In particular, the blood-brain barrier (BBB) and blood-spinal cord barrier (BSCB), two NVU key players, may be affected during the development of chronic pain; in particular, transient permeabilization of the barrier is suggested by several inflammatory- and nerve-injury-based pain models, and we argue that the clarification of molecular BBB/BSCB permeabilization events will shed new light in understanding chronic pain mechanisms. Possible biases in experiments supporting this theory and its translational potentials are discussed. Moving beyond an exclusive focus on the role of the endothelium, we propose that our understanding of the mechanisms subserving chronic pain will benefit from the extension of research efforts to the NVU as a whole. In this view, the available evidence on the interaction between analgesic drugs and the NVU is here reviewed. Chronic pain comorbidities, such as neuroinflammatory and neurodegenerative diseases, are also discussed in view of NVU changes, together with innovative pharmacological solutions targeting NVU components in chronic pain treatment. PMID:23840097

  10. Progressive multifocal leukoencephalopathy and immune reconstitution inflammatory syndrome (IRIS).

    PubMed

    Bauer, Jan; Gold, Ralf; Adams, Ortwin; Lassmann, Hans

    2015-12-01

    Progressive multifocal leukoencephalopathy is a viral encephalitis induced by the John Cunningham (JC) virus, an ubiquitous neurotropic papovavirus of the genus polyomavirus that in healthy people in latency resides in kidney and bone marrow cells. Activation and entry into the CNS were first seen in patients with malignancies of the hematopoietic system and an impaired immune system. During the 1980 and the 1990s with the appearance of human immunodeficiency virus infection in humans, PML was found to be the most important opportunistic infection of the central nervous system. As a result of highly efficient immunosuppressive and immunomodulatory treatments, in recent years, the number of PML cases again increased. PML is prevented by an intact cellular immune response and accordingly immune reconstitution can terminate established disease in the CNS. However, forced immune reconstitution can lead to massive destruction of virus-infected cells. This may result in clinical exacerbation associated with high morbidity and mortality and referred to as PML with immune reconstitution inflammatory syndrome (PML-IRIS). In the present review, we discuss virological properties and routes of infection in the CNS, but mostly focus on the pathology of PML and PML-IRIS and on the role of the immune system in these disorders. We show that PML and PML-IRIS result from predominant JC virus infection of oligodendrocytes and, to a lesser extent, of infected neurons. Inflammation in these encephalitides seems to be driven by a dominant cytotoxic T cell response which is massively exaggerated during IRIS. PMID:26323992

  11. Environmental factors affecting inflammatory bowel disease: have we made progress?

    PubMed

    Lakatos, Peter Laszlo

    2009-01-01

    The pathogenesis of inflammatory bowel disease (IBD) is only partially understood; various environmental and host (e.g. genetic, epithelial, immune, and nonimmune) factors are involved. The critical role for environmental factors is strongly supported by recent worldwide trends in IBD epidemiology. One important environmental factor is smoking. A meta-analysis partially confirms previous findings that smoking was found to be protective against ulcerative colitis and, after the onset of the disease, might improve its course, decreasing the need for colectomy. In contrast, smoking increases the risk of developing Crohn's disease and aggravates its course. The history of IBD is dotted by cyclic reports on the isolation of specific infectious agents responsible for Crohn's disease or ulcerative colitis. The more recently published cold chain hypothesis is providing an even broader platform by linking dietary factors and microbial agents. An additional, recent theory has suggested a breakdown in the balance between putative species of 'protective' versus 'harmful' intestinal bacteria - this concept has been termed dysbiosis resulting in decreased bacterial diversity. Other factors such as oral contraceptive use, appendectomy, dietary factors (e.g. refined sugar, fat, and fast food), perinatal events, and childhood infections have also been associated with both diseases, but their role is more controversial. Nonetheless, there is no doubt that economic development, leading to improved hygiene and other changes in lifestyle ('westernized lifestyle') may play a role in the increase in IBD. This review article focuses on the role of environmental factors in the pathogenesis and progression of IBDs. PMID:19786744

  12. Role of Inflammasome Activation in the Pathophysiology of Vascular Diseases of the Neurovascular Unit

    PubMed Central

    Mohamed, Islam N.; Ishrat, Tauheed; Fagan, Susan C.

    2015-01-01

    Abstract Significance: Inflammation is the standard double-edged defense mechanism that aims at protecting the human physiological homeostasis from devastating threats. Both acute and chronic inflammation have been implicated in the occurrence and progression of vascular diseases. Interference with components of the immune system to improve patient outcome after ischemic injury has been uniformly unsuccessful. There is a need for a deeper understanding of the innate immune response to injury in order to modulate, rather than to block inflammation and improve the outcome for vascular diseases. Recent Advances: Nucleotide-binding oligomerization domain-like receptors or NOD-like receptor proteins (NLRPs) can be activated by sterile and microbial inflammation. NLR family plays a major role in activating the inflammasome. Critical Issues: The aim of this work is to review recent findings that provided insights into key inflammatory mechanisms and define the place of the inflammasome, a multi-protein complex involved in instigating inflammation in neurovascular diseases, including retinopathy, neurodegenerative diseases, and stroke. Future Directions: The significant contribution of NLRP-inflammasome activation to vascular disease of the neurovascular unit in the brain and retina suggests that therapeutic strategies focused on specific targeting of inflammasome components could significantly improve the outcomes of these diseases. Antioxid. Redox Signal. 22, 1188–1206. PMID:25275222

  13. APOE Stabilization by Exercise Prevents Aging Neurovascular Dysfunction and Complement Induction

    PubMed Central

    Soto, Ileana; Graham, Leah C.; Richter, Hannah J.; Simeone, Stephen N.; Radell, Jake E.; Grabowska, Weronika; Funkhouser, W. Keith; Howell, Megan C.; Howell, Gareth R.

    2015-01-01

    Aging is the major risk factor for neurodegenerative diseases such as Alzheimer's disease, but little is known about the processes that lead to age-related decline of brain structures and function. Here we use RNA-seq in combination with high resolution histological analyses to show that aging leads to a significant deterioration of neurovascular structures including basement membrane reduction, pericyte loss, and astrocyte dysfunction. Neurovascular decline was sufficient to cause vascular leakage and correlated strongly with an increase in neuroinflammation including up-regulation of complement component C1QA in microglia/monocytes. Importantly, long-term aerobic exercise from midlife to old age prevented this age-related neurovascular decline, reduced C1QA+ microglia/monocytes, and increased synaptic plasticity and overall behavioral capabilities of aged mice. Concomitant with age-related neurovascular decline and complement activation, astrocytic Apoe dramatically decreased in aged mice, a decrease that was prevented by exercise. Given the role of APOE in maintaining the neurovascular unit and as an anti-inflammatory molecule, this suggests a possible link between astrocytic Apoe, age-related neurovascular dysfunction and microglia/monocyte activation. To test this, Apoe-deficient mice were exercised from midlife to old age and in contrast to wild-type (Apoe-sufficient) mice, exercise had little to no effect on age-related neurovascular decline or microglia/monocyte activation in the absence of APOE. Collectively, our data shows that neurovascular structures decline with age, a process that we propose to be intimately linked to complement activation in microglia/monocytes. Exercise prevents these changes, but not in the absence of APOE, opening up new avenues for understanding the complex interactions between neurovascular and neuroinflammatory responses in aging and neurodegenerative diseases such as Alzheimer’s disease. PMID:26512759

  14. Early neurovascular uncoupling in the brain during community acquired pneumonia

    PubMed Central

    2012-01-01

    Introduction Sepsis leads to microcirculatory dysfunction and therefore a disturbed neurovascular coupling in the brain. To investigate if the dysfunction is also present in less severe inflammatory diseases we studied the neurovascular coupling in patients suffering from community acquired pneumonia. Methods Patients were investigated in the acute phase of pneumonia and after recovery. The neurovascular coupling was investigated with a simultaneous electroencephalogram (EEG)-Doppler technique applying a visual stimulation paradigm. Resting EEG frequencies, visual evoked potentials as well as resting and stimulated hemodynamic responses were obtained. Disease severity was characterized by laboratory and cognitive parameters as well as related scoring systems. Data were compared to a control group. Results Whereas visually evoked potentials (VEP) remained stable a significant slowing and therefore uncoupling of the hemodynamic responses were found in the acute phase of pneumonia (Rate time: control group: 3.6 ± 2.5 vs. acute pneumonia: 1.6 ± 2.4 s; P < 0.0005). In the initial investigation, patients who deteriorated showed a decreased hemodynamic response as compared with those who recovered (gain: recovered: 15% ± 4% vs. deteriorated: 9% ± 3%, P < 0.05; control: 14% ± 5%). After recovery the coupling normalized. Conclusions Our study underlines the role of an early microcirculatory dysfunction in inflammatory syndromes that become evident in pre-septic conditions with a gradual decline according to disease severity. PMID:22520083

  15. Hyperperfusion in progressive multifocal leukoencephalopathy is associated with disease progression and absence of immune reconstitution inflammatory syndrome

    PubMed Central

    Khoury, Michael N.; Gheuens, Sarah; Ngo, Long; Wang, Xiaoen; Alsop, David C.

    2013-01-01

    We sought to characterize perfusion patterns of progressive multifocal leukoencephalopathy lesions by arterial spin labelling perfusion magnetic resonance imaging and to analyse their association with immune reconstitution inflammatory syndrome, and survival. A total of 22 patients with progressive multifocal leukoencephalopathy underwent a clinical evaluation and magnetic resonance imaging of the brain within 190 days of symptom onset. The presence of immune reconstitution inflammatory syndrome was determined based on clinical and laboratory criteria. Perfusion within progressive multifocal leukoencephalopathy lesions was determined by arterial spin labelling magnetic resonance imaging. We observed intense hyperperfusion within and at the edge of progressive multifocal leukoencephalopathy lesions in a subset of subjects. This hyperperfusion was quantified by measuring the fraction of lesion volume showing perfusion in excess of twice normal appearing grey matter. Hyperperfused lesion fraction was significantly greater in progressive multifocal leukoencephalopathy progressors than in survivors (12.8% versus 3.4% P = 0.02) corresponding to a relative risk of progression for individuals with a hyperperfused lesion fraction ≥ 4.0% of 9.1 (95% confidence interval of 1.4–59.5). The presence of hyperperfusion was inversely related to the occurrence of immune reconstitution inflammatory syndrome at the time of scan (P = 0.03). Indeed, within 3 months after symptom onset, hyperperfusion had a positive predictive value of 88% for absence of immune reconstitution inflammatory syndrome. Arterial spin labelling magnetic resonance imaging recognized regions of elevated perfusion within lesions of progressive multifocal leukoencephalopathy. These regions might represent virologically active areas operating in the absence of an effective adaptive immune response and correspond with a worse prognosis. PMID:24088807

  16. Matrix metalloproteinase8 has a central role in inflammatory disorders and cancer progression.

    PubMed

    Dejonckheere, Eline; Vandenbroucke, Roosmarijn E; Libert, Claude

    2011-04-01

    The predominant role of matrix metalloproteinase 8 in extracellular matrix turnover, modulation of inflammatory responses and other physiological processes is well documented. Several recent studies highlight the involvement of MMP8 in a wide range of pathologies. This review will shed light on the putative role of MMP8 as a drug target or disease marker in some inflammatory disorders and in cancer progression. PMID:21388856

  17. Progressive chronic inflammatory demyelinating polyneuropathy in a child with central nervous system involvement and myopathy.

    PubMed

    Barisić, Nina; Horvath, Rita; Grković, Lana; Mihelcić, Dina; Luetić, Tomislav

    2006-12-01

    Chronic inflammatory demyelinating polyneuropathy (CIDP) is a chronic disorder, manifesting with monophasic or relapsing course. Progressive course is rare in children. The article presents a boy with progressive generalized muscle weakness and areflexia since the age of two, developed after viral infection. Electromyoneurography showed severe neurogenic lesion, with myopathic pattern in proximal muscles. Increased serum ganglioside antibody titers (anti-GM1 and anti-GD1b) were registered. Sural nerve biopsy revealed demyelination and onion bulbs. Inflammatory perivascular CD3 positive infiltrates were present in muscle and nerve biopsies. Brain magnetic resonance imaging showed cortical atrophy, hyperintensities of the white matter and gray matter hypointensities. Improvement occurred on intravenous immune globulins and methylprednisolone treatment. Demyelination might develop in central and peripheral nervous system associated with inflammatory myopathy in patients with progressive course of CIDP. PMID:17243577

  18. Inflammatory infratentorial progressive multifocal leukoencephalopathy in a patient with rheumatoid arthritis.

    PubMed

    Lach, Boleslaw; Connolly, Barbara; Wüthrich, Christian; Koralnik, Igor J

    2014-02-01

    An 84-year-old man with rheumatoid arthritis (RA) treated with methotrexate, developed progressive confusion and cerebellar symptoms, and died approximately 2 months later. Neuropathological examination revealed progressive multifocal leukoencephalopathy (PML) involving the cerebellum and brainstem. The affected tissues displayed intense infiltrations by CD8+ T-cells and microglia. JC virus was localized in oligodendroglia and cerebellar granule cells. This case illustrates unusual localization of inflammatory PML in a patient with RA treated with methotrexate. PMID:23683127

  19. Neurovascular coupling: a parallel implementation.

    PubMed

    Dormanns, Katharina; Brown, Richard G; David, Tim

    2015-01-01

    A numerical model of neurovascular coupling (NVC) is presented based on neuronal activity coupled to vasodilation/contraction models via the astrocytic mediated perivascular K(+) and the smooth muscle cell (SMC) Ca(2+) pathway termed a neurovascular unit (NVU). Luminal agonists acting on P2Y receptors on the endothelial cell (EC) surface provide a flux of inositol trisphosphate (IP3) into the endothelial cytosol. This concentration of IP3 is transported via gap junctions between EC and SMC providing a source of sarcoplasmic derived Ca(2+) in the SMC. The model is able to relate a neuronal input signal to the corresponding vessel reaction (contraction or dilation). A tissue slice consisting of blocks, each of which contain an NVU is connected to a space filling H-tree, simulating a perfusing arterial tree (vasculature) The model couples the NVUs to the vascular tree via a stretch mediated Ca(2+) channel on both the EC and SMC. The SMC is induced to oscillate by increasing an agonist flux in the EC and hence increased IP3 induced Ca(2+) from the SMC stores with the resulting calcium-induced calcium release (CICR) oscillation inhibiting NVC thereby relating blood flow to vessel contraction and dilation following neuronal activation. The coupling between the vasculature and the set of NVUs is relatively weak for the case with agonist induced where only the Ca(2+) in cells inside the activated area becomes oscillatory however, the radii of vessels both inside and outside the activated area oscillate (albeit small for those outside). In addition the oscillation profile differs between coupled and decoupled states with the time required to refill the cytosol with decreasing Ca(2+) and increasing frequency with coupling. The solution algorithm is shown to have excellent weak and strong scaling. Results have been generated for tissue slices containing up to 4096 blocks. PMID:26441619

  20. Neurovascular coupling: a parallel implementation

    PubMed Central

    Dormanns, Katharina; Brown, Richard G.; David, Tim

    2015-01-01

    A numerical model of neurovascular coupling (NVC) is presented based on neuronal activity coupled to vasodilation/contraction models via the astrocytic mediated perivascular K+ and the smooth muscle cell (SMC) Ca2+ pathway termed a neurovascular unit (NVU). Luminal agonists acting on P2Y receptors on the endothelial cell (EC) surface provide a flux of inositol trisphosphate (IP3) into the endothelial cytosol. This concentration of IP3 is transported via gap junctions between EC and SMC providing a source of sarcoplasmic derived Ca2+ in the SMC. The model is able to relate a neuronal input signal to the corresponding vessel reaction (contraction or dilation). A tissue slice consisting of blocks, each of which contain an NVU is connected to a space filling H-tree, simulating a perfusing arterial tree (vasculature) The model couples the NVUs to the vascular tree via a stretch mediated Ca2+ channel on both the EC and SMC. The SMC is induced to oscillate by increasing an agonist flux in the EC and hence increased IP3 induced Ca2+ from the SMC stores with the resulting calcium-induced calcium release (CICR) oscillation inhibiting NVC thereby relating blood flow to vessel contraction and dilation following neuronal activation. The coupling between the vasculature and the set of NVUs is relatively weak for the case with agonist induced where only the Ca2+ in cells inside the activated area becomes oscillatory however, the radii of vessels both inside and outside the activated area oscillate (albeit small for those outside). In addition the oscillation profile differs between coupled and decoupled states with the time required to refill the cytosol with decreasing Ca2+ and increasing frequency with coupling. The solution algorithm is shown to have excellent weak and strong scaling. Results have been generated for tissue slices containing up to 4096 blocks. PMID:26441619

  1. Neurovascular dysfunction and neurodegeneration in dementia and Alzheimer's disease.

    PubMed

    Nelson, Amy R; Sweeney, Melanie D; Sagare, Abhay P; Zlokovic, Berislav V

    2016-05-01

    Vascular insults can initiate a cascade of molecular events leading to neurodegeneration, cognitive impairment, and dementia. Here, we review the cellular and molecular mechanisms in cerebral blood vessels and the pathophysiological events leading to cerebral blood flow dysregulation and disruption of the neurovascular unit and the blood-brain barrier, which all may contribute to the onset and progression of dementia and Alzheimer's disease (AD). Particularly, we examine the link between neurovascular dysfunction and neurodegeneration including the effects of AD genetic risk factors on cerebrovascular functions and clearance of Alzheimer's amyloid-β peptide toxin, and the impact of vascular risk factors, environment, and lifestyle on cerebral blood vessels, which in turn may affect synaptic, neuronal, and cognitive functions. Finally, we examine potential experimental treatments for dementia and AD based on the neurovascular model, and discuss some critical questions to be addressed by future studies. This article is part of a Special Issue entitled: Vascular Contributions to Cognitive Impairment and Dementia edited by M. Paul Murphy, Roderick A. Corriveau and Donna M. Wilcock. PMID:26705676

  2. Brain imaging of neurovascular dysfunction in Alzheimer's disease.

    PubMed

    Montagne, Axel; Nation, Daniel A; Pa, Judy; Sweeney, Melanie D; Toga, Arthur W; Zlokovic, Berislav V

    2016-05-01

    Neurovascular dysfunction, including blood-brain barrier (BBB) breakdown and cerebral blood flow (CBF) dysregulation and reduction, are increasingly recognized to contribute to Alzheimer's disease (AD). The spatial and temporal relationships between different pathophysiological events during preclinical stages of AD, including cerebrovascular dysfunction and pathology, amyloid and tau pathology, and brain structural and functional changes remain, however, still unclear. Recent advances in neuroimaging techniques, i.e., magnetic resonance imaging (MRI) and positron emission tomography (PET), offer new possibilities to understand how the human brain works in health and disease. This includes methods to detect subtle regional changes in the cerebrovascular system integrity. Here, we focus on the neurovascular imaging techniques to evaluate regional BBB permeability (dynamic contrast-enhanced MRI), regional CBF changes (arterial spin labeling- and functional-MRI), vascular pathology (structural MRI), and cerebral metabolism (PET) in the living human brain, and examine how they can inform about neurovascular dysfunction and vascular pathophysiology in dementia and AD. Altogether, these neuroimaging approaches will continue to elucidate the spatio-temporal progression of vascular and neurodegenerative processes in dementia and AD and how they relate to each other. PMID:27038189

  3. Progressive inflammatory pathology in the retina of aluminum-fed 5xFAD transgenic mice.

    PubMed

    Pogue, A I; Dua, P; Hill, J M; Lukiw, W J

    2015-11-01

    At least 57 murine transgenic models for Alzheimer's disease (Tg-AD) have been developed to overexpress the 42 amino acid amyloid-beta (Aβ42) peptide in the central nervous system (CNS). These 'humanized murine Tg-AD models' have greatly expanded our understanding of the contribution of Aβ42 peptide-mediated pro-inflammatory neuropathology to the AD process. A number of independent laboratories using different amyloid-overexpressing Tg-AD models have shown that supplementation of murine Tg-AD diets and/or drinking water with aluminum significantly enhances Aβ42 peptide-mediated inflammatory pathology and AD-type cognitive change compared to animals receiving control diets. In humans AD-type pathology appears to originate in the limbic system and progressively spreads into primary processing and sensory regions such as the retina. In these studies, for the first time, we assess the propagation of Aβ42 and inflammatory signals into the retina of 5xFAD Tg-AD amyloid-overexpressing mice whose diets were supplemented with aluminum. The two most interesting findings were (1) that similar to other Tg-AD models, there was a significantly accelerated development of Aβ42 and inflammatory pathology in 5xFAD Tg-AD mice fed aluminum; and (2) in aluminum-supplemented animals, markers for inflammatory pathology appeared in both the brain and the retina as evidenced by an evolving presence of Aβ42 peptides, and accompanied by inflammatory markers - cyclooxygenase-2 (COX-2) and C-reactive protein (CRP). The results indicate that in the 5xFAD Tg-AD model aluminum not only enhances an Aβ42-mediated inflammatory degeneration of the brain but also appears to induce AD-type pathology in an anatomically-linked primary sensory area that involves vision. PMID:26213226

  4. Inflammatory Leukocyte Phenotypes Correlate with Disease Progression in Idiopathic Pulmonary Fibrosis

    PubMed Central

    Moore, Bethany B.; Fry, Chris; Zhou, Yueren; Murray, Susan; Han, MeiLan K.; Martinez, Fernando J.; Flaherty, Kevin R.

    2014-01-01

    Idiopathic pulmonary fibrosis (IPF) is characterized by progressive deposition of extracellular matrix, worsening dyspnea, and eventual mortality. Pathogenesis of IPF is poorly understood and the role inflammation and activated leukocytes play in the disease process is controversial. Previous studies demonstrated that activated leukocyte subsets characterize IPF patients. We sought to validate this observation in a well-defined cohort of 35 IPF patients and to correlate the observed leukocyte phenotypes with robust parameters of disease progression. We demonstrate that in univariate and multivariate analyses, increases in the CD14hi, CD16hi subset of monocytes measured at baseline correlated with disease progression, with a threshold value >0.5% of the total peripheral blood mononuclear cells being a significant predictor for worse outcome. In addition, several T cell subsets, including CD25 expressing CD4 cells, and CXCR3 expressing CD4 and CD8 subsets correlated with disease progression when found in increased percentages in the peripheral blood of IPF patients when sampled at baseline. Somewhat surprising in comparison to previous literature, the CD4 T cells did not appear to have lost expression of the co-stimulatory molecule, CD28, but the CD8 T cells did. Taken together, these results are consistent with the presence of an inflammatory process in IPF patients who eventually progress. However, when longitudinal measurements of these same markers were examined, there was significant heterogeneity of expression and these biomarkers did not necessarily remain elevated in IPF patients with progressive disease. We interpret this heterogeneity to suggest that IPF patients experience episodic inflammatory events that once triggered, may lead to disease progression. This longitudinal heterogeneity in biomarker analyses may explain why such markers are not consistently measured in all IPF cohorts. PMID:25580363

  5. Progress with anti-tumor necrosis factor therapeutics for the treatment of inflammatory bowel disease.

    PubMed

    Fernandes, Carlos; Allocca, Mariangela; Danese, Silvio; Fiorino, Gionata

    2015-01-01

    Anti-tumor necrosis factor (TNF) therapy is a valid, effective and increasingly used option in inflammatory bowel disease management. Nevertheless, further knowledge and therapeutic indications regarding these drugs are still evolving. Anti-TNF therapy may be essential to achieve recently proposed end points, namely mucosal healing, prevention of bowel damage and prevention of patient's disability. Anti-TNF drugs are also suggested to be more effective in early disease, particularly in early Crohn's disease. Moreover, its efficacy for prevention of postoperative recurrence in Crohn's disease is still debated. Costs and adverse effects, the relevance of drug monitoring and the possibility of anti-TNF therapy withdrawal in selected patients are still debated issues. This review aimed to describe and discuss the most relevant data about the progress with anti-TNF therapy for the management of inflammatory bowel disease. PMID:25713992

  6. Biphasic Mechanisms of Neurovascular Unit Injury and Protection In CNS Diseases

    PubMed Central

    Maki, Takakuni; Hayakawa, Kazuhide; Pham, Loc-Duyen D.; Xing, Changhong; Lo, Eng H.; Arai, Ken

    2013-01-01

    In the past decade, evidence has emerged that there is a variety of bidirectional cell-cell and/or cell-extracellular matrix interactions within the neurovascular unit (NVU), which is composed of neuronal, glial, and vascular cells along with extracellular matrix. Many central nervous system (CNS) diseases, which lead to NVU dysfunction, have common features such as glial activation/transformation and vascular/blood-brain-barrier alteration. These phenomena show dual opposite roles, harmful at acute phase and beneficial at chronic phase. This diverse heterogeneity may induce biphasic clinical courses, i.e. degenerative and regenerative processes in the context of a dynamically coordinated cell-cell/cell-matrix interactions in the NVU. A deeper understanding of the seemingly contradictory actions in cellular levels is essential for NVU protection or regeneration to suppress the deleterious inflammatory reactions and promote adaptive remodeling after CNS injury. This mini-review will present an overview of recent progress in the biphasic roles of the NVU and discuss the clinical relevance of NVU responses associated with CNS diseases, such as stroke and other chronic neurodegenerative disease. PMID:23469847

  7. Investigating the Limits of Neurovascular Coupling.

    PubMed

    Denfield, George H; Fahey, Paul G; Reimer, Jacob; Tolias, Andreas S

    2016-09-01

    O'Herron et al. (2016) perform two-photon imaging of vascular and neural responses in cat and rodent primary visual cortex to investigate the limits of neurovascular coupling. Their results suggest important constraints on making inferences about neuronal responses from hemodynamic activity. PMID:27608758

  8. Progressive Mitral Stenosis After MitraClip Implantation in a Patient With Systemic Inflammatory Disease.

    PubMed

    Saji, Mike; Ailawadi, Gorav; Fowler, Dale E; LaPar, Damien J; Dent, John M; Ragosta, Michael; Lim, D Scott

    2016-08-01

    We describe a patient at high surgical risk who was successfully treated with a MitraClip (Abbott Vascular, Menlo Park, CA) without transmitral gradient. She received corticosteroid therapy for systemic lupus erythematosus, and progressive mitral stenosis developed late after MitraClip implantation. It gradually increased and reached 23 mm Hg at 28 months after the procedure; during the same period, her dose of prednisone had to be increased owing to lupus flare. Systemic inflammatory disease has the potential to result in mitral valve inflammation and fibrosis, ultimately causing thickening of the tissue bridge and worsening of the mitral valve obstruction. Preprocedural counseling regarding durability may help in this population. PMID:27449466

  9. Radiation promotes colorectal cancer initiation and progression by inducing senescence-associated inflammatory responses.

    PubMed

    Kim, S B; Bozeman, R G; Kaisani, A; Kim, W; Zhang, L; Richardson, J A; Wright, W E; Shay, J W

    2016-06-30

    Proton radiotherapy is becoming more common as protons induce more precise DNA damage at the tumor site with reduced side effects to adjacent normal tissues. However, the long-term biological effects of proton irradiation in cancer initiation compared with conventional photon irradiation are poorly characterized. In this study, using a human familial adenomatous polyposis syndrome susceptible mouse model, we show that whole-body irradiation with protons are more effective in inducing senescence-associated inflammatory responses (SIRs), which are involved in colon cancer initiation and progression. After proton irradiation, a subset of SIR genes (Troy, Sox17, Opg, Faim2, Lpo, Tlr2 and Ptges) and a gene known to be involved in invasiveness (Plat), along with the senescence-associated gene (P19Arf), are markedly increased. Following these changes, loss of Casein kinase Iα and induction of chronic DNA damage and TP53 mutations are increased compared with X-ray irradiation. Proton irradiation also increases the number of colonic polyps, carcinomas and invasive adenocarcinomas. Pretreatment with the non-steroidal anti-inflammatory drug, 2-cyano-3,12-dioxooleana-1,9(11)-dien-28-oic acid-ethyl amide (CDDO-EA), reduces proton irradiation-associated SIR and tumorigenesis. Thus exposure to proton irradiation elicits significant changes in colorectal cancer initiation and progression that can be mitigated using CDDO-EA. PMID:26477319

  10. Radiation Promotes Colorectal Cancer Initiation and Progression by Inducing Senescence-Associated Inflammatory Responses

    PubMed Central

    Kim, Sang Bum; Bozeman, Ronald; Kaisani, Aadil; Kim, Wanil; Zhang, Lu; Richardson, James A.; Wright, Woodring E.; Shay, Jerry W.

    2015-01-01

    Proton radiotherapy is becoming more common since protons induce more precise DNA damage at the tumor site with reduced side effects to adjacent normal tissues. However, the long-term biological effects of proton irradiation in cancer initiation compared to conventional photon irradiation are poorly characterized. In this study, using a human familial adenomatous polyposis syndrome susceptible mouse model, we show that whole body irradiation with protons are more effective in inducing senescence-associated inflammatory responses (SIR) which are involved in colon cancer initiation and progression. After proton irradiation, a subset of SIR genes (Troy, Sox17, Opg, Faim2, Lpo, Tlr2 and Ptges) and a gene known to be involved in invasiveness (Plat), along with the senescence associated gene (P19Arf) are markedly increased. Following these changes loss of Casein kinase Iα (CKIα) and induction of chronic DNA damage and TP53 mutations are increased compared to x-ray irradiation. Proton irradiation also increases the number of colonic polyps, carcinomas and invasive adenocarcinomas. Pretreatment with the non-steroidal anti-inflammatory drug, CDDO-EA, reduces proton irradiation associated SIR and tumorigenesis. Thus, exposure to proton irradiation elicits significant changes in colorectal cancer initiation and progression that can be mitigated using CDDO-EA. PMID:26477319

  11. Anti-inflammatory therapies in TRAMP mice: delay in PCa progression.

    PubMed

    Kido, Larissa Akemi; Montico, Fabio; Sauce, Rafael; Macedo, Aline Barbosa; Minatel, Elaine; Costa, Débora Barbosa Vendramini; de Carvalho, João Ernesto; Pilli, Ronaldo Aloise; Cagnon, Valeria Helena Alves

    2016-04-01

    The aim of this study was to characterize the structural and molecular biology as well as evaluate the immediate and late responses of prostatic cancer in the transgenic adenocarcinoma of the mouse prostate (TRAMP) model after treatment with goniothalamin (GTN) and celecoxib. The treated mice received GTN (150 mg/kg, gavage) or celecoxib (10 mg/kg, gavage) from 8 to 12 weeks of age. They were killed at different ages: the immediate-response groups at 12 weeks and the late-response groups at 22 weeks. The ventral prostate was collected for light microscopy, immunohistochemistry, western blotting, TUNEL, and ELISA. Morphological analyses indicated that GTN treatment delayed the progression of prostatic adenocarcinoma, leading to a significant decrease of prostatic lesion frequency in both experimental period responses to this treatment, mainly high-grade prostatic intraepithelial neoplasia and well-differentiated adenocarcinoma. Also, the celecoxib treatment showed a particular decrease in the proliferative processes (PCNA) in both the experimental periods. Despite celecoxib diminishing the COX2 and IGFR1 levels, GTN presented higher action spectrum considering the decrease of a greater molecular number involved in the proliferative and inflammatory processes in prostatic cancer. Goniothalamin attenuated the pro-inflammatory response in TRAMP prostatic microenvironment, delaying prostate cancer (PCa) progression. Celecoxib treatment was efficient in the regulation of COX2 in the TRAMP mice, mainly in the advanced disease grade. Finally, we concluded that inflammatory process control in early grades of PCa was crucial for the downregulation of the signaling pathways involved in the proliferative processes in advanced cancer grades. PMID:26772819

  12. Hydrogen Sulfide Attenuates Neurodegeneration and Neurovascular Dysfunction Induced by Intracerebral Administered Homocysteine in Mice

    PubMed Central

    Kamat, Pradip K.; Kalani, Anuradha; Givvimani, Srikanth; Sathnur, PB; Tyagi, Suresh C.; Tyagi, Neetu

    2014-01-01

    High levels of homocysteine (Hcy), known as hyperhomocysteinemia (HHcy) are associated with neurovascular diseases. H2S, a metabolite of Hcy, has a potent anti-oxidant and anti-inflammatory activity; however, the effect of H2S has not been explored in Hcy (IC) induced neurodegeneration and neurovascular dysfunction in mice. Therefore, the present study was designed to explore the neuroprotective role of H2S on Hcy induced neurodegeneration and neurovascular dysfunction. To test this hypothesis we employed wild type (WT) males ages 8–10 weeks, WT+ artificial cerebrospinal fluid (aCSF), WT+ Hcy (0.5μmol/μl) intracerebral injection (I.C., one time only prior to NaHS treatment), WT+Hcy +NaHS (sodium hydrogen sulfide, precursor of H2S, 30 μmol/kg, body weight). NaHS was injected intra-peritoneally (I.P.) once daily for the period of 7 days after the Hcy (IC) injection. Hcy treatment significantly increased MDA, nitrite level, acetylcholinestrase activity, TNFα, IL1β, GFAP, iNOS, eNOS and decreased glutathione level indicating oxidative-nitrosative stress and neuroinflammation as compared to control and aCSF treated groups. Further, increased expression of NSE, S100B and decreased expression of (PSD95, SAP97) synaptic protein indicated neurodegeneration. Brain sections of Hcy treated mice showed damage in the cortical area and periventricular cells. TUNEL positive cells and Fluro Jade-C staining indicated apoptosis and neurodegeneration. The increased expression of MMP9, MMP2 and decreased expression of TIMP-1, TIMP-2, tight junction proteins (ZO1, Occuldin) in Hcy treated group indicate neurovascular remodeling. Interestingly, NaHS treatment significantly attenuated Hcy induced oxidative stress, memory deficit, neurodegeneration, neuroinflammation and cerebrovascular remodeling. The results indicate that H2S is effective in providing protection against neurodegeneration and neurovascular dysfunction. PMID:23912038

  13. Involvement of astrocytes in neurovascular communication.

    PubMed

    Nuriya, M; Hirase, H

    2016-01-01

    The vascular interface of the brain is distinct from that of the peripheral tissue in that astrocytes, the most numerous glial cell type in the gray matter, cover the vasculature with their endfeet. This morphological feature of the gliovascular junction has prompted neuroscientists to suggest possible functional roles of astrocytes including astrocytic modulation of the vasculature. Additionally, astrocytes develop an intricate morphology that intimately apposes neuronal synapses, making them an ideal cellular mediator of neurovascular coupling. In this article, we first introduce the classical anatomical and physiological findings that led to the proposal of various gliovascular interaction models. Next, we touch on the technological advances in the past few decades that enabled investigations and evaluations of neuro-glio-vascular interactions in situ. We then review recent experimental findings on the roles of astrocytes in neurovascular coupling from the viewpoints of intra- and intercellular signalings in astrocytes. PMID:27130410

  14. The Multiple Sclerosis Degradome: Enzymatic Cascades in Development and Progression of Central Nervous System Inflammatory Disease

    PubMed Central

    Scarisbrick, I.A.

    2014-01-01

    An array of studies implicate different classes of protease and their endogenous inhibitors in multiple sclerosis (MS) pathogenesis based on expression patterns in MS lesions, sera, and/or cerebrospinal fluid (CSF). Growing evidence exists regarding their mechanistic roles in inflammatory and neurodegenerative aspects of this disease. Proteolytic events participate in demyelination, axon injury, apoptosis, and development of the inflammatory response including immune cell activation and extravasation, cytokine and chemokine activation/inactivation, complement activation, and epitope spreading. The potential significance of proteolytic activity to MS therefore relates not only to their potential use as important biomarkers of disease activity, but additionally as prospective therapeutic targets. Experimental data indicate that understanding the net physiological consequence of altered protease levels in MS development and progression necessitates understanding protease activity in the context of substrates, endogenous inhibitors, and proteolytic cascade interactions, which together make up the MS degradome. This review will focus on evidence regarding the potential physiologic role of those protease families already identified as markers of disease activity in MS; that is, the metallo-, serine, and cysteine proteases. PMID:18219817

  15. Immune reconstitution inflammatory syndrome in a patient with progressive multifocal leukoencephalopathy.

    PubMed

    Shahani, Lokesh; Shah, Minal; Tavakoli-Tabasi, Shahriar

    2015-01-01

    Progressive multifocal leukoencephalopathy (PML) is a severe opportunistic infection of the central nervous system. A 52-year-old man with HIV infection, recently started on antiretroviral therapy, presented with symptoms of mental cloudiness, blurry vision and ataxia. MRI of the brain showed nodular perivascular space enhancement with surrounding vasogenic oedema and midline shift. A lumbar puncture revealed non-inflammatory cerebrospinal fluid and was positive for JC virus. As the patient developed worsening symptoms in the setting of initiation of antiretroviral therapy with immune recovery, a diagnosis of JC virus-associated immune reconstitution inflammatory syndrome (IRIS) was made. With recent literature on the use of CCR5 antagonist maraviroc in PML, our patient was started on maraviroc and noted to have improvement in PML IRIS. This is the first case of an HIV-positive patient successfully treated for PML IRIS with maraviroc, as verified by our literature review; also, our case has clinical implications in improving outcome in PML IRIS. PMID:26063110

  16. 21 CFR 882.5950 - Neurovascular embolization device.

    Code of Federal Regulations, 2011 CFR

    2011-04-01

    ... embolization device. (a) Identification. A neurovascular embolization device is an intravascular implant intended to permanently occlude blood flow to cerebral aneurysms and cerebral ateriovenous...

  17. Pathogenesis of diabetic neuropathy: focus on neurovascular mechanisms.

    PubMed

    Sytze Van Dam, P; Cotter, Mary A; Bravenboer, Bert; Cameron, Norman E

    2013-11-01

    Neuropathies of the peripheral and autonomic nervous systems affect up to half of all people with diabetes, and are major risk factors for foot ulceration and amputation. The aetiology is multifactorial: metabolic changes in diabetes may directly affect neural tissue, but importantly, neurodegenerative changes are precipitated by compromised nerve vascular supply. Experiments in animal models of diabetic neuropathy suggest that similar metabolic sequelae affect neurons and vasa nervorum endothelium. These include elevated polyol pathway activity, oxidative stress, the formation of advanced glycation and lipoxidation end products, and various pro-inflammatory changes such as elevated protein kinase C, nuclear factor κB and p38 mitogen activated protein kinase signalling. These mechanisms do not work in isolation but strongly interact in a mutually facilitatory fashion. Nitrosative stress and the induction of the enzyme poly (ADP-ribose) polymerase form one important link between physiological stressors such as reactive oxygen species and the pro-inflammatory mechanisms. Recently, evidence points to endoplasmic stress and the unfolded protein response as forming another crucial link. This review focuses on the aetiopathogenesis of neurovascular changes in diabetic neuropathy, elucidated in animal studies, and on putative therapeutic targets the majority of which have yet to be tested for efficacy in clinical trials. PMID:23872412

  18. Surgical management of malignant cerebral edema secondary to immune reconstitution inflammatory syndrome from natalizumab-associated progressive multifocal encephalopathy.

    PubMed

    Tan, Lee A; Lopes, Demetrius K

    2015-10-01

    We report a rare multiple sclerosis (MS) patient who developed malignant cerebral edema related to progressive multifocal encephalopathy (PML) immune reconstitution inflammatory syndrome (IRIS) after natalizumab discontinuation. The patient subsequently required a decompressive hemicraniectomy to reduce intracranial pressure and to avoid uncal herniation. PML is a demyelinating disease of the central nervous system (CNS) which affects oligodendrocytes and is caused by reactivation of latent John Cunningham virus. Natalizumab is a known risk factor (1 in 1000) for MS patients treated with this drug. Discontinuation of natalizumab treatment decreases the risk of PML progression, but a massive inflammatory response can occur after cell-mediated immune surveillance is reestablished in the CNS, causing immune reconstitution inflammatory syndrome (IRIS). Treatment of IRIS usually consists of steroids and plasma exchange to lessen the immune response, however, mortality has been reported at up to 29.4%, despite aggressive medical treatment. We discuss our management strategy with a review of the pertinent literature. PMID:26115897

  19. Low level arsenic promotes progressive inflammatory angiogenesis and liver blood vessel remodeling in mice

    SciTech Connect

    Straub, Adam C.; Stolz, Donna B.; Vin, Harina; Ross, Mark A.; Soucy, Nicole V.; Klei, Linda R.; Barchowsky, Aaron

    2007-08-01

    The vascular effects of arsenic in drinking water are global health concerns contributing to human disease worldwide. Arsenic targets the endothelial cells lining blood vessels, and endothelial cell activation or dysfunction may underlie the pathogenesis of both arsenic-induced vascular diseases and arsenic-enhanced tumorigenesis. The purpose of the current studies was to demonstrate that exposing mice to drinking water containing environmentally relevant levels of arsenic promoted endothelial cell dysfunction and pathologic vascular remodeling. Increased angiogenesis, neovascularization, and inflammatory cell infiltration were observed in Matrigel plugs implanted in C57BL/6 mice following 5-week exposures to 5-500 ppb arsenic [Soucy, N.V., Mayka, D., Klei, L.R., Nemec, A.A., Bauer, J.A., Barchowsky, A., 2005. Neovascularization and angiogenic gene expression following chronic arsenic exposure in mice. Cardiovasc.Toxicol 5, 29-42]. Therefore, functional in vivo effects of arsenic on endothelial cell function and vessel remodeling in an endogenous vascular bed were investigated in the liver. Liver sinusoidal endothelial cells (LSEC) became progressively defenestrated and underwent capillarization to decrease vessel porosity following exposure to 250 ppb arsenic for 2 weeks. Sinusoidal expression of PECAM-1 and laminin-1 proteins, a hallmark of capillarization, was also increased by 2 weeks of exposure. LSEC caveolin-1 protein and caveolae expression were induced after 2 weeks of exposure indicating a compensatory change. Likewise, CD45/CD68-positive inflammatory cells did not accumulate in the livers until after LSEC porosity was decreased, indicating that inflammation is a consequence and not a cause of the arsenic-induced LSEC phenotype. The data demonstrate that the liver vasculature is an early target of pathogenic arsenic effects and that the mouse liver vasculature is a sensitive model for investigating vascular health effects of arsenic.

  20. Persistent trigeminal artery causing "double" neurovascular conflict.

    PubMed

    Clerici, Angelo Maurizio; Merlo, Paola; Rognone, Felice; Noce, Monica; Rognone, Elisa; Bono, Giorgio

    2009-03-01

    We report the case of a 73-year-old woman who presented with right VI nerve palsy and homolateral atypical trigeminal neuralgia; standard neuroradiological investigation of orbital/retroorbital regions and intracranial arteries excluded the most commonly demonstrable underlying causes while brain magnetic resonance (T1-weighted fat suppression; T2-weighted thin-section) and magnetic resonance angiography disclosed the evidence of "double" neurovascular conflict because of persistent trigeminal artery with aneurysmal dilation. A role of this almost rare vascular condition in causing painful ophthalmoplegia is discussed. PMID:19267790

  1. Major neurovascular complications of clavicle fracture surgery

    PubMed Central

    Clitherow, Harry DS

    2014-01-01

    Clavicle fracture fixation is becoming an increasingly common operation, with good clinical outcomes and a low rate of significant complications. However, there are several reports of rare but potentially life or limb threatening, neurovascular complications. Arterial injuries are usually pseudoaneurysms associated with prominent screws. These may be clinically silent for several years before presenting as subcritical upper limb ischaemia. Venous injuries are a result of tearing of the vessel wall by fracture manipulation, drills or implants. This produces intra-operative haemorrhage and potentially air embolism, which can be fatal if not rapidly recognized and managed. Brachial plexopathy is the result of traction on adherent plexus or impingement by fracture fragments or callus. It presents as severe arm pain and paralysis immediately postoperatively. Neurovascular injuries can be avoided by a combination of pre-operative planning, communication with anaesthetic staff and strategic surgical technique. The plane of the surgical exposure, release of the soft tissues, drill direction and depth and screw length are all important factors.

  2. Sphenopalatine Ganglion Stimulation in Neurovascular Headaches.

    PubMed

    Schoenen, Jean

    2015-01-01

    The interest for the sphenopalatine ganglion (SPG) in neurovascular headaches dates back to 1908 when Sluder presented his work on the role of the SPG in 'nasal headaches', which are now part of the trigeminal autonomic cephalalgias and cluster headache (ICHD-III-beta). Since then various interventions with blocking or lesional properties have targeted the SPG (transnasal injection of lidocaine and other agents, alcohol or steroid injections, radiofrequency lesions, or even ganglionectomy); success rates vary, but benefit is usually transient. Here we briefly review some anatomophysiological characteristics of the SPG and hypotheses about its pathophysiological role in neurovascular headaches before describing recent therapeutic results obtained with electrical stimulation of the SPG. Based on results of a prospective randomized controlled study, SPG stimulation appears to be an effective treatment option for patients with chronic cluster headaches; efficacy data indicate that acute electrical stimulation of the SPG provides significant attack pain relief and in many cases pain freedom compared to sham stimulation. Moreover, in some patients SPG stimulation has been associated with a significant and clinically meaningful reduction in cluster headache attack frequency; this preventive effect of SPG stimulation warrants further investigation. For migraine attacks, the outcome of a proof-of-concept study using a temporary electrode implanted in the pterygopalatine fossa was less encouraging; however, an ongoing multicenter trial is evaluating the efficacy of long-term SPG stimulation against sham stimulation for acute and preventive treatment in patients with frequent migraine. PMID:26394372

  3. THE ROLE OF TUMOR PROGRESSION LOCUS 2 (TPL-2) PROTEIN KINASE IN GLIAL INFLAMMATORY RESPONSE

    PubMed Central

    Hirschhorn, Joshua; Mohanty, Sangeeta; Bhat, Narayan R.

    2013-01-01

    Tumor progression locus 2 (Tpl2)/Cot kinase is a newer member of MAP3K family that is now known for its essential role in TNFα expression in macrophages, but its proinflammatory signaling, if any, in glia is unknown. When cultures of murine microglia and astrocytes were exposed to lipopolysaccharide, there was a rapid activation (i.e., phosphorylation) of Tpl2 in parallel to the activation of down-stream effector MAPKs i.e., ERK, p38 MAPK and JNK. Pre-incubation of the cultures with a Tpl2 inhibitor selectively suppressed the activation of the primary down-stream target i.e., ERK relative to p38 MAPK and JNK. That Tpl2 activation was functionally involved in glial inflammatory response was indicated by a reduced release of the cytokines i.e., TNFα and the expression of inducible nitric oxide synthase (iNOS) in the presence of the kinase inhibitor. Further, overexpression of a wild-type Tpl2 construct in C-6 glia resulted in an enhanced transcriptional activation of iNOS while transfection with a dominant negative form of Tpl-2 had the opposite effect. The findings assign an important proinflammatory signaling function for Tpl2 pathway in glial cells. PMID:24188160

  4. Plant-Derived Anti-Inflammatory Compounds: Hopes and Disappointments regarding the Translation of Preclinical Knowledge into Clinical Progress

    PubMed Central

    Fürst, Robert; Zündorf, Ilse

    2014-01-01

    Many diseases have been described to be associated with inflammatory processes. The currently available anti-inflammatory drug therapy is often not successful or causes intolerable side effects. Thus, new anti-inflammatory substances are still urgently needed. Plants were the first source of remedies in the history of mankind. Since their chemical characterization in the 19th century, herbal bioactive compounds have fueled drug development. Also, nowadays, new plant-derived agents continuously enrich our drug arsenal (e.g., vincristine, galantamine, and artemisinin). The number of new, pharmacologically active herbal ingredients, in particular that of anti-inflammatory compounds, rises continuously. The major obstacle in this field is the translation of preclinical knowledge into evidence-based clinical progress. Human trials of good quality are often missing or, when available, are frequently not suitable to really prove a therapeutical value. This minireview will summarize the current situation of 6 very prominent plant-derived anti-inflammatory compounds: curcumin, colchicine, resveratrol, capsaicin, epigallocatechin-3-gallate (EGCG), and quercetin. We will highlight their clinical potential and/or pinpoint an overestimation. Moreover, we will sum up the planned trials in order to provide insights into the inflammatory disorders that are hypothesized to be beneficially influenced by the compound. PMID:24987194

  5. ALS and Oxidative Stress: The Neurovascular Scenario

    PubMed Central

    Thakur, Keshav; Gupta, Pawan Kumar

    2013-01-01

    Oxidative stress and angiogenic factors have been placed as the prime focus of scientific investigations after an establishment of link between vascular endothelial growth factor promoter (VEGF), hypoxia, and amyotrophic lateral sclerosis (ALS) pathogenesis. Deletion of the hypoxia-response element in the vascular endothelial growth factor promoter and mutant superoxide dismutase 1 (SOD1) which are characterised by atrophy and muscle weakness resulted in phenotype resembling human ALS in mice. This results in lower motor neurodegeneration thus establishing an important link between motor neuron degeneration, vasculature, and angiogenic molecules. In this review, we have presented human, animal, and in vitro studies which suggest that molecules like VEGF have a therapeutic, diagnostic, and prognostic potential in ALS. Involvement of vascular growth factors and hypoxia response elements also highlights the converging role of oxidative stress and neurovascular network for understanding and treatment of various neurodegenerative disorders like ALS. PMID:24367722

  6. Long term follow up of neurovascular island flaps.

    PubMed

    Henderson, H P; Reid, D A

    1980-06-01

    The results of a ten year mean follow up of twenty Neurovascular Island Flaps and two Radial Nerve Innervated Cross Finger Flaps are presented. Sensory acuity sufficient for tactile gnosis was achieved in nineteen cases. In only one case had sensory acuity deteriorated since operation. Use of the flap was hampered in one patient by a pre-existing neuroma. Complete sensory reorientation occurred in five patients. Sensory misreference persisted more commonly on dominant hands. It was our impression that Porter's Letter Test revealed the patients making most use of their neurovascular island flaps. The place of neurovascular island flaps in the management of the mutilated hand is discussed. PMID:7409615

  7. The Neurovascular Retina in Retinopathy of Prematurity

    PubMed Central

    Fulton, Anne B.; Hansen, Ronald M.; Moskowitz, Anne; Akula, James D.

    2009-01-01

    The continuing worldwide epidemic of retinopathy of prematurity (ROP), a leading cause of childhood visual impairment, strongly motivates further research into mechanisms of the disease. Although the hallmark of ROP is abnormal retinal vasculature, a growing body of evidence supports a critical role for the neural retina in the ROP disease process. The age of onset of ROP coincides with the rapid developmental increase in rod photoreceptor outer segment length and rhodopsin content of the retina with escalation of energy demands. Using a combination of non-invasive electroretinographic (ERG), psychophysical, and image analysis procedures, the neural retina and its vasculature have been studied in prematurely born human subjects, both with and without ROP, and in rats that model the key vascular and neural parameters found in human ROP subjects. These data are compared to comprehensive numeric summaries of the neural and vascular features in normally developing human and rat retina. In rats, biochemical, anatomical, and molecular biological investigations are paired with the non-invasive assessments. ROP, even if mild, primarily and persistently alters the structure and function of photoreceptors. Post-receptor neurons and retinal vasculature, which are intimately related, are also affected by ROP; conspicuous neurovascular abnormalities disappear, but subtle structural anomalies and functional deficits may persist years after clinical ROP resolves. The data from human subjects and rat models identify photoreceptor and post-receptor targets for interventions that promise improved outcomes for children at risk for ROP. PMID:19563909

  8. Progressive loss of nigrostriatal dopaminergic neurons induced by inflammatory responses to fipronil.

    PubMed

    Park, Jae Hyeon; Park, Youn Sun; Koh, Hyun Chul

    2016-09-01

    Inflammatory responses are involved in mechanisms of neuronal cell damage in the pathogenesis of neurodegenerative diseases such as Parkinson's disease (PD). We investigated the mechanisms whereby inflammatory responses contribute to loss of dopaminergic neurons in fipronil (FPN)-treated rats. After stereotaxic injection of FPN in the substantia nigra (SN), the number of tyrosine hydroxylase (TH)-positive neurons and the levels of TH expression in the SN decreased at 7days, and a significant decrease was observed at 14days with a subsequent reduction in striatal TH expression. Decreases in dopamine (DA) levels, however, began at 3days post-injection, preceding the changes in TH expression. In contrast, glial fibrillary acidic protein (GFAP) expression was significantly increased at 3days and persisted for up to 14days post-lesion; these changes in GFAP expression appeared to be inversely correlated with TH expression. Furthermore, we found that FPN administration induced an inflammatory response characterized by increased levels of inducible NO synthase (iNOS), cyclooxygenase-2 (COX-2), and tumor necrosis factor-α (TNF-α), which was mediated by activated microglia following infusion of FPN unilaterally into the SN. Intranigral injection of FPN underwent an inflammatory response with a resultant ongoing loss of dopaminergic neurons, indicating that pesticides may have important implication for the study of PD. PMID:27313094

  9. Andrographolide Ameliorates Abdominal Aortic Aneurysm Progression by Inhibiting Inflammatory Cell Infiltration through Downregulation of Cytokine and Integrin Expression.

    PubMed

    Ren, Jun; Liu, Zhenjie; Wang, Qiwei; Giles, Jasmine; Greenberg, Jason; Sheibani, Nader; Kent, K Craig; Liu, Bo

    2016-01-01

    Abdominal aortic aneurysm (AAA), characterized by exuberant inflammation and tissue deterioration, is a common aortic disease associated with a high mortality rate. There is currently no established pharmacological therapy to treat this progressive disease. Andrographolide (Andro), a major bioactive component of the herbaceous plant Andrographis paniculata, has been found to exhibit potent anti-inflammatory properties by inhibiting nuclear factor κ-light-chain-enhancer of activated B cells (NF-κB) activity in several disease models. In this study, we investigated the ability of Andro to suppress inflammation associated with aneurysms, and whether it may be used to block the progression of AAA. Whereas diseased aortae continued to expand in the solvent-treated group, daily administration of Andro to mice with small aneurysms significantly attenuated aneurysm growth, as measured by the diminished expansion of aortic diameter (165.68 ± 15.85% vs. 90.62 ± 22.91%, P < 0.05). Immunohistochemistry analyses revealed that Andro decreased infiltration of monocytes/macrophages and T cells. Mechanistically, Andro inhibited arterial NF-κB activation and reduced the production of proinflammatory cytokines [CCL2, CXCL10, tumor necrosis factor α, and interferon-γ] in the treated aortae. Furthermore, Andro suppressed α4 integrin expression and attenuated the ability of monocytes/macrophages to adhere to activated endothelial cells. These results indicate that Andro suppresses progression of AAA, likely through inhibition of inflammatory cell infiltration via downregulation of NF-κB-mediated cytokine production and α4 integrin expression. Thus, Andro may offer a pharmacological therapy to slow disease progression in patients with small aneurysms. PMID:26483397

  10. Transcranial Doppler ultrasound in neurovascular diseases: diagnostic and therapeutic aspects.

    PubMed

    Topcuoglu, M Akif

    2012-11-01

    Albeit no direct anatomical information can be obtained, neurosonological methods provide real-time determination of velocity, and spectral waveform of blood flow in basal intracranial arteries adds significant benefit to the care of the patients with neurovascular diseases. Several features, such as relative simplicity in terms of interpretation and performance, significantly low cost, totally non-invasiveness, portability, and excellent temporal resolution, make neurosonology increasingly popular tool for evaluation, planning, and monitoring of treatment, and for determining prognosis in various neurovascular diseases. Usefulness of transcranial Doppler in diagnosing/monitoring subarachnoid hemorrhage related vasospasm and sickle cell vasculopathy is already well known. Utility in diagnosis of intracranial arterial stenosis, acute occlusion and recanalization, intracranial hemodynamic effect of the cervical arterial pathologies, intracranial pressure increase, and cerebral circulatory arrest are also well established. Neurosonological determination of vasomotor reactivity, cerebral autoregulation, neurovascular coupling, and micro-embolic signals detection are useful in the assessment of stroke risk, diagnosis of right-to-left shunting, and monitoring during surgery and interventional procedures. Transcranial Doppler is also an evolving ultrasound method with a therapeutic potential such as augmentation of clot lysis and cerebral delivery of thrombolytic or neuroprotective agent loaded nanobubbles in neurovascular diseases. The aim of this study is to give an overview of current usage of the different ultrasound modalities in different neurovascular diseases. PMID:23050641

  11. Neurovascular anatomy of the embryonic quail hindlimb.

    PubMed

    Bentley, Matthew T; Poole, Thomas J

    2009-10-01

    Blood vessel and nerve development in the vertebrate embryo possess certain similarities in pattern and molecular guidance cues. To study the specific influence of shared guidance molecules on nervous and vascular development, an understanding of the normal neurovascular anatomy must be in place. The present study documents the pattern of nervous and vascular development in the Japanese quail hindlimb using immunohistochemistry and fluorescently labeled intravital injection combined with confocal and epifluorescent microscopy. The developmental patterns of major nerves and blood vessels of embryonic hindlimbs between stages E2.75 (HH18) and E6.0 (HH29) are described. By E2.75, the dorsal aortae have begun to fuse into a single vessel at the level of the hindlimb, and have completely fused by E3 (HH20). The posterior cardinal vein is formed at the level of the hindlimb by E3, as is the main artery of the early hindlimb, the ischiadic artery, as an offshoot of the dorsal aorta. Our data suggest that eight spinal segments, versus seven as reported by others (Tanaka and Landmesser,1986a; Tyrrell et al.,1990), contribute to innervation of the quail hindlimb. Lumbosacral neurites reach the plexus region by E3.5 (HH21 & 22), pause for approximately 24 hr, and then enter the hindlimb along with the ischiadic and crural arteries through shared foramina in the pelvic anlage. The degree of anterior-posterior spatial congruency between major nerves and blood vessels of the quail hindlimb was found to be highest medial to the pelvic girdle precursor, versus in the hindlimb proper. PMID:19685501

  12. Anti-inflammatory nutritional intervention in patients with relapsing-remitting and primary-progressive multiple sclerosis: A pilot study.

    PubMed

    Riccio, Paolo; Rossano, Rocco; Larocca, Marilena; Trotta, Vincenzo; Mennella, Ilario; Vitaglione, Paola; Ettorre, Michele; Graverini, Antonio; De Santis, Alessandro; Di Monte, Elisabetta; Coniglio, Maria Gabriella

    2016-03-01

    The aim of this work was to assess the influence of nutritional intervention on inflammatory status and wellness in people with multiple sclerosis. To this end, in a seven-month pilot study we investigated the effects of a calorie-restricted, semi-vegetarian diet and administration of vitamin D and other dietary supplements (fish oil, lipoic acid, omega-3 polyunsaturated fatty acids, resveratrol and multivitamin complex) in 33 patients with relapsing-remitting multiple sclerosis and 10 patients with primary-progressive multiple sclerosis. At 0/3/6 months, patients had neurological examination, filled questionnaires and underwent anthropometric measurements and biochemical analyses. Serum fatty acids and vitamin D levels were measured as markers of dietary compliance and nutritional efficacy of treatment, whereas serum gelatinase levels were analyzed as markers of inflammatory status. All patients had insufficient levels of vitamin D at baseline, but their values did not ameliorate following a weekly administration of 5000  IU, and rather decreased over time. Conversely, omega-3 polyunsaturated fatty acids increased already after three months, even under dietary restriction only. Co-treatment with interferon-beta in relapsing-remitting multiple sclerosis was irrelevant to vitamin D levels. After six months nutritional treatment, no significant changes in neurological signs were observed in any group. However, serum levels of the activated isoforms of gelatinase matrix metalloproteinase-9 decreased by 59% in primary-progressive multiple sclerosis and by 51% in relapsing-remitting multiple sclerosis patients under nutritional intervention, including dietary supplements. This study indicates that a healthy nutritional intervention is well accepted by people with multiple sclerosis and may ameliorate their physical and inflammatory status. PMID:26785711

  13. Fulminant inflammatory leukoencephalopathy associated with HAART-induced immune restoration in AIDS-related progressive multifocal leukoencephalopathy.

    PubMed

    Vendrely, Aurélie; Bienvenu, Boris; Gasnault, Jacques; Thiebault, Jean Baptiste; Salmon, Dominique; Gray, Françoise

    2005-04-01

    HAART-induced immune restoration is beneficial for patients with AIDS-related progressive multifocal leukoencephalopathy (PML). However, in rare instances, an immune-reconstitution inflammatory syndrome (IRIS) may cause paradoxical clinical deterioration. We report the neuropathological study of an AIDS patient who presented with progressive cognitive deterioration; CD4(+) count was 117 and the HIV viral load >10(4); imaging showed non-enhancing lesions consistent with PML. Following initiation of HAART, CD4(+) was 300 and HIV viral load <10(3), but his neurological symptoms continued to deteriorate. Imaging revealed an increase in the size and number of lesions and enhancement of all the lesions. A stereotactic biopsy showed severe inflammatory and demyelinating lesions with marked infiltration by macrophages and T lymphocytes in the absence of a detectable infectious agent. Despite high doses of steroids, the patient died 3 months after admission. Autopsy showed two types of lesions: (1) active inflammatory PML changes with abundant JC virus, and intraparenchymal and perivascular infiltration by T lymphocytes, and (2) acute perivenous leukoencephalitis devoid of JC virus. Most lymphocytes were CD8(+) lymphocytes; CD4(+) lymphocytes were virtually absent. Two pathological reactions were associated with the paradoxical clinical deterioration related to dysregulation of the immune response characteristic of IRIS in PML: (1) an accentuation of JCV infection, and (2) a nonspecific acute perivenous leukoencephalitis. We suggest that both these types of lesions are due to an imbalance of CD8(+)/CD4(+) T cells, with massive infiltration of the cerebral parenchyma by CD8(+) cytotoxic T lymphocytes in the absence of sufficient CD4(+) response. Better understanding of the mechanisms of the IRIS may enable prevention or cure of this severe, sometimes fatal complication of HAART. PMID:15739098

  14. Inflammatory monocytes promote progression of Duchenne muscular dystrophy and can be therapeutically targeted via CCR2

    PubMed Central

    Mojumdar, Kamalika; Liang, Feng; Giordano, Christian; Lemaire, Christian; Danialou, Gawiyou; Okazaki, Tatsuma; Bourdon, Johanne; Rafei, Moutih; Galipeau, Jacques; Divangahi, Maziar; Petrof, Basil J

    2014-01-01

    Myofiber necrosis and fibrosis are hallmarks of Duchenne muscular dystrophy (DMD), leading to lethal weakness of the diaphragm. Macrophages (MPs) are required for successful muscle regeneration, but the role of inflammatory monocyte (MO)-derived MPs in either promoting or mitigating DMD is unclear. We show that DMD (mdx) mouse diaphragms exhibit greatly increased expression of CCR2 and its chemokine ligands, along with inflammatory (Ly6Chigh) MO recruitment and accumulation of CD11bhigh MO-derived MPs. Loss-of-function of CCR2 preferentially reduced this CD11bhigh MP population by impeding the release of Ly6Chigh MOs from the bone marrow but not the splenic reservoir. CCR2 deficiency also helped restore the MP polarization balance by preventing excessive skewing of MPs toward a proinflammatory phenotype. These effects were linked to amelioration of histopathological features and increased muscle strength in the diaphragm. Chronic inhibition of CCR2 signaling by mutated CCL2 secreted from implanted mesenchymal stem cells resulted in similar improvements. These data uncover a previously unrecognized role of inflammatory MOs in DMD pathogenesis and indicate that CCR2 inhibition could offer a novel strategy for DMD management. PMID:25312642

  15. Antioxidant modulation of skin inflammation: preventing inflammatory progression by inhibiting neutrophil influx

    PubMed Central

    McGilvray, Ian D.; Rotstein, Ori D.

    1999-01-01

    Objective To test the hypothesis that antioxidants might affect local inflammation by impairing inflammatory cell influx. Design A laboratory study using a Swiss–Webster mouse model of local inflammation. Setting A university-affiliated hospital. Methods Intradermal injection of 30 μg of S. minnesota endotoxin (LPS) to Swiss–Webster mice initiates a local inflammatory reaction characterized by an early rise in vascular permeability and a later influx of neutrophils. Animals were pretreated intraperitoneally with either pyrrolidine dithiocarbamate (PDTC, 2 mmol/kg), which inhibits free radical generation, or dimethylthiourea (DMTU, 450 mg/kg), a free radical scavenger. Main outcome measures Histologic findings of tissue samples taken at sites of injection; local changes in tissue vascular permeability (PI) determined by iodine-125 albumin injection before sacrifice; neutrophil accumulation quantified by tissue myeloperoxidase levels; tissue levels of the endothelial adhesion molecules intercellular adhesion molecule-1 protein (ICAM-1) and vascular cell adhesion molecule-1 protein (VCAM-1) assessed by immunohistochemistry and Western blot, respectively. Results Neither antioxidant had a significant effect on the early increase in PI, but both decreased the late rise in PI and reduced neutrophil influx. Both ICAM-1 and VCAM-1 were upregulated in response to LPS; however, only the increase in VCAM-1 was attenuated by antioxidant pretreatment. Conclusion These data suggest that antioxidants disrupt the propagation phase of an inflammatory response, possibly by altering neutrophil migration. PMID:10223071

  16. Mechanisms of Neurovascular Dysfunction in Acute Ischemic Brain

    PubMed Central

    Terasaki, Y.; Liu, Y.; Hayakawa, K.; Pham, L.D.; Lo, E.H.; Ji, X.; Arai, K.

    2014-01-01

    The neurovascular unit is now well accepted as a conceptual framework for investigating the mechanisms of ischemic stroke. From a molecular and cellular perspective, three broad mechanisms may underlie stroke pathophysiology – excitotoxicity, oxidative stress and inflammation. To date, however, most investigations of these basic mechanisms have focused on neuronal responses. In this mini-review, we ask whether these mechanisms of excitotoxicity, oxidative stress and inflammation can also be examined in terms of non-neuronal interactions in the neurovascular unit, including the release of extracellular vesicles for cell-cell signaling. PMID:24372202

  17. Prospective Association Between Inflammatory Markers and Progression of Coronary Artery Calcification in Adults With and Without Type 1 Diabetes

    PubMed Central

    Alman, Amy C.; Kinney, Gregory L.; Tracy, Russell P.; Maahs, David M.; Hokanson, John E.; Rewers, Marian J.; Snell-Bergeon, Janet K.

    2013-01-01

    OBJECTIVE The role of inflammation in the increased risk of cardiovascular disease in type 1 diabetes is unclear. We examined the association of inflammation and progression of coronary artery calcification (CAC)—a marker of subclinical atherosclerosis—in adults with and without type 1 diabetes. RESEARCH DESIGN AND METHODS A nested case-control study was performed within the prospective cohort of the Coronary Artery Calcification in Type 1 Diabetes (CACTI) study. Participants underwent two CAC measurements ∼2.5 years apart. Case subjects (n = 204) were those with significant progression of CAC. Control subjects (n = 258) were frequency-matched to case subjects on diabetes status, sex, age, and baseline CAC status. Inflammatory marker assessments were performed on stored blood samples from baseline. A principal components analysis (PCA) was performed and a composite score derived from that analysis. The composite score was constructed by assigning a value of 1 for each PCA component where at least one of the markers exceeded the 75th percentile (range 0–4). Conditional logistic regression was used for the matching strategy. RESULTS The first two components of the PCA were modestly (odds ratio 1.38 [95% CI 1.08–1.77] and 1.27 [1.02–1.59], respectively) associated with CAC progression after adjustment for other risk factors. The composite score was more strongly associated with CAC progression for those with elevated markers in three or four of the principal components compared with those with none. CONCLUSIONS Measures of inflammation were associated with progression of CAC in a population of adults with and without type 1 diabetes. PMID:23340891

  18. Immune-inflammatory Dysregulation Modulates the Incidence of Progressive Fibrosis and Diastolic Stiffness in the Aging Heart

    PubMed Central

    Cieslik, Katarzyna A.; Taffet, George E.; Carlson, Signe; Hermosillo, Jesus; Trial, JoAnn; Entman, Mark L.

    2010-01-01

    Diastolic dysfunction in the aging heart is a grave condition that challenges the life and lifestyle of a growing segment of our population. This report seeks to examine the role and interrelationship of inflammatory dysregulation in interstitial myocardial fibrosis and progressive diastolic dysfunction in aging mice. We studied a population of C57BL/6 mice that developed progressive diastolic dysfunction over 30 months of life. This progressive dysfunction was associated with increasing infiltration of CD45+ fibroblasts of myeloid origin. In addition, increased rates of collagen expression as measured by cellular procollagen were apparent in the heart as a function of age. These cellular and functional changes were associated with progressive increases in mRNA for MCP-1 and IL-13 which correlated both temporally and quantitatively with changes in fibrosis and cellular procollagen levels. MCP-1 protein was also increased and found to be primarily in the venular endothelium. Protein assays also demonstrated elevation of IL-4 and IL-13 suggesting a shift to a Th2 phenotype in the aging heart. In vitro studies demonstrated that IL-13 markedly enhanced monocyte fibroblast transformation. Our results indicate that immunoinflammatory dysregulation in the aging heart induces progressive MCP-1 production and an increased shift to a Th2 phenotype paralleled by an associated increase in myocardial interstitial fibrosis, cellular collagen synthesis, and increased numbers of CD45+ myeloid-derived fibroblasts that contain procollagen. The temporal association and functional correlations suggests a causative relationship between age-dependent immunoinflammatory dysfunction, fibrosis and diastolic dysfunction. PMID:20974150

  19. Modulation of glioma risk and progression by dietary nutrients and anti-inflammatory agents

    PubMed Central

    Kyritsis, Athanassios P.; Bondy, Melissa L.; Levin, Victor A.

    2011-01-01

    Gliomas are tumors of glial origin formed in the central nervous system and exhibit profound morphological and genetic heterogeneity. The etiology of this heterogeneity involves an interaction between genetic alterations and environmental risk factors. Scientific evidence suggests that certain natural dietary components, such as phytoestrogens, flavonoids, polyunsaturated fatty acids and vitamins may exert a protective effect against gliomas by changing the nature of the interaction between genetics and environment. Similarly, certain anti-inflammatory drugs and dietary modifications, such as methionine restriction and the adoption of low-calorie or ketogenic diets, may take advantage of glioma and normal glial cells’ differential requirements for glucose, methionine, and ketone bodies and may therefore be effective as part of preventive or treatment strategies for gliomas. Treatment trials of glioma patients and chemoprevention trials of individuals with a known genetic predisposition to glioma using the most promising of these agents, such as the anti-inflammatory drugs curcumin and gamma-linolenic acid, are needed to validate or refute these agents’ putative role in gliomas. PMID:21302177

  20. Lipid-lowering drugs prevent neurovascular and cognitive consequences of cardiopulmonary bypass.

    PubMed

    Ouk, Thavarak; Amr, Gilles; Azzaoui, Richard; Delassus, Laëtitia; Fossaert, Emilie; Tailleux, Anne; Bordet, Régis; Modine, Thomas

    2016-05-01

    Inflammatory injury and hypoperfusion following cardiopulmonary bypass (CPB) are associated with potential brain injury in relationship between CPB, memory impairment, changes in cerebral vascular reactivity and both systemic and cerebral inflammatory reaction. The objective of this study was to assess the preventive effect of a pretreatment with simvastatin or fenofibrate on neurovascular and cognitive consequences of CPB. Male Sprague-Dawley rats were treated by control diet, simvastatin 10mg/kg/day or fenofibrate 200mg/kg/day for 14days before CPB surgery and were sacrificed immediately after surgery or 24h later. Cognitive function, vascular reactivity, neuronal counts in CA1 and CA3 hippocampal regions, and inflammatory markers were assessed. CPB induced memory impairment and endothelial dysfunction 24h after surgery associated with neuronal loss. Neuronal loss was reduced by simvastatin or fenofibrate treatment in parallel to memory alteration prevention. Pretreatment by simvastatin and fenofibrate prevented CPB-induced endothelial dysfunction. CPB led to early and marked release of TNFα and overexpression of ICAM-1. Both inflammatory marker expression was decreased in the pretreated groups by lipid-lowering drugs. In a rat model of CPB, we demonstrated that simvastatin and fenofibrate protected against CPB-induced endothelial dysfunction, cerebral and systemic inflammation in parallel to memory impairment prevention. PMID:26779598

  1. Telmisartan inhibits hyperalgesia and inflammatory progression in a diabetic neuropathic pain model of Wistar rats

    PubMed Central

    Al-Rejaie, Salim S.; Abuohashish, Hatem M.; Ahmed, Mohammed M.; Arrejaie, Aws S.; Aleisa, Abdulaziz M.; AlSharari, Shakir D.

    2015-01-01

    Objective: To evaluate the potential therapeutic value of telmisartan (TMT) against diabetic neuropathy (DN) and associated pain in Wistar rats. Methods: Peripheral DN was induced by a single intraperitoneal streptozotocin injection (55 mg/kg), and 3 weeks later TMT treatment was started (5 and 10 mg/kg/day), and continued for 4 weeks. Mechanical nociceptive threshold, motor coordination, and thermal nociceptive threshold tests were performed before and after TMT treatment. In serum, glucose, pro-inflammatory cytokines including tumor necrosis factor-α, interleukin-1β, and interleukin-6 were assessed. Nerve growth factor (NGF) levels and histopathological changes were estimated in the sciatic nerve. This study was conducted at the Experimental Animal Care Center, Department of Pharmacology, College of Pharmacy, King Saud University, Riyadh, Kingdom of Saudi Arabia between January 2013 and May 2014. Results: We observed a significant reduction in mechanical nociceptive threshold, motor coordination, and thermal nociceptive threshold in diabetic animals. The TMT treatment significantly enhanced the reduced mechanical nociceptive threshold. The untreated diabetic animals revealed a significant decrease in sciatic NGF, which was markedly attenuated by TMT. The elevated serum levels of cytokines in diabetic animals were inhibited by the TMT treatments. Histopathological evaluation showed obvious nerve degeneration in the diabetic group that was eliminated in the TMT treated diabetic groups. Conclusion: Telmisartan has a potential neuro-protective effect on peripheral DN; this is mediated through its anti-inflammatory effects and its dual properties as an angiotensin receptor blocker, and a partial peroxisome proliferator activator receptor-g ligand. PMID:25864063

  2. Houshiheisan compound prescription protects neurovascular units after cerebral ischemia.

    PubMed

    Wang, Haizheng; Wang, Lei; Zhang, Nan; Zhang, Qi; Zhao, Hui; Zhang, Qiuxia

    2014-04-01

    Houshiheisan is composed of wind-dispelling (chrysanthemun flower, divaricate saposhnikovia root, Manchurian wild ginger, cassia twig, Szechwan lovage rhizome, and platycodon root) and deficiency-nourishing (ginseng, Chinese angelica, large-head atractylodes rhizome, Indian bread, and zingiber) drugs. In this study, we assumed these drugs have protective effects against cerebral ischemia, on neurovascular units. Houshiheisan was intragastrically administered in a rat model of focal cerebral ischemia. Hematoxylin-eosin staining, transmission electron microscopy, immunofluorescence staining, and western blot assays showed that Houshiheisan reduced pathological injury to the ischemic penumbra, protected neurovascular units, visibly up-regulated neuronal nuclear antigen expression, and down-regulated amyloid precursor protein and amyloid-β 42 expression. Wind-dispelling and deficiency-nourishing drugs maintained NeuN expression to varying degrees, but did not affect amyloid precursor protein or amyloid-β 42 expression in the ischemic penumbra. Our results suggest that the compound prescription Houshiheisan effectively suppresses abnormal amyloid precursor protein accumulation, reduces amyloid substance deposition, maintains stabilization of the internal environment of neurovascular units, and minimizes injury to neurovascular units in the ischemic penumbra. PMID:25206882

  3. Imaging of Neurovascular Compression Syndromes: Trigeminal Neuralgia, Hemifacial Spasm, Vestibular Paroxysmia, and Glossopharyngeal Neuralgia.

    PubMed

    Haller, S; Etienne, L; Kövari, E; Varoquaux, A D; Urbach, H; Becker, M

    2016-08-01

    Neurovascular compression syndromes are usually caused by arteries that directly contact the cisternal portion of a cranial nerve. Not all cases of neurovascular contact are clinically symptomatic. The transition zone between the central and peripheral myelin is the most vulnerable region for symptomatic neurovascular compression syndromes. Trigeminal neuralgia (cranial nerve V) has an incidence of 4-20/100,000, a transition zone of 4 mm, with symptomatic neurovascular compression typically proximal. Hemifacial spasm (cranial nerve VII) has an incidence of 1/100,000, a transition zone of 2.5 mm, with symptomatic neurovascular compression typically proximal. Vestibular paroxysmia (cranial nerve VIII) has an unknown incidence, a transition zone of 11 mm, with symptomatic neurovascular compression typically at the internal auditory canal. Glossopharyngeal neuralgia (cranial nerve IX) has an incidence of 0.5/100,000, a transition zone of 1.5 mm, with symptomatic neurovascular compression typically proximal. The transition zone overlaps the root entry zone close to the brain stem in cranial nerves V, VII, and IX, yet it is more distal and does not overlap the root entry zone in cranial nerve VIII. Although symptomatic neurovascular compression syndromes may also occur if the neurovascular contact is outside the transition zone, symptomatic neurovascular compression syndromes are more common if the neurovascular contact occurs at the transition zone or central myelin section, in particular when associated with nerve displacement and atrophy. PMID:26892985

  4. Neurophysiological, metabolic and cellular compartments that drive neurovascular coupling and neuroimaging signals.

    PubMed

    Moreno, Andrea; Jego, Pierrick; de la Cruz, Feliberto; Canals, Santiago

    2013-01-01

    Complete understanding of the mechanisms that coordinate work and energy supply of the brain, the so called neurovascular coupling, is fundamental to interpreting brain energetics and their influence on neuronal coding strategies, but also to interpreting signals obtained from brain imaging techniques such as functional magnetic resonance imaging. Interactions between neuronal activity and cerebral blood flow regulation are largely compartmentalized. First, there exists a functional compartmentalization in which glutamatergic peri-synaptic activity and its electrophysiological events occur in close proximity to vascular responses. Second, the metabolic processes that fuel peri-synaptic activity are partially segregated between glycolytic and oxidative compartments. Finally, there is cellular segregation between astrocytic and neuronal compartments, which has potentially important implications on neurovascular coupling. Experimental data is progressively showing a tight interaction between the products of energy consumption and neurotransmission-driven signaling molecules that regulate blood flow. Here, we review some of these issues in light of recent findings with special attention to the neuron-glia interplay on the generation of neuroimaging signals. PMID:23543907

  5. Neurophysiological, metabolic and cellular compartments that drive neurovascular coupling and neuroimaging signals

    PubMed Central

    Moreno, Andrea; Jego, Pierrick; de la Cruz, Feliberto; Canals, Santiago

    2013-01-01

    Complete understanding of the mechanisms that coordinate work and energy supply of the brain, the so called neurovascular coupling, is fundamental to interpreting brain energetics and their influence on neuronal coding strategies, but also to interpreting signals obtained from brain imaging techniques such as functional magnetic resonance imaging. Interactions between neuronal activity and cerebral blood flow regulation are largely compartmentalized. First, there exists a functional compartmentalization in which glutamatergic peri-synaptic activity and its electrophysiological events occur in close proximity to vascular responses. Second, the metabolic processes that fuel peri-synaptic activity are partially segregated between glycolytic and oxidative compartments. Finally, there is cellular segregation between astrocytic and neuronal compartments, which has potentially important implications on neurovascular coupling. Experimental data is progressively showing a tight interaction between the products of energy consumption and neurotransmission-driven signaling molecules that regulate blood flow. Here, we review some of these issues in light of recent findings with special attention to the neuron-glia interplay on the generation of neuroimaging signals. PMID:23543907

  6. Dynamic changes in pro- and anti-inflammatory cytokines in microglia after PPAR-γ agonist neuroprotective treatment in the MPTPp mouse model of progressive Parkinson's disease.

    PubMed

    Pisanu, Augusta; Lecca, Daniela; Mulas, Giovanna; Wardas, Jadwiga; Simbula, Gabriella; Spiga, Saturnino; Carta, Anna R

    2014-11-01

    Neuroinflammatory changes play a pivotal role in the progression of Parkinson's disease (PD) pathogenesis. Recent findings have suggested that activated microglia may polarize similarly to peripheral macrophages in the central nervous system (CNS), assuming a pro-inflammatory M1 phenotype or the alternative anti-inflammatory M2 phenotype via cytokine production. A skewed M1 activation over M2 has been related to disease progression in Alzheimer disease, and modulation of microglia polarization may be a therapeutic target for neuroprotection. By using the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine-probenecid (MPTPp) mouse model of progressive PD, we investigated dynamic changes in the production of pro-inflammatory cytokines, such as tumor necrosis factor (TNF)-α and interleukin (IL)-1β, and anti-inflammatory cytokines, such as transforming growth factor (TGF)-β and IL-10, within Iba-1-positive cells in the substantia nigra compacta (SNc). In addition, to further characterize changes in the M2 phenotype, we measured CD206 in microglia. Moreover, in order to target microglia polarization, we evaluated the effect of the peroxisome-proliferator-activated receptor (PPAR)-γ agonist rosiglitazone, which has been shown to exert neuroprotective effects on nigral dopaminergic neurons in PD models, and acts as a modulator of cytokine production and phenotype in peripheral macrophages. Chronic treatment with MPTPp induced a progressive degeneration of SNc neurons. The neurotoxin treatment was associated with a gradual increase in both TNF-α and IL-1β colocalization with Iba-1-positive cells, suggesting an increase in pro-inflammatory microglia. In contrast, TGF-β colocalization was reduced by the neurotoxin treatment, while IL-10 was mostly unchanged. Administration of rosiglitazone during the full duration of MPTPp treatment reverted both TNF-α and IL-1β colocalization with Iba-1 to control levels. Moreover, rosiglitazone induced an increase in TGF-β and IL-10

  7. White adipose tissue cells and the progression of cachexia: inflammatory pathways

    PubMed Central

    Neves, Rodrigo X.; Rosa‐Neto, José Cesar; Yamashita, Alex S.; Matos‐Neto, Emidio M.; Riccardi, Daniela M. R.; Lira, Fabio S.; Batista, Miguel L.

    2015-01-01

    Abstract Background Cachexia is a systemic syndrome leading to body wasting, systemic inflammation, and to metabolic chaos. It is a progressive condition, and little is known about its dynamics. Detection of the early signs of the disease may lead to the attenuation of the associated symptoms. The white adipose tissue is an organ with endocrine functions, capable of synthesising and secreting a plethora of proteins, including cytokines, chemokines, and adipokines. It is well established that different adipose tissue depots demonstrate heterogeneous responses to physiological and pathological stimuli. The present study aimed at providing insight into adipocyte involvement in inflammation along the progression of cachexia. Methods Eight‐weeks‐old male rats were subcutaneously inoculated with a Walker 256 carcinosarcoma cell suspension (2 × 107 cells in 1.0 mL; tumour‐bearing, T) or Phosphate‐buffered saline (control, C). The retroperitoneal, epididymal, and mesenteric adipose pads were excised on Days 0, 7, and 14 post‐tumour cell injection, and the adipocytes were isolated. Results Mesenteric and epididymal adipocytes showed up‐regulation of IL‐1β protein expression and activation of the inflammasome pathway, contributing for whole tissue inflammation. The stromal vascular fraction of the retroperitoneal adipose tissue, on the other hand, seems to be the major contributor for the inflammation in this specific pad. Conclusion Adipocytes seem to play a relevant role in the establishment of white adipose tissue inflammation, through the activation of the NF‐κB and inflammasome pathways. In epididymal adipocytes, induction of the inflammasome may be detected already on Day 7 post‐tumour cell inoculation.

  8. Nuclear export inhibitors avert progression in preclinical models of inflammatory demyelination.

    PubMed

    Haines, Jeffery D; Herbin, Olivier; de la Hera, Belén; Vidaurre, Oscar G; Moy, Gregory A; Sun, Qingxiang; Fung, Ho Yee Joyce; Albrecht, Stefanie; Alexandropoulos, Konstantina; McCauley, Dilara; Chook, Yuh Min; Kuhlmann, Tanja; Kidd, Grahame J; Shacham, Sharon; Casaccia, Patrizia

    2015-04-01

    Axonal damage has been associated with aberrant protein trafficking. We examined a newly characterized class of compounds that target nucleo-cytoplasmic shuttling by binding to the catalytic groove of the nuclear export protein XPO1 (also known as CRM1, chromosome region maintenance protein 1). Oral administration of reversible CRM1 inhibitors in preclinical murine models of demyelination significantly attenuated disease progression, even when started after the onset of paralysis. Clinical efficacy was associated with decreased proliferation of immune cells, characterized by nuclear accumulation of cell cycle inhibitors, and preservation of cytoskeletal integrity even in demyelinated axons. Neuroprotection was not limited to models of demyelination, but was also observed in another mouse model of axonal damage (that is, kainic acid injection) and detected in cultured neurons after knockdown of Xpo1, the gene encoding CRM1. A proteomic screen for target molecules revealed that CRM1 inhibitors in neurons prevented nuclear export of molecules associated with axonal damage while retaining transcription factors modulating neuroprotection. PMID:25706475

  9. Pericytes of the neurovascular unit: key functions and signaling pathways.

    PubMed

    Sweeney, Melanie D; Ayyadurai, Shiva; Zlokovic, Berislav V

    2016-05-26

    Pericytes are vascular mural cells embedded in the basement membrane of blood microvessels. They extend their processes along capillaries, pre-capillary arterioles and post-capillary venules. CNS pericytes are uniquely positioned in the neurovascular unit between endothelial cells, astrocytes and neurons. They integrate, coordinate and process signals from their neighboring cells to generate diverse functional responses that are critical for CNS functions in health and disease, including regulation of the blood-brain barrier permeability, angiogenesis, clearance of toxic metabolites, capillary hemodynamic responses, neuroinflammation and stem cell activity. Here we examine the key signaling pathways between pericytes and their neighboring endothelial cells, astrocytes and neurons that control neurovascular functions. We also review the role of pericytes in CNS disorders including rare monogenic diseases and complex neurological disorders such as Alzheimer's disease and brain tumors. Finally, we discuss directions for future studies. PMID:27227366

  10. Treatment of complex neurovascular lesions: an interdisciplinary angio suite approach

    PubMed Central

    Breyer, Tobias; Wrede, Karsten H.; Stein, Klaus-Peter; Wanke, Isabel; Grams, Astrid E.; Gizewski, Elke R.; Schlamann, Marc; Forsting, Michael; Sandalcioglu, I. Erol; Sure, Ulrich

    2014-01-01

    Objective: The objective of this study was to analyse our initial experience using an interdisciplinary angio suite approach to neurosurgical treatment of complex neurovascular lesions and expound technical feasibility and possible applications. Subjects: Six out of 451 patients with cranial or spinal neurovascular lesions were surgically treated in the angio suite (biplane angiographic system) during a 28-month observation period. Clinical baseline data, radiological and intraoperative findings as well as clinical and radiological outcome were assessed. Results: A ventral spinal perimedullary arteriovenous malformation, a ventral spinal perimedullary fistula, two diffuse frontal dural arteriovenous fistulas, a multifocal temporal arteriovenous malformation and a partially embolized fronto-temporo-basal dural arteriovenous fistula were successfully treated with angiographically confirmed complete occlusion and unimpaired neurological condition of the patients at the 12-month follow up. Conclusion: This study demonstrates the feasibility of this approach and points out possible indications, namely ventrally located spinal lesions and diffuse, deep seated cranial lesions. PMID:24409203

  11. Calcium dynamics in astrocyte processes during neurovascular coupling

    PubMed Central

    Otsu, Yo; Couchman, Kiri; Lyons, Declan G; Collot, Mayeul; Agarwal, Amit; Mallet, Jean-Maurice; Pfrieger, Frank W; Bergles, Dwight E; Charpak, Serge

    2015-01-01

    Enhanced neuronal activity in the brain triggers a local increase in blood flow, termed functional hyperemia, via several mechanisms, including calcium (Ca2+) signaling in astrocytes. However, recent in vivo studies have questioned the role of astrocytes in functional hyperemia because of the slow and sparse dynamics of their somatic Ca2+ signals and the absence of glutamate metabotropic receptor 5 in adults. Here, we reexamined their role in neurovascular coupling by selectively expressing a genetically encoded Ca2+ sensor in astrocytes of the olfactory bulb. We show that in anesthetized mice, the physiological activation of olfactory sensory neuron (OSN) terminals reliably triggers Ca2+ increases in astrocyte processes but not in somata. These Ca2+ increases systematically precede the onset of functional hyperemia by 1–2 s, reestablishing astrocytes as potential regulators of neurovascular coupling. PMID:25531572

  12. Oral neurovascular hamartoma: an extraordinary verdict in the oral cavity

    PubMed Central

    Junaid, Montasir; Ahmed, Sadaf Qadeer; Kazi, Maliha; Haroon, Saroona

    2014-01-01

    The presence of a neurovascular hamartoma within the oral cavity is truly a rare entity. Scarcely reported in the literature, these hamartomas are smooth, pinkish masses and are painless, and therefore difficult to diagnose. They are benign in nature and apply pressure to their surroundings. The histological diagnosis remains the gold standard as it comprises of neural tissue and vascular components. Treatment is surgical excision with adequate margins. Recurrence is reported in cases of incomplete resection. PMID:24969068

  13. Analysis and Visualization of Nerve Vessel Contacts for Neurovascular Decompression

    NASA Astrophysics Data System (ADS)

    Süßmuth, Jochen; Piazza, Alexander; Enders, Frank; Naraghi, Ramin; Greiner, Günther; Hastreiter, Peter

    Neurovascular compression syndromes are caused by a pathological contact between cranial nerves and vascular structures at the surface of the brainstem. Aiming at improved pre-operative analysis of the target structures, we propose calculating distance fields to provide quantitative information of the important nerve-vessel contacts. Furthermore, we suggest reconstructing polygonal models for the nerves and vessels. Color-coding with the respective distance information is used for enhanced visualization. Overall, our new strategy contributes to a significantly improved clinical understanding.

  14. Anesthesia and the quantitative evaluation of neurovascular coupling

    PubMed Central

    Masamoto, Kazuto; Kanno, Iwao

    2012-01-01

    Anesthesia has broad actions that include changing neuronal excitability, vascular reactivity, and other baseline physiologies and eventually modifies the neurovascular coupling relationship. Here, we review the effects of anesthesia on the spatial propagation, temporal dynamics, and quantitative relationship between the neural and vascular responses to cortical stimulation. Previous studies have shown that the onset latency of evoked cerebral blood flow (CBF) changes is relatively consistent across anesthesia conditions compared with variations in the time-to-peak. This finding indicates that the mechanism of vasodilation onset is less dependent on anesthesia interference, while vasodilation dynamics are subject to this interference. The quantitative coupling relationship is largely influenced by the type and dosage of anesthesia, including the actions on neural processing, vasoactive signal transmission, and vascular reactivity. The effects of anesthesia on the spatial gap between the neural and vascular response regions are not fully understood and require further attention to elucidate the mechanism of vascular control of CBF supply to the underlying focal and surrounding neural activity. The in-depth understanding of the anesthesia actions on neurovascular elements allows for better decision-making regarding the anesthetics used in specific models for neurovascular experiments and may also help elucidate the signal source issues in hemodynamic-based neuroimaging techniques. PMID:22510601

  15. Complex rostral neurovascular system in a giant pliosaur

    NASA Astrophysics Data System (ADS)

    Foffa, Davide; Sassoon, Judyth; Cuff, Andrew R.; Mavrogordato, Mark N.; Benton, Michael J.

    2014-05-01

    Pliosaurs were a long-lived, ubiquitous group of Mesozoic marine predators attaining large body sizes (up to 12 m). Despite much being known about their ecology and behaviour, the mechanisms they adopted for prey detection have been poorly investigated and represent a mystery to date. Complex neurovascular systems in many vertebrate rostra have evolved for prey detection. However, information on the occurrence of such systems in fossil taxa is extremely limited because of poor preservation potential. The neurovascular complex from the snout of an exceptionally well-preserved pliosaur from the Kimmeridgian (Late Jurassic, c. 170 Myr ago) of Weymouth Bay (Dorset, UK) is described here for the first time. Using computed tomography (CT) scans, the extensive bifurcating neurovascular channels could be traced through the rostrum to both the teeth and the foramina on the dorsal and lateral surface of the snout. The structures on the surface of the skull and the high concentrations of peripheral rami suggest that this could be a sensory system, perhaps similar to crocodile pressure receptors or shark electroreceptors.

  16. The wound inflammatory response exacerbates growth of pre-neoplastic cells and progression to cancer

    PubMed Central

    Antonio, Nicole; Bønnelykke-Behrndtz, Marie Louise; Ward, Laura Chloe; Collin, John; Christensen, Ib Jarle; Steiniche, Torben; Schmidt, Henrik; Feng, Yi; Martin, Paul

    2015-01-01

    There is a long-standing association between wound healing and cancer, with cancer often described as a “wound that does not heal”. However, little is known about how wounding, such as following surgery, biopsy collection or ulceration, might impact on cancer progression. Here, we use a translucent zebrafish larval model of RasG12V-driven neoplasia to image the interactions between inflammatory cells drawn to a wound, and to adjacent pre-neoplastic cells. We show that neutrophils are rapidly diverted from a wound to pre-neoplastic cells and these interactions lead to increased proliferation of the pre-neoplastic cells. One of the wound-inflammation-induced trophic signals is prostaglandin E2 (PGE2). In an adult model of chronic wounding in zebrafish, we show that repeated wounding with subsequent inflammation leads to a greater incidence of local melanoma formation. Our zebrafish studies led us to investigate the innate immune cell associations in ulcerated melanomas in human patients. We find a strong correlation between neutrophil presence at sites of melanoma ulceration and cell proliferation at these sites, which is associated with poor prognostic outcome. PMID:26136213

  17. The wound inflammatory response exacerbates growth of pre-neoplastic cells and progression to cancer.

    PubMed

    Antonio, Nicole; Bønnelykke-Behrndtz, Marie Louise; Ward, Laura Chloe; Collin, John; Christensen, Ib Jarle; Steiniche, Torben; Schmidt, Henrik; Feng, Yi; Martin, Paul

    2015-09-01

    There is a long-standing association between wound healing and cancer, with cancer often described as a "wound that does not heal". However, little is known about how wounding, such as following surgery, biopsy collection or ulceration, might impact on cancer progression. Here, we use a translucent zebrafish larval model of Ras(G12V)-driven neoplasia to image the interactions between inflammatory cells drawn to a wound, and to adjacent pre-neoplastic cells. We show that neutrophils are rapidly diverted from a wound to pre-neoplastic cells and these interactions lead to increased proliferation of the pre-neoplastic cells. One of the wound-inflammation-induced trophic signals is prostaglandin E2 (PGE2). In an adult model of chronic wounding in zebrafish, we show that repeated wounding with subsequent inflammation leads to a greater incidence of local melanoma formation. Our zebrafish studies led us to investigate the innate immune cell associations in ulcerated melanomas in human patients. We find a strong correlation between neutrophil presence at sites of melanoma ulceration and cell proliferation at these sites, which is associated with poor prognostic outcome. PMID:26136213

  18. Near infrared spectroscopy--investigations in neurovascular diseases.

    PubMed

    Schytz, Henrik Winther

    2015-12-01

    The purpose of this thesis was to explore and develop methods, where continuous wave near infrared spectroscopy (CW-NIRS) can be applied in different neurovascular diseases, in order to find biological markers that are useful in clinical neurology. To develop a new method to detect changes in cerebral blood flow (CBF), the first study investigated a multi-source detector separation configuration and indocyanine green (ICG) as a tracer to calculate a corrected blood flow index (BFI) value. The study showed no correlation between CBF changes measured by 133Xenon single photon emission computer tomography (133Xe-SPECT) and the corrected BFI value. It was concluded, that it was not possible to obtain reliable BFI data with the ICG CW-NIRS method. NIRS measurements of low frequency oscillations (LFOs) may be a reliable method to investigate vascular alterations in neurovascular diseases, but this requires an acceptable LFOs variation between hemispheres and over time in the healthy brain. The second study therefore investigated day-to-day and hemispheric variations in LFOs with NIRS. It was shown that NIRS might be useful in assessing LFOs between hemispheres, as well as interhemispheric phase and gain directly and over time. Migraine may be associated with persistent impairment of neurovascular coupling, but there is no experimental evidence to support this. The third study therefore investigated interictal neurovascular coupling during a mental task by a Stroop test in migraine without aura (MO) patients, which is the most common type of migraine. The study showed intact neurovascular coupling in the prefrontal cortex outside of attacks in patients with MO. The fourth study aimed to investigate possible changes in LFOs amplitude following nitric oxide (NO) donor infusion in familial hemiplegic migraine (FHM), which is a rare Mendelian subtype of migraine with aura. This study showed increased LFOs amplitude only in FHM patients with co-existing common type of migraine

  19. Protection after stroke: cellular effectors of neurovascular unit integrity

    PubMed Central

    Posada-Duque, Rafael Andres; Barreto, George E.; Cardona-Gomez, Gloria Patricia

    2014-01-01

    Neurological disorders are prevalent worldwide. Cerebrovascular diseases (CVDs), which account for 55% of all neurological diseases, are the leading cause of permanent disability, cognitive and motor disorders and dementia. Stroke affects the function and structure of blood-brain barrier, the loss of cerebral blood flow regulation, oxidative stress, inflammation and the loss of neural connections. Currently, no gold standard treatments are available outside the acute therapeutic window to improve outcome in stroke patients. Some promising candidate targets have been identified for the improvement of long-term recovery after stroke, such as Rho GTPases, cell adhesion proteins, kinases, and phosphatases. Previous studies by our lab indicated that Rho GTPases (Rac and RhoA) are involved in both tissue damage and survival, as these proteins are essential for the morphology and movement of neurons, astrocytes and endothelial cells, thus playing a critical role in the balance between cell survival and death. Treatment with a pharmacological inhibitor of RhoA/ROCK blocks the activation of the neurodegeneration cascade. In addition, Rac and synaptic adhesion proteins (p120 catenin and N-catenin) play critical roles in protection against cerebral infarction and in recovery by supporting the neurovascular unit and cytoskeletal remodeling activity to maintain the integrity of the brain parenchyma. Interestingly, neuroprotective agents, such as atorvastatin, and CDK5 silencing after cerebral ischemia and in a glutamate-induced excitotoxicity model may act on the same cellular effectors to recover neurovascular unit integrity. Therefore, future efforts must focus on individually targeting the structural and functional roles of each effector of neurovascular unit and the interactions in neural and non-neural cells in the post-ischemic brain and address how to promote the recovery or prevent the loss of homeostasis in the short, medium and long term. PMID:25177270

  20. Feed the brain: insights into the study of neurovascular coupling.

    PubMed

    Welsh, Donald G; Ledoux, Jonathan

    2015-04-01

    The microcirculation is tightly regulated by a diverse range of mechanisms which share the common goal of matching blood flow delivery with tissue metabolic demand. Despite in-depth examination of tissues like skeletal muscle, brain microcirculation has remained largely unexplored due to methodological limitations. Recent, technological advances have, however, started to grant greater access to this vital microcirculatory bed. This overview is part of a Special Topics Issue centered on the methodology, theory, and mechanistic basis of neurovascular coupling. Solicited manuscripts have been purposely written in an opinionated manner to provoke thought and to illuminate new emerging areas of investigation. PMID:25771945

  1. Digital tomosynthesis: technique modifications and clinical applications for neurovascular anatomy

    SciTech Connect

    Maravilla, K.R.; Murry, R.C. Jr.; Diehl, J.; Suss, R.; Allen, L.; Chang, K.; Crawford, J.; McCoy, R.

    1984-09-01

    Digital tomosynthesis studies (DTS) using a linear tomographic motion can provide good quality clinical images when combined with subtraction angiotomography. By modifying their hardware system and the computer software algorithms, the authors were able to reconstruct tomosynthesis images using an isocentric rotation (IR) motion. Applying a combination of linear tomographic and IR techniques in clinical cases, they performed DTS studies in six patients, five with aneurysms and one with a hypervascular tumor. The results showed detailed definitions of the pathologic entities and the regional neurovascular anatomy. Based on this early experience, DTS would seem to be a useful technique for the preoperative surgical planning of vascular abnormalities.

  2. Inflammatory/Hemostatic Biomarkers and Coronary Artery Calcium Progression in Women at Midlife (from the Study of Women's Health Across the Nation, Heart Study).

    PubMed

    Wang, Norman C; Matthews, Karen A; Barinas-Mitchell, Emma J M; Chang, Chung-Chou H; El Khoudary, Samar R

    2016-08-01

    It is unknown whether inflammatory/hemostatic biomarkers are associated with coronary artery calcium (CAC) progression. Our purpose was to evaluate the associations of baseline levels of C-reactive protein, fibrinogen, plasminogen activator inhibitor-1 (PAI-1), tissue plasminogen activator antigen, and circulating factor VII with CAC progression in healthy midlife women. Inflammatory/hemostatic biomarkers were measured at baseline. CAC was quantified by computed tomography scans at baseline and after 2.3 ± 0.5 years of follow-up. Significant CAC progression was defined as present if (1) follow-up CAC Agatston score was >0 if baseline CAC score = 0; (2) annualized change in CAC score was ≥10 if baseline CAC score >0 to <100; and (3) annualized percent change in CAC score was ≥10% if baseline CAC score ≥100. Extent of CAC progression was defined as [log(CAC(follow-up)+25) - log(CAC(baseline)+25)]/year. Logistic and linear regression models were used as appropriate, and the final models were adjusted for baseline CAC score, age, study site, race/ethnicity, menopausal status, sociodemographics, traditional cardiovascular disease (CVD) risk factors, family history of CVD, and CVD medication use. The study included 252 women (baseline age 51.2 ± 2.6 years; 67.5% white; 56.4% premenopausal or early perimenopausal). In final models, only log(PAI-1) was associated with presence of CAC progression (odds ratio 1.91, 95% CI 1.24 to 2.93; per 1 log unit increase in PAI-1; p = 0.003). In addition, higher log(PAI-1) was marginally associated with greater extent of CAC progression (p = 0.06). In conclusion, PAI-1 is associated with the presence of CAC progression in middle-aged women. Targeting PAI-1 may decrease atherogenesis beyond conventional CVD risk factors. PMID:27289291

  3. Neurovascular coupling, cerebral white matter integrity, and response to cocoa in older people

    PubMed Central

    Hurwitz, Shelley; Salat, David H.; Greve, Douglas N.; Fisher, Naomi D.L.

    2013-01-01

    Objective: To investigate the relationship between neurovascular coupling and cognitive function in elderly individuals with vascular risk factors and to determine whether neurovascular coupling could be modified by cocoa consumption. Methods: Sixty older people (aged 72.9 ± 5.4 years) were studied in a parallel-arm, double-blind clinical trial of neurovascular coupling and cognition in response to 24 hours and 30 days of cocoa consumption. Cognitive measures included Mini-Mental State Examination and Trail Making Test A and B. Neurovascular coupling was measured from the beat-to-beat blood flow velocity responses in the middle cerebral arteries to the N-Back Task. In a subset of MRI-eligible participants, cerebral white matter structural integrity was also measured. Results: Neurovascular coupling was associated with Trails B scores (p = 0.002) and performance on the 2-Back Task. Higher neurovascular coupling was also associated with significantly higher fractional anisotropy in cerebral white matter hyperintensities (p = 0.02). Finally, 30 days of cocoa consumption was associated with increased neurovascular coupling (5.6% ± 7.2% vs −2.4% ± 4.8%; p = 0.001) and improved Trails B times (116 ± 78 seconds vs 167 ± 110 seconds; p = 0.007) in those with impaired neurovascular coupling at baseline. Conclusion: There is a strong correlation between neurovascular coupling and cognitive function, and both can be improved by regular cocoa consumption in individuals with baseline impairments. Better neurovascular coupling is also associated with greater white matter structural integrity. PMID:23925758

  4. Potassium Buffering in the Neurovascular Unit: Models and Sensitivity Analysis

    PubMed Central

    Witthoft, Alexandra; Filosa, Jessica A.; Karniadakis, George Em

    2013-01-01

    Astrocytes are critical regulators of neural and neurovascular network communication. Potassium transport is a central mechanism behind their many functions. Astrocytes encircle synapses with their distal processes, which express two potassium pumps (Na-K and NKCC) and an inward rectifying potassium channel (Kir), whereas the vessel-adjacent endfeet express Kir and BK potassium channels. We provide a detailed model of potassium flow throughout the neurovascular unit (synaptic region, astrocytes, and arteriole) for the cortex of the young brain. Our model reproduces several phenomena observed experimentally: functional hyperemia, in which neural activity triggers astrocytic potassium release at the perivascular endfoot, inducing arteriole dilation; K+ undershoot in the synaptic space after periods of neural activity; neurally induced astrocyte hyperpolarization during Kir blockade. Our results suggest that the dynamics of the vascular response during functional hyperemia are governed by astrocytic Kir for the fast onset and astrocytic BK for maintaining dilation. The model supports the hypothesis that K+ undershoot is caused by excessive astrocytic uptake through Na-K and NKCC pumps, whereas the effect is balanced by Kir. We address parametric uncertainty using high-dimensional stochastic sensitivity analysis and identify possible model limitations. PMID:24209849

  5. Patterned optogenetic modulation of neurovascular and metabolic signals

    PubMed Central

    Richner, Thomas J; Baumgartner, Ryan; Brodnick, Sarah K; Azimipour, Mehdi; Krugner-Higby, Lisa A; Eliceiri, Kevin W; Williams, Justin C; Pashaie, Ramin

    2015-01-01

    The hemodynamic and metabolic response of the cortex depends spatially and temporally on the activity of multiple cell types. Optogenetics enables specific cell types to be modulated with high temporal precision and is therefore an emerging method for studying neurovascular and neurometabolic coupling. Going beyond temporal investigations, we developed a microprojection system to apply spatial photostimulus patterns in vivo. We monitored vascular and metabolic fluorescence signals after photostimulation in Thy1-channelrhodopsin-2 mice. Cerebral arteries increased in diameter rapidly after photostimulation, while nearby veins showed a slower smaller response. The amplitude of the arterial response was depended on the area of cortex stimulated. The fluorescence signal emitted at 450/100 nm and excited with ultraviolet is indicative of reduced nicotinamide adenine dinucleotide, an endogenous fluorescent enzyme involved in glycolysis and the citric acid cycle. This fluorescence signal decreased quickly and transiently after optogenetic stimulation, suggesting that glucose metabolism is tightly locked to optogenetic stimulation. To verify optogenetic stimulation of the cortex, we used a transparent substrate microelectrode array to map cortical potentials resulting from optogenetic stimulation. Spatial optogenetic stimulation is a new tool for studying neurovascular and neurometabolic coupling. PMID:25388678

  6. The neurovascular protection afforded by delayed local hypothermia after transient middle cerebral artery occlusion.

    PubMed

    Kim, Jong-Heon; Seo, Minchul; Han, Hyung Soo; Park, Jaechan; Suk, Kyoungho

    2013-05-01

    Therapeutic hypothermia is a robust therapeutic tool in experimental stroke models but its clinical applications are limited. Furthermore, optimal conditions for therapeutic hypothermia, such as, temperature and the initiation and duration of cooling must be individualized. Here, we evaluated the therapeutic effects of delayed local hypothermia, administered for 44 hr after 4 hr of reperfusion in a rat model of transient middle cerebral artery occlusion (tMCAo), using a cooling device that allowed controlled local hypothermia (31 °C) in brain. Histological data revealed that local hypothermia significantly reduced infarct volumes and glial hypertrophic activation. Brain water contents, IgG leakage, and Evans Blue extravasation were notably reduced by local hypothermia. Furthermore, local hypothermia had strong vasculoprotective effects, as determined by immunohistochemistry and Western blot analyses for endothelial barrier antigen (EBA), laminin, aquaporin-4, and tight junction proteins in brain. Our data indicate that delayed/prolonged local hypothermia confers neurovascular protection, reduces brain edema, and inhibits inflammatory glial activation, and suggest that hypothermic conservation of vascular structures and functions account for the therapeutic effects of local hypothermia observed in this model of experimental stroke. PMID:23469955

  7. Emerging roles of pericytes in the regulation of the neurovascular unit in health and disease

    PubMed Central

    Hill, Jeremy; Rom, Slava; Ramirez, Servio H.; Persidsky, Yuri

    2014-01-01

    Pericytes of the central nervous system (CNS) are uniquely positioned within a multicellular structure termed the neurovascular unit (NVU) to provide crucial support to blood brain barrier (BBB) formation, maintenance, and stability. Numerous CNS diseases are associated with some aspect of BBB dysfunction. A dysfunction can manifest as one or multiple disruptions to any of the following barriers: physical, metabolic, immunological and transport barrier. A breach in the BBB can notably result in BBB hyper-permeability, endothelial activation and enhanced immune-endothelial interaction. How the BBB is regulated within this integrated unit remains largely unknown, especially as it relates to pericyte-endothelial interaction. We summarize the latest findings on pericyte origin, possible marker expression, and availability within different organ systems. We highlight pericyte-endothelial cell interactions, concentrating on extra- and intra- cellular signaling mechanisms linked to platelet derived growth factor-B, transforming growth factor -β, angiopoietins, Notch, and gap junctions. We discuss the role of pericytes in the NVU under inflammatory insult, focusing on how pericytes may indirectly affect leukocyte CNS infiltration, the direct role of pericyte-mediated basement membrane modifications, and immune responses. We review new findings of pericyte actions in CNS pathologies including Alzheimer’s disease, stroke, multiple sclerosis, diabetic retinopathy, and HIV-1 infection. The uncovering of the regulatory role of pericytes on the BBB will provide key insight into how barrier integrity can be re-established during neuroinflammation. PMID:25119834

  8. Physical exercise training and neurovascular unit in ischemic stroke.

    PubMed

    Wang, X; Zhang, M; Feng, R; Li, W B; Ren, S Q; Zhang, J; Zhang, F

    2014-06-20

    Physical exercise could exert a neuroprotective effect in both clinical studies and animal experiments. A series of related studies have indicated that physical exercise could reduce infarct volume, alleviate neurological deficits, decrease blood-brain barrier dysfunction, promote angiogenesis in cerebral vascular system and increase the survival rate after ischemic stroke. In this review, we summarized the protective effects of physical exercise on neurovascular unit (NVU), including neurons, astrocytes, pericytes and the extracellular matrix. Furthermore, it was demonstrated that exercise training could decrease the blood-brain barrier dysfunction and promote angiogenesis in cerebral vascular system. An awareness of the exercise intervention benefits pre- and post stroke may lead more stroke patients and people with high-risk factors to accept exercise therapy for the prevention and treatment of stroke. PMID:24780769

  9. Vascular endothelial growth factor: a neurovascular target in neurological diseases.

    PubMed

    Lange, Christian; Storkebaum, Erik; de Almodóvar, Carmen Ruiz; Dewerchin, Mieke; Carmeliet, Peter

    2016-08-01

    Brain function critically relies on blood vessels to supply oxygen and nutrients, to establish a barrier for neurotoxic substances, and to clear waste products. The archetypal vascular endothelial growth factor, VEGF, arose in evolution as a signal affecting neural cells, but was later co-opted by blood vessels to regulate vascular function. Consequently, VEGF represents an attractive target to modulate brain function at the neurovascular interface. On the one hand, VEGF is neuroprotective, through direct effects on neural cells and their progenitors and indirect effects on brain perfusion. In accordance, preclinical studies show beneficial effects of VEGF administration in neurodegenerative diseases, peripheral neuropathies and epilepsy. On the other hand, pathologically elevated VEGF levels enhance vessel permeability and leakage, and disrupt blood-brain barrier integrity, as in demyelinating diseases, for which blockade of VEGF may be beneficial. Here, we summarize current knowledge on the role and therapeutic potential of VEGF in neurological diseases. PMID:27364743

  10. [The neurovascular unit in health and ischemic stroke].

    PubMed

    Ago, Tetsuro

    2016-04-01

    The neurovascular unit (NVU), a minimal unit to exert neurological functions, is composed of neurons, astrocytes, endothelial cells, pericytes, and extracellular matrix proteins forming basal membranes. The cell components interact with one another and function cooperatively under both physiological and pathological conditions. Pericytes and astrocytes participate crucially in the formation and maintenance of the blood-brain barrier (BBB), the tight junction formed by endothelial cells, and regulate cerebral blood flow in response to neurological activities. The BBB actively regulate molecular import and export. The concept of the NVU is also useful for understanding pathogenesis and exploring therapeutic targets in various CNS disorders. In this review, recent research advances regarding the NVU and its components in health and ischemic stroke are summarized. PMID:27333744

  11. Neurovascular Interactions in the Neurologically Compromised Neonatal Brain.

    PubMed

    Singh, H; Cooper, R; Lee, C W; Dempsey, L; Brigadoi, S; Edwards, A; Airantzis, D; Everdell, N; Michell, A; Holder, D; Austin, T; Hebden, J

    2016-01-01

    Neurological brain injuries such as hypoxic ischaemic encephalopathy (HIE) and associated conditions such as seizures have been associated with poor developmental outcome in neonates. Our limited knowledge of the neurological and cerebrovascular processes underlying seizures limits their diagnosis and timely treatment. Diffuse optical tomography (DOT) provides haemodynamic information in the form of changes in concentration of de/oxygenated haemoglobin, which can improve our understanding of seizures and the relationship between neural and vascular processes. Using simultaneous EEG-DOT, we observed distinct haemodynamic changes which are temporally correlated with electrographic seizures. Here, we present DOT-EEG data from two neonates clinically diagnosed as HIE. Our results highlight the wealth of mutually-informative data that can be obtained using DOT-EEG techniques to understand neurovascular coupling in HIE neonates. PMID:26782249

  12. The neurovascular unit and combination treatment strategies for stroke

    PubMed Central

    Zhang, Li; Zhang, Zhang Gang; Chopp, Michael

    2012-01-01

    Tissue plasminogen activator (tPA) administered within 4.5 hours of symptom onset restores cerebral blood flow and promotes neurological recovery of stroke patients. However, the narrow therapeutic time window and the risk of intracerebral hemorrhage after tPA treatment pose major hurdles to its clinical usage. In light of the failures of neuroprotective therapies in clinical trials, emerging concepts suggest that neuroprotection alone without restoration of tissue perfusion and vascular integrity may not be adequate for treatment of acute stroke. Here we review evidence of the use of adjuvant pharmacological agents to extend the therapeutic window for tPA via targeting the neurovascular unit and the underlying mechanisms of the combination therapy in experimental stroke. PMID:22595494

  13. Intermittent hypoglossal nerve palsy caused by a calcified persistent hypoglossal artery: an uncommon neurovascular compression syndrome.

    PubMed

    Meila, Dan; Wetter, Axel; Brassel, Friedhelm; Nacimiento, Wilhelm

    2012-12-15

    Neurovascular compression is assumed to cause symptoms like trigeminal neuralgia, hemifacial spasm and vestibular paroxysmia. We present a patient with recurrent episodes of transient dysarthria due to isolated right hypoglossal nerve (HN) palsy. We describe the first case of a calcified persistent hypoglossal artery (PHA) as the putative cause of a hypoglossal neurovascular compression syndrome. Our patient received a daily low-dose medication of carbamazepine resulting in complete relief of symptoms. In conclusion, PHA is not only an anatomic variation but also a possible cause of a neurovascular compression syndrome leading to intermittent HN palsy. PMID:23020989

  14. OCT/PS-OCT imaging of brachial plexus neurovascular structures

    NASA Astrophysics Data System (ADS)

    Raphael, David T.; Zhang, Jun; Zhang, Yaoping; Chen, Zhongping; Miller, Carol; Zhou, Li

    2004-07-01

    Introduction: Optical coherence tomography (OCT) allows high-resolution imaging (less than 10 microns) of tissue structures. A pilot study with OCT and polarization-sensitive OCT (PS-OCT) was undertaken to image ex-vivo neurovascular structures (vessels, nerves) of the canine brachial plexus. Methods: OCT is an interferometry-based optical analog of B-mode ultrasound, which can image through non-transparent biological tissues. With approval of the USC Animal Care and Use Committee, segments of the supra- and infraclavicular brachial plexus were excised from euthanized adult dogs, and the ex-vivo specimens were placed in cold pH-buffered physiologic solution. An OCT beam, in micrometer translational steps, scanned the fixed-position bisected specimens in transverse and longitudinal views. Two-dimensional images were obtained from identified arteries and nerves, with specific sections of interest stained with hematoxylin-eosin for later imaging through a surgical microscope. Results: with the beam scan direction transverse to arteries, the resulting OCT images showed an identifiable arterial lumen and arterial wall tissue layers. By comparison, transverse beam OCT images of nerves revealed a multitude of smaller nerve bundles contained within larger circular-shaped fascicles. PS-OCT imaging was helpful in showing the characteristic birefringence exhibited by arrayed neural structures. Discussion: High-resolution OCT imaging may be useful in the optical identification of neurovascular structures during attempted regional nerve blockade. If incorporated into a needle-shaped catheter endoscope, such a technology could prevent intraneural and intravascular injections immediately prior to local anesthetic injection. The major limitation of OCT is that it can form a coherent image of tissue structures only to a depth of 1.5 - 2 mm.

  15. Neurovascular unit on a chip: implications for translational applications

    PubMed Central

    2013-01-01

    The blood-brain barrier (BBB) dynamically controls exchange between the brain and the body, but this interaction cannot be studied directly in the intact human brain or sufficiently represented by animal models. Most existing in vitro BBB models do not include neurons and glia with other BBB elements and do not adequately predict drug efficacy and toxicity. Under the National Institutes of Health Microtissue Initiative, we are developing a three-dimensional, multicompartment, organotypic microphysiological system representative of a neurovascular unit of the brain. The neurovascular unit system will serve as a model to study interactions between the central nervous system neurons and the cerebral spinal fluid (CSF) compartment, all coupled to a realistic blood-surrogate supply and venous return system that also incorporates circulating immune cells and the choroid plexus. Hence all three critical brain barriers will be recapitulated: blood-brain, brain-CSF, and blood-CSF. Primary and stem cell-derived human cells will interact with a variety of agents to produce critical chemical communications across the BBB and between brain regions. Cytomegalovirus, a common herpesvirus, will be used as an initial model of infections regulated by the BBB. This novel technological platform, which combines innovative microfluidics, cell culture, analytical instruments, bioinformatics, control theory, neuroscience, and drug discovery, will replicate chemical communication, molecular trafficking, and inflammation in the brain. The platform will enable targeted and clinically relevant nutritional and pharmacologic interventions for or prevention of such chronic diseases as obesity and acute injury such as stroke, and will uncover potential adverse effects of drugs. If successful, this project will produce clinically useful technologies and reveal new insights into how the brain receives, modifies, and is affected by drugs, other neurotropic agents, and diseases. PMID:24564885

  16. Neurovascular unit impairment in early Alzheimer's disease measured with magnetic resonance imaging.

    PubMed

    van de Haar, Harm J; Jansen, Jacobus F A; van Osch, Matthias J P; van Buchem, Mark A; Muller, Majon; Wong, Sau May; Hofman, Paul A M; Burgmans, Saartje; Verhey, Frans R J; Backes, Walter H

    2016-09-01

    The neurovascular unit, which protects neuronal cells and supplies them with essential molecules, plays an important role in the pathophysiology of Alzheimer's Disease (AD). The aim of this study was to noninvasively investigate 2 linked functional elements of the neurovascular unit, blood-brain barrier (BBB) permeability and cerebral blood flow (CBF), in patients with early AD and healthy controls. Therefore, both dynamic contrast-enhanced magnetic resonance imaging and arterial spin labeling magnetic resonance imaging were applied to measure BBB permeability and CBF, respectively. The patients with early AD showed significantly lower CBF and local blood volume in the gray matter, compared with controls. In the patients, we also found that a reduction in CBF is correlated with an increase in leakage rate. This finding supports the hypothesis that neurovascular damage, and in particular impairment of the neurovascular unit constitutes the pathophysiological link between CBF reduction and BBB impairment in AD. PMID:27459939

  17. Advancing Cardiovascular, Neurovascular, and Renal Magnetic Resonance Imaging in Small Rodents Using Cryogenic Radiofrequency Coil Technology

    PubMed Central

    Niendorf, Thoralf; Pohlmann, Andreas; Reimann, Henning M.; Waiczies, Helmar; Peper, Eva; Huelnhagen, Till; Seeliger, Erdmann; Schreiber, Adrian; Kettritz, Ralph; Strobel, Klaus; Ku, Min-Chi; Waiczies, Sonia

    2015-01-01

    Research in pathologies of the brain, heart and kidney have gained immensely from the plethora of studies that have helped shape new methods in magnetic resonance (MR) for characterizing preclinical disease models. Methodical probing into preclinical animal models by MR is invaluable since it allows a careful interpretation and extrapolation of data derived from these models to human disease. In this review we will focus on the applications of cryogenic radiofrequency (RF) coils in small animal MR as a means of boosting image quality (e.g., by supporting MR microscopy) and making data acquisition more efficient (e.g., by reducing measuring time); both being important constituents for thorough investigational studies on animal models of disease. This review attempts to make the (bio)medical imaging, molecular medicine, and pharmaceutical communities aware of this productive ferment and its outstanding significance for anatomical and functional MR in small rodents. The goal is to inspire a more intense interdisciplinary collaboration across the fields to further advance and progress non-invasive MR methods that ultimately support thorough (patho)physiological characterization of animal disease models. In this review, current and potential future applications for the RF coil technology in cardiovascular, neurovascular, and renal disease will be discussed. PMID:26617515

  18. Iron transport across the blood-brain barrier; Development, neurovascular regulation and cerebral amyloid angiopathy

    PubMed Central

    McCarthy, Ryan C; Kosman, Daniel J

    2014-01-01

    There are two barriers for iron entry into the brain: 1) the brain-cerebrospinal fluid (CSF) barrier and 2) the blood-brain barrier (BBB). Here, we review the literature on developmental iron accumulation by the brain, focusing on the transport of iron through the brain microvascular endothelial cells (BMVEC) of the BBB. We review the iron trafficking proteins which may be involved in the iron flux across BMVEC and discuss the plausible mechanisms of BMVEC iron uptake and efflux. We suggest a model for how BMVEC iron uptake and efflux are regulated and a mechanism by which the majority of iron is trafficked across the developing BBB under the direct guidance of neighboring astrocytes. Thus, we place brain iron uptake in the context of the neurovascular unit of the adult brain. Last, we propose that BMVEC iron is involved in the aggregation of amyloid-β peptides leading to the progression of cerebral amyloid angiopathy which often occurs prior to dementia and the onset of Alzheimer's disease. PMID:25355056

  19. Dexamethasone Rescues Neurovascular Unit Integrity from Cell Damage Caused by Systemic Administration of Shiga Toxin 2 and Lipopolysaccharide in Mice Motor Cortex

    PubMed Central

    Pinto, Alipio; Jacobsen, Mariana; Geoghegan, Patricia A.; Cangelosi, Adriana; Cejudo, María Laura; Tironi-Farinati, Carla; Goldstein, Jorge

    2013-01-01

    Shiga toxin 2 (Stx2)-producing Escherichia coli (STEC) causes hemorrhagic colitis and hemolytic uremic syndrome (HUS) that can lead to fatal encephalopathies. Neurological abnormalities may occur before or after the onset of systemic pathological symptoms and motor disorders are frequently observed in affected patients and in studies with animal models. As Stx2 succeeds in crossing the blood-brain barrier (BBB) and invading the brain parenchyma, it is highly probable that the observed neurological alterations are based on the possibility that the toxin may trigger the impairment of the neurovascular unit and/or cell damage in the parenchyma. Also, lipopolysaccharide (LPS) produced and secreted by enterohemorrhagic Escherichia coli (EHEC) may aggravate the deleterious effects of Stx2 in the brain. Therefore, this study aimed to determine (i) whether Stx2 affects the neurovascular unit and parenchymal cells, (ii) whether the contribution of LPS aggravates these effects, and (iii) whether an inflammatory event underlies the pathophysiological mechanisms that lead to the observed injury. The administration of a sub-lethal dose of Stx2 was employed to study in detail the motor cortex obtained from a translational murine model of encephalopathy. In the present paper we report that Stx2 damaged microvasculature, caused astrocyte reaction and neuronal degeneration, and that this was aggravated by LPS. Dexamethasone, an anti-inflammatory, reversed the pathologic effects and proved to be an important drug in the treatment of acute encephalopathies. PMID:23894578

  20. Neurovascular Coupling is Impaired in Slow Walkers: The MOBILIZE Boston Study

    PubMed Central

    Sorond, Farzaneh A.; Kiely, Dan K.; Galica, Andrew; Moscufo, Nicola; Serrador, Jorge M.; Iloputaife, Ike; Egorova, Svetlana; Dell'Oglio, Elisa; Meier, Dominik; Newton, Elizabeth; Milberg, William P.; Guttmann, Charles; Lipsitz, Lewis A.

    2011-01-01

    Objective Neurovascular coupling may be involved in compensatory mechanisms responsible for preservation of gait speed in elderly people with cerebrovascular disease. Our study examines the association between neurovascular coupling in the middle cerebral artery and gait speed in elderly individuals with impaired cerebral vasoreactivity. Methods Twenty-two fast and 20 slow walkers in the lowest quartile of cerebral vasoreactivity were recruited from the MOBILIZE Boston Study. Neurovascular coupling was assessed in bilateral middle cerebral arteries by measuring cerebral blood flow during the N-Back Task. Cerebral white matter hyperintensities were measured for each group using magnetic resonance imaging. Results Neurovascular coupling was attenuated in slow compared to fast walkers (2.8% [CI95%: −0.9–6.6] vs. 8.2% [CI95%: 4.7–11.8]; p=0.02). The odds of being a slow walker were 6.4 (CI95%: 1.7–24.9, p=0.007) if there was a high burden of white matter hyperintensity, however, this risk increased to 14.5 (CI95%: 2.3–91.1, p=0.004) if neurovascular coupling was also attenuated. Interpretation Our results suggest that intact neurovascular coupling may help preserve mobility in elderly people with cerebral microvascular disease. PMID:21674588

  1. Blood Pressure Increases in OSA due to Maintained Neurovascular Sympathetic Transduction: Impact of CPAP

    PubMed Central

    Tamisier, Renaud; Tan, Can Ozan; Pepin, Jean-Louis; Levy, Patrick; Taylor, J. Andrew

    2015-01-01

    Study Objectives: To test the hypothesis that greater resting sympathetic activity in obstructive sleep apnea (OSA) syndrome would not induce a lesser sympathetic neurovascular transduction. Design: Case-controlled cohort study. Participants: 33 patients with newly diagnosed OSA without comorbidities and 14 healthy controls. Interventions: 6 months of continuous positive airway pressure (CPAP) treatment for OSA patients and follow-up for 9 healthy controls. Measurements and Results: We assessed resting sympathetic outflow and sympathetic neurovascular transduction. Sympathetic activity was directly measured (microneurography) at rest and in response to sustained isometric handgrip exercise. Neurovascular transduction was derived from the relationship of sympathetic activity and blood pressure to leg blood flow during exercise. Despite an elevated sympathetic activity of ∼50% in OSA compared to controls, neurovascular transduction was not different (i.e., absence of tachyphylaxis). After six months of CPAP, there were significant declines in diastolic pressure, averaging ∼4 mm Hg, and in sympathetic activity, averaging ∼20% with no change in transduction. Conclusions: Greater sympathetic activity in obstructive sleep apnea does not appear to be associated with lesser neurovascular transduction. Hence, elevated sympathetic outflow without lesser transduction may underlie the prevalent development of hypertension in this population that is well controlled by continuous positive airway pressure treatment. Citation: Tamisier R, Tan CO, Pepin JL, Levy P, Taylor JA. Blood pressure increases in OSA due to maintained neurovascular sympathetic transduction: impact of CPAP. SLEEP 2015;38(12):1973–1980. PMID:26039959

  2. Neurovascular pathophysiology in cerebral ischemia, dementia and the ageing brain – current trends in basic, translational and clinical research

    PubMed Central

    2012-01-01

    The 7th International Symposium on Neuroprotection and Neurorepair was held from May 2nd to May 5th, 2012 in Potsdam, Germany. The symposium, which directly continues the successful Magdeburg meeting series, attracted over 330 colleagues from 29 countries to discuss recent findings and advances in the field. The focus of the 2012 symposium was widened from stroke and traumatic brain injury to neurodegenerative diseases, notably dementia, and more generally the ageing brain. Thereby, emphasis was given on neurovascular aspects of neurodegeneration and stroke including the blood–brain barrier, recent findings regarding the pathomechanism of Alzheimer’s disease, and brain imaging approaches. In addition, neurobiochemical aspects of neuroprotection, the role of astrogliosis, the clinical progress of cell-based approaches as well as translational hurdles and opportunities were discussed in-depth. This review summarizes some of the most stimulating discussions and reports from the meeting. PMID:22883324

  3. The temporo-spatial localization of polymorphonuclear cells related to the neurovascular unit after transient focal cerebral ischemia.

    PubMed

    Ullrich, Nora; Strecker, Jan-Kolja; Minnerup, Jens; Schilling, Matthias

    2014-10-24

    Inflammatory responses after cerebral ischemia are important for the development of final infarct size but the role of polymorphonuclear cells (PMN) is still a matter of debate, since previously used antibodies were recently declared as non-specific. In the present study, we investigated the temporo-spatial localization of PMN related to the neurovascular unit using specific antibodies, 7/4 and Ly6G, and application of G-CSF to induce proliferation and mobilization of PMN precursors after transient focal cerebral ischemia in mice. Infarct volumes, sensorimotor function, neurological outcome and immunohistochemical analysis of PMN were performed after G-CSF administration or placebo treatment. G-CSF-treated mice showed reduced infarct size (51.15±15.68 mm(2) vs. 39.31±16.13 mm(2) at day 1; 50.11±16.68 mm(2) vs. 33.16±4.86 mm(2) at day 4; p<0.05). They showed improved motor-function recovery and had a significantly better outcome compared to placebo-treated animals. Comparison of the two PMN detecting antibodies showed no difference in saturation plots or cell quantification. Studying the basement membrane-associated localization revealed ca. 60% extravascular PMN, independent of G-CSF administration. Extravascular PMNs were without any connection to laminin, but all near to the vessels. We conclude that 7/4 is a suitable marker to investigate PMN compared to Ly6G, which confirms results from former studies using the 7/4-antibody. Furthermore we report the observation that PMN were detected outside the laminin barrier but almost exclusively in close vicinity to the neurovascular unit. PMID:25152468

  4. Ageing is a process where the growth effect of neuronal noradrenaline changes progressively in favour of the flow mediated, neurodegenerative and inflammatory effect of plasma noradrenaline.

    PubMed

    Crotty, T P

    2016-08-01

    The noradrenaline stimulus has two components, one excitor, the other inhibitory. Neuronal noradrenaline is the excitor component and plasma noradrenaline is the inhibitory. The balance of effect between the two, the noradrenergic balance, is the controlled variable of the sympathetic system and determines the effect of noradrenaline. Neuronal noradrenaline stimulates tissues by diffusion from their sympathetic nerve endings, plasma noradrenaline does so by diffusion from their microcirculations. Changes in microcirculatory flow, by altering the flow mediated effect of plasma noradrenaline, are mainly responsible for altering the noradrenergic balance in the peripheral tissues; changes in CSF flow are speculated to be mainly responsible for doing the same in the brain, by altering the balance between synaptic noradrenaline in the brain and nonsynaptic noradrenaline in the subarachnoid CSF. When plasma noradrenaline alters the noradrenergic balance it triggers afferent sympathetic activity that alerts hypothalamic neurons to the event and they restore the balance and tissue homeostasis, within milliseconds, by adjusting the level of efferent sympathetic activity they project back to the affected tissue. Because the restoration is so rapid the effect of plasma noradrenaline is normally unobservable and dismissed as not having occurred. Because the hypothalamus is not involved with the responses of isolated canine lateral saphenous vein segments to noradrenaline, the effects of plasma noradrenaline in that preparation are not countered by reactive efferent activity and, consequently, are readily apparent in it. Quantitatively, they have been found to be a function of microcirculatory flow and noradrenaline concentration and, qualitatively, to be inhibitory, dilator, pro inflammatory and neurodegenerative. In life, due to a progressive increase in plasma noradrenaline concentration and, more so, in microcirculatory flow, the noradrenergic balance moves progressively in

  5. Neurovascular factors in resting-state functional MRI

    PubMed Central

    Liu, Thomas T.

    2013-01-01

    There has been growing interest in the use of resting-state functional magnetic resonance imaging (rsfMRI) for the assessment of disease and treatment, and a number of studies have reported significant diseaserelated changes in resting-state blood oxygenation level dependent (BOLD) signal amplitude and functional connectivity. rsfMRI is particularly suitable for clinical applications because the approach does not require the patient to perform a task and scans can be obtained in a relatively short amount of time. However, the mechanisms underlying resting-state BOLD activity are not well understood and thus the interpretation of changes in resting state activity is not always straightforward. The BOLD signal represents the hemodynamic response to neural activity, and changes in resting-state activity can reflect a complex combination of neural, vascular, and metabolic factors. This paper examines the role of neurovascular factors in rsfMRI and reviews approaches for the interpretation and analysis of resting state measures in the presence of confounding factors. PMID:23644003

  6. Neuro-vascular link: from genetic insights to therapeutic perspectives.

    PubMed

    Carmeliet, P

    2008-01-01

    Understanding the molecular basis of the formation of blood vessels (angiogenesis) and nerves (neurogenesis) is of great medical relevance. It is well known that dysregulation of angiogenesis leads to tissue ischemia, cancer, inflammation and other disorders, while a dysfunction of the nerve system contributes to motorneuron disorders like amyotrophic lateral sclerosis (ALs) and other neurodegenerative diseases. The observations of Andreas Vesalius--Belgian anatomist of the 16th century--that patterning ofvessels and nerves show more than remarkable similarities, are currently revisited in exciting studies. Indeed, often, vessels and nerves even track alongside each other. Recent genetic studies revealed that vessels and nerves share many more common principles and signals for navigation, proliferation and survival than previously suspected. For instance, gene inactivation studies in mice and zebrafish showed that axon guidance signals regulate vessel navigation. Conversely, prototypic angiogenic factors such as VEGF control neurogenesis and regulate axon and neuron guidance, independently of their angiogenic activity. The next coming years promise to become an exciting journey to further unravel the molecular basis and explore the therapeutic potential of the neurovascular link. PMID:20120252

  7. Gaining Surgical Access for Repositioning the Inferior Alveolar Neurovascular Bundle

    PubMed Central

    Al-Siweedi, Saif Yousif Abdullah; Nambiar, P.; Shanmuhasuntharam, P.; Ngeow, W. C.

    2014-01-01

    This study is aimed at determining anatomical landmarks that can be used to gain access to the inferior alveolar neurovascular (IAN) bundle. Scanned CBCT (i-CAT machine) data of sixty patients and reconstructions performed using the SimPlant dental implant software were reviewed. Outcome variables were the linear distances of the mandibular canal to the inferior border and the buccal cortex of the mandible, measured immediately at the mental foramen (D1) and at 10, 20, 30, and 40 mm (D2–D5) distal to it. Predictor variables were age, ethnicity, and gender of subjects. Apicobasal assessment of the canal reveals that it is curving downward towards the inferior mandibular border until 20 mm (D3) distal to the mental foramen where it then curves upwards, making an elliptic-arc curve. The mandibular canal also forms a buccolingually oriented elliptic arc in relation to the buccal cortex. Variations due to age, ethnicity, and gender were evident and this study provides an accurate anatomic zone for gaining surgical access to the IAN bundle. The findings indicate that the buccal cortex-IAN distance was greatest at D3. Therefore, sites between D2 and D5 can be used as favorable landmarks to access the IAN bundle with the least complications to the patient. PMID:24892077

  8. Microstructured Thin Film Nitinol for a Neurovascular Flow-Diverter

    NASA Astrophysics Data System (ADS)

    Chen, Yanfei; Howe, Connor; Lee, Yongkuk; Cheon, Seongsik; Yeo, Woon-Hong; Chun, Youngjae

    2016-03-01

    A cerebral aneurysm occurs as a result of a weakened blood vessel, which allows blood to flow into a sac or a ballooned section. Recent advancement shows that a new device, ‘flow-diverter’, can divert blood flow away from the aneurysm sac. People found that a flow-diverter based on thin film nitinol (TFN), works very effectively, however there are no studies proving the mechanical safety in irregular, curved blood vessels. Here, we study the mechanical behaviors and structural safety of a novel microstructured TFN membrane through the computational and experimental studies, which establish the fundamental aspects of stretching and bending mechanics of the structure. The result shows a hyper-elastic behavior of the TFN with a negligible strain change up to 180° in bending and over 500% in radial stretching, which is ideal in the use in neurovascular curved arteries. The simulation determines the optimal joint locations between the TFN and stent frame. In vitro experimental test qualitatively demonstrates the mechanical flexibility of the flow-diverter with multi-modal bending. In vivo micro X-ray and histopathology study demonstrate that the TFN can be conformally deployed in the curved blood vessel of a swine model without any significant complications or abnormalities.

  9. Advanced and standardized evaluation of neurovascular compression syndromes

    NASA Astrophysics Data System (ADS)

    Hastreiter, Peter; Vega Higuera, Fernando; Tomandl, Bernd; Fahlbusch, Rudolf; Naraghi, Ramin

    2004-05-01

    Caused by a contact between vascular structures and the root entry or exit zone of cranial nerves neurovascular compression syndromes are combined with different neurological diseases (trigeminal neurolagia, hemifacial spasm, vertigo, glossopharyngeal neuralgia) and show a relation with essential arterial hypertension. As presented previously, the semi-automatic segmentation and 3D visualization of strongly T2 weighted MR volumes has proven to be an effective strategy for a better spatial understanding prior to operative microvascular decompression. After explicit segmentation of coarse structures, the tiny target nerves and vessels contained in the area of cerebrospinal fluid are segmented implicitly using direct volume rendering. However, based on this strategy the delineation of vessels in the vicinity of the brainstem and those at the border of the segmented CSF subvolume are critical. Therefore, we suggest registration with MR angiography and introduce consecutive fusion after semi-automatic labeling of the vascular information. Additionally, we present an approach of automatic 3D visualization and video generation based on predefined flight paths. Thereby, a standardized evaluation of the fused image data is supported and the visualization results are optimally prepared for intraoperative application. Overall, our new strategy contributes to a significantly improved 3D representation and evaluation of vascular compression syndromes. Its value for diagnosis and surgery is demonstrated with various clinical examples.

  10. Microstructured Thin Film Nitinol for a Neurovascular Flow-Diverter

    PubMed Central

    Chen, Yanfei; Howe, Connor; Lee, Yongkuk; Cheon, Seongsik; Yeo, Woon-Hong; Chun, Youngjae

    2016-01-01

    A cerebral aneurysm occurs as a result of a weakened blood vessel, which allows blood to flow into a sac or a ballooned section. Recent advancement shows that a new device, ‘flow-diverter’, can divert blood flow away from the aneurysm sac. People found that a flow-diverter based on thin film nitinol (TFN), works very effectively, however there are no studies proving the mechanical safety in irregular, curved blood vessels. Here, we study the mechanical behaviors and structural safety of a novel microstructured TFN membrane through the computational and experimental studies, which establish the fundamental aspects of stretching and bending mechanics of the structure. The result shows a hyper-elastic behavior of the TFN with a negligible strain change up to 180° in bending and over 500% in radial stretching, which is ideal in the use in neurovascular curved arteries. The simulation determines the optimal joint locations between the TFN and stent frame. In vitro experimental test qualitatively demonstrates the mechanical flexibility of the flow-diverter with multi-modal bending. In vivo micro X-ray and histopathology study demonstrate that the TFN can be conformally deployed in the curved blood vessel of a swine model without any significant complications or abnormalities. PMID:27009500

  11. Targeting the neurovascular unit for treatment of neurological disorders

    PubMed Central

    VanGilder, Reyna L.; Rosen, Charles L.; Barr, Taura L.; Huber, Jason D.

    2011-01-01

    Drug discovery for CNS disorders has been restricted by the inability for therapeutic agents to cross the blood-brain barrier (BBB). Moreover, current drugs aim to correct neuron cell signaling, thereby neglecting pathophysiological changes affecting other cell types of the neurovascular unit (NVU). Components of the NVU (pericytes, microglia, astrocytes, and neurons, and basal lamina) act as an intricate network to maintain the neuronal homeostatic microenvironment. Consequently, disruptions to this intricate cell network lead to neuron malfunction and symptoms characteristic of CNS diseases. A lack of understanding in NVU signaling cascades may explain why current treatments for CNS diseases are not curative. Current therapies treat symptoms by maintaining neuron function. Refocusing drug discovery to sustain NVU function may provide a better method of treatment by promoting neuron survival. In this review, we will examine current therapeutics for common CNS diseases, describe the importance of the NVU in cerebral homeostasis and discuss new possible drug targets and technologies that aim to improve treatment and drug delivery to the diseased brain. PMID:21172386

  12. Microstructured Thin Film Nitinol for a Neurovascular Flow-Diverter.

    PubMed

    Chen, Yanfei; Howe, Connor; Lee, Yongkuk; Cheon, Seongsik; Yeo, Woon-Hong; Chun, Youngjae

    2016-01-01

    A cerebral aneurysm occurs as a result of a weakened blood vessel, which allows blood to flow into a sac or a ballooned section. Recent advancement shows that a new device, 'flow-diverter', can divert blood flow away from the aneurysm sac. People found that a flow-diverter based on thin film nitinol (TFN), works very effectively, however there are no studies proving the mechanical safety in irregular, curved blood vessels. Here, we study the mechanical behaviors and structural safety of a novel microstructured TFN membrane through the computational and experimental studies, which establish the fundamental aspects of stretching and bending mechanics of the structure. The result shows a hyper-elastic behavior of the TFN with a negligible strain change up to 180° in bending and over 500% in radial stretching, which is ideal in the use in neurovascular curved arteries. The simulation determines the optimal joint locations between the TFN and stent frame. In vitro experimental test qualitatively demonstrates the mechanical flexibility of the flow-diverter with multi-modal bending. In vivo micro X-ray and histopathology study demonstrate that the TFN can be conformally deployed in the curved blood vessel of a swine model without any significant complications or abnormalities. PMID:27009500

  13. Cigarette Smoke Amplifies Inflammatory Response and Atherosclerosis Progression Through Activation of the H1R-TLR2/4-COX2 Axis

    PubMed Central

    Barua, Rajat S.; Sharma, Mukut; Dileepan, Kottarappat N.

    2015-01-01

    Emerging evidence suggests that infection and persistent inflammation are key players in the pathogenesis of atherosclerotic cardiovascular disease (CVD). Although it is well established that cigarette smoke (CS) promotes atherosclerotic CVD, very little is known about the potential impact of the collective effects of CS and intermittent or chronic subclinical infection on atherosclerosis. Our previous studies demonstrated that mast cell-derived histamine and lipopolysaccharide (LPS) synergistically enhance endothelial cell inflammatory response. We further noted that the synergy between histamine and LPS was due to reciprocal upregulation of histamine receptor and Toll-like receptor 4 (TLR4) expression and functions. These results suggest that the combined and persistent effects of mast cell mediators and bacterial agents on the vasculature are risk factors of CVD. Our recent data demonstrated that CS extract enhances histamine- and LPS-induced expression of cyclooxygenase-2 (COX-2) in endothelial cells, suggesting that CS and mast cell mediators may collectively amplify inflammatory response in the vessel wall. We hypothesize that CS enhances histamine-mediated upregulation of TLR2/TLR4 signaling in the endothelium and promotes progression of atherosclerosis. This article presents our perspective on the modulatory effects of CS and nicotine on the “histamine-TLR-COX-2 axis.” PMID:26617606

  14. Inflammatory stress exacerbates the progression of cardiac fibrosis in high-fat-fed apolipoprotein E knockout mice via endothelial-mesenchymal transition.

    PubMed

    Ma, Kun Ling; Liu, Jing; Ni, Jie; Zhang, Yang; Lv, Lin Li; Tang, Ri Ning; Ni, Hai Feng; Ruan, Xiong Zhong; Liu, Bi Cheng

    2013-01-01

    Background Chronic inflammation plays a crucial role in the progression of cardiac fibrosis. This study investigated whether inflammation exacerbated the progression of cardiac fibrosis in high-fat-fed apolipoprotein E knockout (ApoE KO) mice via endothelial-mesenchymal transition (EndMT). Methods Twenty-four male ApoE KO mice were divided into normal chow diet (Control), high-fat diet (HFD), or high-fat diet plus 10% casein injection (inflamed) groups for 8 weeks. The body weight of ApoE KO mice was measured at each week. The lipid profile and serum amyloid A (SAA) levels were examined using clinical biochemistry and enzyme-linked immunosorbent assays, respectively. Cardiac lipid and collagen accumulation was visualised with haematoxylin-eosin (HE) and Masson's trichrome staining. EndMT-related molecule expression was examined by immunohistochemistry and Western blotting. Results SAA levels were increased in the inflamed group compared with the HFD and control groups, suggesting that inflammation was successfully induced. There were no differences in body weight among three groups at each week. Interestingly, inflammation significantly reduced serum total cholesterol, triglyceride, and low-density lipoprotein (LDL) levels compared with the HFD mice. However, both foam cell formation in cardiac blood vessels and cardiac collagen deposition were increased in the inflamed group, as demonstrated by HE and Masson trichrome staining. Furthermore, inflammation reduced protein expression of CD31 and increased protein expression of alpha-smooth muscle actin (α-SMA) and collagen I, which contribute to cardiac EndMT. Conclusions Inflammatory stress exacerbates the progression of cardiac fibrosis in high-fat-fed ApoE KO mice via EndMT, suggesting that hyperlipidaemia and inflammation act synergistically to redistribute plasma lipids to cardiac tissues and accelerate the progression of cardiac fibrosis. PMID:23471419

  15. Progression of radiographic changes in the temporomandibular joints of patients with rheumatoid arthritis in relation to inflammatory markers and mediators in the blood.

    PubMed

    Voog, Ulle; Alstergren, Per; Eliasson, Sören; Leibur, Edvitar; Kallikorm, Riina; Kopp, Sigvard

    2004-02-01

    The aim of this study was to investigate longitudinal radiographic changes in the temporomandibular joint (TMJ) with clinical involvement of rheumatoid arthritis (RA) and its relation to the blood level of inflammatory mediators and markers. Sixteen patients were investigated by computed tomography on two occasions 25-46 months apart. The radiographs were assessed independently for changes in presence of erosions, sclerosis, flattening, osteophytes, and subchondral pseudocysts. The serum (S) or plasma (P) concentrations of C-reactive protein (CRP), thrombocyte particle concentration, scrotonin (S-5-HT and P-5-HT), tumor necrosis factor alpha, interleukin-1 receptor antagonist, tumor necrosis factor soluble receptor type II, interleukin-1 soluble receptor type II (P-IL-1sRII) and interleukin 6 as well as the erythrocyte sedimentation rate (ESR) were measured. The radiographic status showed no consistent or significant change during the observation period, but the individual variation was considerable. The radiographic signs of erosion and sclerosis varied most. Regression of erosions was associated with high S-5-HT and P-IL-1sRII, while progression of erosions was associated with high P-5-HT. Regression of sclerosis was associated with an increase in P-5-HT and high ESR. Progression of flattening was associated with high CRP. In conclusion, this study indicates that the progression of radiographic changes that occurs in the TMJ of patients with well-controlled RA during a period of 25-46 months seems to be related to the blood levels of CRP, 5-HT, and IL-1sRII. However, only minor progression can be expected to occur, and with considerable individual variation. PMID:15124777

  16. Adult Neurogenesis: Ultrastructure of a Neurogenic Niche and Neurovascular Relationships

    PubMed Central

    Chaves da Silva, Paula Grazielle; Benton, Jeanne L.; Beltz, Barbara S.; Allodi, Silvana

    2012-01-01

    neurovascular relationships in the brain of P. clarkii by characterizing the organization and ultrastructure of the neurogenic niche and associated vascular tissues. PMID:22723980

  17. Vestibular paroxysmia: a treatable neurovascular cross-compression syndrome.

    PubMed

    Brandt, Thomas; Strupp, Michael; Dieterich, Marianne

    2016-04-01

    The leading symptoms of vestibular paroxysmia (VP) are recurrent, spontaneous, short attacks of spinning or non-spinning vertigo that generally last less than one minute and occur in a series of up to 30 or more per day. VP may manifest when arteries in the cerebellar pontine angle cause a segmental, pressure-induced dysfunction of the eighth nerve. The symptoms are usually triggered by direct pulsatile compression with ephaptic discharges, less often by conduction blocks. MR imaging reveals the neurovascular compression of the eighth nerve (3D constructive interference in steady state and 3D time-of-flight sequences) in more than 95 % of cases. A loop of the anterior inferior cerebellar artery seems to be most often involved, less so the posterior inferior cerebellar artery, the vertebral artery, or a vein. The frequent attacks of vertigo respond to carbamazepine or oxcarbazepine, even in low dosages (200-600 mg/d or 300-900 mg/d, respectively), which have been shown to also be effective in children. Alternative drugs to try are lamotrigine, phenytoin, gabapentin, topiramate or baclofen or other non-antiepileptic drugs used in trigeminal neuralgia. The results of ongoing randomized placebo-controlled treatment studies, however, are not yet available. Surgical microvascular decompression of the eighth nerve is the "ultima ratio" for medically intractable cases or in exceptional cases of non-vascular compression of the eighth nerve by a tumor or cyst. The International Barany Society for Neuro-Otology is currently working on a consensus document on the clinical criteria for establishing a diagnosis of VP as a clinical entity. PMID:27083889

  18. Vaccine against MUC1 antigen expressed in inflammatory bowel disease and cancer lessens colonic inflammation and prevents progression to colitis associated colon cancer

    PubMed Central

    Beatty, Pamela L.; Narayanan, Sowmya; Gariépy, Jean; Ranganathan, Sarangarajan; Finn, Olivera J.

    2009-01-01

    Association of chronic inflammation with an increased risk of cancer is well established but the contributions of innate versus adaptive immunity are not fully delineated. There has furthermore been little consideration of the role played by chronic inflammation-associated antigens, including cancer antigens, and the possibility to use them as vaccines to lower the cancer risk. We studied the human tumor antigen MUC1 that is abnormally expressed in colon cancers and also in inflammatory bowel disease (IBD) that gives rise to colitis associated colon cancer (CACC). Using our new mouse model of MUC1+ IBD that progresses to CACC, IL-10−/− mice crossed with MUC1 transgenic mice, we show that vaccination against MUC1 delays IBD and prevents progression to CAAC. One mechanism is the induction of MUC1-specific adaptive immunity (anti-MUC1 IgG, anti-MUC1 CTL) that appears to eliminate abnormal MUC1+ cells in IBD colons. The other mechanism is the change in the local and the systemic microenvironments. Compared to IBD in vaccinated mice, IBD in control mice is dominated by larger numbers of neutrophils in the colon and myeloid-derived suppressor cells (MDSC) in the spleen, which can compromise adaptive immunity and facilitate tumor growth. This suggests that the tumor-promoting microenvironment of chronic inflammation can be converted to a tumor-inhibiting environment by increasing adaptive immunity against a disease-associated antigen. PMID:20332301

  19. The pro-inflammatory peptide LL-37 promotes ovarian tumor progression through recruitment of multipotent mesenchymal stromal cells.

    PubMed

    Coffelt, Seth B; Marini, Frank C; Watson, Keri; Zwezdaryk, Kevin J; Dembinski, Jennifer L; LaMarca, Heather L; Tomchuck, Suzanne L; Honer zu Bentrup, Kerstin; Danka, Elizabeth S; Henkle, Sarah L; Scandurro, Aline B

    2009-03-10

    Bone marrow-derived mesenchymal stem cells or multipotent mesenchymal stromal cells (MSCs) have been shown to engraft into the stroma of several tumor types, where they contribute to tumor progression and metastasis. However, the chemotactic signals mediating MSC migration to tumors remain poorly understood. Previous studies have shown that LL-37 (leucine, leucine-37), the C-terminal peptide of human cationic antimicrobial protein 18, stimulates the migration of various cell types and is overexpressed in ovarian, breast, and lung cancers. Although there is evidence to support a pro-tumorigenic role for LL-37, the function of the peptide in tumors remains unclear. Here, we demonstrate that neutralization of LL-37 in vivo significantly reduces the engraftment of MSCs into ovarian tumor xenografts, resulting in inhibition of tumor growth as well as disruption of the fibrovascular network. Migration and invasion experiments conducted in vitro indicated that the LL-37-mediated migration of MSCs to tumors likely occurs through formyl peptide receptor like-1. To assess the response of MSCs to the LL-37-rich tumor microenvironment, conditioned medium from LL-37-treated MSCs was assessed and found to contain increased levels of several cytokines and pro-angiogenic factors compared with controls, including IL-1 receptor antagonist, IL-6, IL-10, CCL5, VEGF, and matrix metalloproteinase-2. Similarly, Matrigel mixed with LL-37, MSCs, or the combination of the two resulted in a significant number of vascular channels in nude mice. These data indicate that LL-37 facilitates ovarian tumor progression through recruitment of progenitor cell populations to serve as pro-angiogenic factor-expressing tumor stromal cells. PMID:19234121

  20. The pro-inflammatory peptide LL-37 promotes ovarian tumor progression through recruitment of multipotent mesenchymal stromal cells

    PubMed Central

    Coffelt, Seth B.; Marini, Frank C.; Watson, Keri; Zwezdaryk, Kevin J.; Dembinski, Jennifer L.; LaMarca, Heather L.; Tomchuck, Suzanne L.; zu Bentrup, Kerstin Honer; Danka, Elizabeth S.; Henkle, Sarah L.; Scandurro, Aline B.

    2009-01-01

    Bone marrow-derived mesenchymal stem cells or multipotent mesenchymal stromal cells (MSCs) have been shown to engraft into the stroma of several tumor types, where they contribute to tumor progression and metastasis. However, the chemotactic signals mediating MSC migration to tumors remain poorly understood. Previous studies have shown that LL-37 (leucine, leucine-37), the C-terminal peptide of human cationic antimicrobial protein 18, stimulates the migration of various cell types and is overexpressed in ovarian, breast, and lung cancers. Although there is evidence to support a pro-tumorigenic role for LL-37, the function of the peptide in tumors remains unclear. Here, we demonstrate that neutralization of LL-37 in vivo significantly reduces the engraftment of MSCs into ovarian tumor xenografts, resulting in inhibition of tumor growth as well as disruption of the fibrovascular network. Migration and invasion experiments conducted in vitro indicated that the LL-37-mediated migration of MSCs to tumors likely occurs through formyl peptide receptor like-1. To assess the response of MSCs to the LL-37-rich tumor microenvironment, conditioned medium from LL-37-treated MSCs was assessed and found to contain increased levels of several cytokines and pro-angiogenic factors compared with controls, including IL-1 receptor antagonist, IL-6, IL-10, CCL5, VEGF, and matrix metalloproteinase-2. Similarly, Matrigel mixed with LL-37, MSCs, or the combination of the two resulted in a significant number of vascular channels in nude mice. These data indicate that LL-37 facilitates ovarian tumor progression through recruitment of progenitor cell populations to serve as pro-angiogenic factor-expressing tumor stromal cells. PMID:19234121

  1. Inflammation and cancer: inhibiting the progression of residual hepatic VX2 carcinoma by anti-inflammatory drug after incomplete radiofrequency ablation

    PubMed Central

    Jiang, Tao; Zhang, Xianjie; Ding, Jing; Duan, Bingwei; Lu, Shichun

    2015-01-01

    Background: Accelerated progression of residual hepatocellular carcinoma (HCC) after incomplete radiofrequency ablation (RFA) has been reported more frequently. Recent data have redefined the concept of inflammation as a critical component of tumor progression. However, there has been little understanding regarding the relationship between progression of residual HCC and the inflammation induced by thermal destruction of the tumor after RFA. The present study was designed to determine whether inflammation facilitates rapid progression of residual hepatic VX2 carcinoma and to clarify the possible underlying mechanisms. Methods: Forty-eight rabbits were each implanted with two VX2 hepatic tumors via supraumbilical median laparotomy. One of the tumors in two different lobes was ablated by RFA. All the rabbits were then randomly divided into four groups (12 rabbits in each group) receiving anti-inflammatory treatment with different doses of aspirin: control group, AS-L group (aspirin, 5 mg/kg/d), AS-M group (aspirin, 20 mg/kg/d), and AS-H group (aspirin, 100 mg/kg/d). The levels of serum interleukin-6 (IL-6), high sensitivity C-reactive protein (hs-CRP), and tumor necrosis factor-α (TNF-α) were detected to evaluate the effect of the anti-inflammation. Tumor growth, lung and kidney metastasis, and survival were assessed. The expression of proliferating cell nuclear antigen (PCNA), matrix metalloproteinase 9 (MMP-9), vascular endothelial growth factor (VEGF), and cysteinyl aspartate specific proteinase 3 (caspase-3) in residual tumor was examined by immunohistochemistry and Western-blotting. Results: The levels of serum IL-6, hs-CRP, and TNF-α in the AS-H group decreased significantly in comparison with those of the control group (P<0.05). The focal tumor volume and lung and kidney metastases of rabbits in the AS-H group were less significant compared with those of the control group (P<0.05). The expression of PCNA, MMP-9, and VEGF in the AS-H group decreased

  2. Iron behaving badly: inappropriate iron chelation as a major contributor to the aetiology of vascular and other progressive inflammatory and degenerative diseases

    PubMed Central

    Kell, Douglas B

    2009-01-01

    Background The production of peroxide and superoxide is an inevitable consequence of aerobic metabolism, and while these particular 'reactive oxygen species' (ROSs) can exhibit a number of biological effects, they are not of themselves excessively reactive and thus they are not especially damaging at physiological concentrations. However, their reactions with poorly liganded iron species can lead to the catalytic production of the very reactive and dangerous hydroxyl radical, which is exceptionally damaging, and a major cause of chronic inflammation. Review We review the considerable and wide-ranging evidence for the involvement of this combination of (su)peroxide and poorly liganded iron in a large number of physiological and indeed pathological processes and inflammatory disorders, especially those involving the progressive degradation of cellular and organismal performance. These diseases share a great many similarities and thus might be considered to have a common cause (i.e. iron-catalysed free radical and especially hydroxyl radical generation). The studies reviewed include those focused on a series of cardiovascular, metabolic and neurological diseases, where iron can be found at the sites of plaques and lesions, as well as studies showing the significance of iron to aging and longevity. The effective chelation of iron by natural or synthetic ligands is thus of major physiological (and potentially therapeutic) importance. As systems properties, we need to recognise that physiological observables have multiple molecular causes, and studying them in isolation leads to inconsistent patterns of apparent causality when it is the simultaneous combination of multiple factors that is responsible. This explains, for instance, the decidedly mixed effects of antioxidants that have been observed, since in some circumstances (especially the presence of poorly liganded iron) molecules that are nominally antioxidants can actually act as pro-oxidants. The reduction of redox

  3. Ganoderma lucidum Combined with the EGFR Tyrosine Kinase Inhibitor, Erlotinib Synergize to Reduce Inflammatory Breast Cancer Progression.

    PubMed

    Suárez-Arroyo, Ivette J; Rios-Fuller, Tiffany J; Feliz-Mosquea, Yismeilin R; Lacourt-Ventura, Mercedes; Leal-Alviarez, Daniel J; Maldonado-Martinez, Gerónimo; Cubano, Luis A; Martínez-Montemayor, Michelle M

    2016-01-01

    The high incidence of resistance to Tyrosine Kinase Inhibitors (TKIs) targeted against EGFR and downstream pathways has increased the necessity to identify agents that may be combined with these therapies to provide a sustained response for breast cancer patients. Here, we investigate the therapeutic potential of Ganoderma lucidum extract (GLE) in breast cancer, focusing on the regulation of the EGFR signaling cascade when treated with the EGFR TKI, Erlotinib. SUM-149, or intrinsic Erlotinib resistant MDA-MB-231 cells, and a successfully developed Erlotinib resistant cell line, rSUM-149 were treated with increasing concentrations of Erlotinib, GLE, or their combination (Erlotinib/GLE) for 72h. Treatment effects were tested on cell viability, cell proliferation, cell migration and invasion. To determine tumor progression, severe combined immunodeficient mice were injected with SUM-149 cells and then treated with Erlotinib/GLE or Erlotinib for 13 weeks. We assessed the protein expression of ERK1/2 and AKT in in vitro and in vivo models. Our results show that GLE synergizes with Erlotinib to sensitize SUM-149 cells to drug treatment, and overcomes intrinsic and developed Erlotinib resistance. Also, Erlotinib/GLE decreases SUM-149 cell viability, proliferation, migration and invasion. GLE increases Erlotinib sensitivity by inactivating AKT and ERK signaling pathways in our models. We conclude that a combinatorial therapeutic approach may be the best way to increase prognosis in breast cancer patients with EGFR overexpressing tumors. PMID:26958085

  4. Ganoderma lucidum Combined with the EGFR Tyrosine Kinase Inhibitor, Erlotinib Synergize to Reduce Inflammatory Breast Cancer Progression

    PubMed Central

    Suárez-Arroyo, Ivette J.; Rios-Fuller, Tiffany J.; Feliz-Mosquea, Yismeilin R.; Lacourt-Ventura, Mercedes; Leal-Alviarez, Daniel J.; Maldonado-Martinez, Gerónimo; Cubano, Luis A.; Martínez-Montemayor, Michelle M.

    2016-01-01

    The high incidence of resistance to Tyrosine Kinase Inhibitors (TKIs) targeted against EGFR and downstream pathways has increased the necessity to identify agents that may be combined with these therapies to provide a sustained response for breast cancer patients. Here, we investigate the therapeutic potential of Ganoderma lucidum extract (GLE) in breast cancer, focusing on the regulation of the EGFR signaling cascade when treated with the EGFR TKI, Erlotinib. SUM-149, or intrinsic Erlotinib resistant MDA-MB-231 cells, and a successfully developed Erlotinib resistant cell line, rSUM-149 were treated with increasing concentrations of Erlotinib, GLE, or their combination (Erlotinib/GLE) for 72h. Treatment effects were tested on cell viability, cell proliferation, cell migration and invasion. To determine tumor progression, severe combined immunodeficient mice were injected with SUM-149 cells and then treated with Erlotinib/GLE or Erlotinib for 13 weeks. We assessed the protein expression of ERK1/2 and AKT in in vitro and in vivo models. Our results show that GLE synergizes with Erlotinib to sensitize SUM-149 cells to drug treatment, and overcomes intrinsic and developed Erlotinib resistance. Also, Erlotinib/GLE decreases SUM-149 cell viability, proliferation, migration and invasion. GLE increases Erlotinib sensitivity by inactivating AKT and ERK signaling pathways in our models. We conclude that a combinatorial therapeutic approach may be the best way to increase prognosis in breast cancer patients with EGFR overexpressing tumors. PMID:26958085

  5. SENP1-mediated NEMO deSUMOylation in adipocytes limits inflammatory responses and type-1 diabetes progression

    PubMed Central

    Shao, Lan; Zhou, Huanjiao Jenny; Zhang, Haifeng; Qin, Lingfeng; Hwa, John; Yun, Zhong; Ji, Weidong; Min, Wang

    2015-01-01

    Adipocyte dysfunction correlates with the development of diabetes. Here we show that mice with a adipocyte-specific deletion of the SUMO-specific protease SENP1 gene develop symptoms of type-1 diabetes mellitus (T1DM), including hyperglycaemia and glucose intolerance with mild insulin resistance. Peri-pancreatic adipocytes from SENP1-deficient mice exhibit heightened NF-κB activity and production of proinflammatory cytokines, which induce CCL5 expression in adjacent pancreatic islets and direct cytotoxic effects on pancreatic islets. Mechanistic studies show that SENP1 deletion in adipocytes enhances SUMOylation of the NF-κB essential molecule, NEMO, at lysine 277/309, leading to increased NF-κB activity, cytokine production and pancreatic inflammation. We further show that NF-κB inhibitors could inhibit pre-diabetic cytokine production, β-cell damages and ameliorate the T1DM phenotype in SENP1-deficient mice. Feeding a high-fat diet augments both type-1 and type-2 diabetes phenotypes in SENP1-deficient mice, consistent with the effects on adipocyte-derived NF-κB and cytokine signalling. Our study reveals previously unrecognized mechanism regulating the onset and progression of T1DM associated with adipocyte dysfunction. PMID:26596471

  6. Technetium 99m-methylene diphosphonate bone scans in children with reflex neurovascular dystrophy

    SciTech Connect

    Laxer, R.M.; Allen, R.C.; Malleson, P.N.; Morrison, R.T.; Petty, R.E.

    1985-03-01

    Eleven children with reflex neurovascular dystrophy were investigated by technetium-labeled methylene diphosphonate bone scanning. Eight of 12 scans demonstrated abnormal findings, four showing diffusely decreased uptake and four diffusely increased uptake of the radionuclide in the affected site. Three scans showed normal findings initially, as did one previously abnormal scan when repeated in the asymptomatic patient 6 months later. Diffusely abnormal findings can be helpful in the diagnosis of childhood reflex neurovascular dystrophy, but a normal scan does not exclude the diagnosis.

  7. Pyrroloquinoline Quinone Decelerates Rheumatoid Arthritis Progression by Inhibiting Inflammatory Responses and Joint Destruction via Modulating NF-κB and MAPK Pathways.

    PubMed

    Liu, Zhongbing; Sun, Chi; Tao, Ran; Xu, Xinbao; Xu, Libin; Cheng, Hongbing; Wang, Youhua; Zhang, Dongmei

    2016-02-01

    Pyrroloquinoline quinone (PQQ) is a naturally occurring redox cofactor that acts as an essential nutrient and antioxidant and has been reported to exert potent immunosuppressive effects. However, the therapeutically potential of PQQ on rheumatoid arthritis (RA) has not been explored. In the present study, the anti-inflammatory effects of PQQ were investigated in interleukin (IL)-1β-treated SW982 cells, a RA-like fibroblast-like synoviocytes (FLSs) injury model. Our observations showed that pretreatment with PQQ significantly inhibited the expression of matrix metalloproteinase (MMP)-1 and MMP-3 and suppressed the production of proinflammatory mediators such as TNF-α and IL-6 in IL-1β-treated SW982 cells. The nuclear translocation of nuclear factor kappa B (NF-κB) and the phosphorylation level of p65, p38, and JNK MAP kinase pathways were also inhibited by PQQ in IL-1β-stimulated SW982 cells. To further confirm the therapeutic effects of PQQ on RA in vivo, a collagen-induced arthritis (CIA) model was used. Mice treated with PQQ demonstrated marked attenuation of arthritic symptoms based on histopathology and clinical arthritis scores. These results collectively suggested that PQQ might be a promising therapeutic agent for alleviating the progress of RA. PMID:26319019

  8. Preliminary methods for wearable neuro-vascular assessment with non-invasive, active sensing.

    PubMed

    Carek, Andrew M; Töreyin, Hakan; Hersek, Sinan; Inan, Omer T

    2015-01-01

    In this study, a non-invasive and active sensing scheme that is ultimately aimed to be integrated in a wearable system for neuro-vascular health assessment is presented with preliminary results. With this system, vascular tone is modulated by local heating and cooling of the palm, and the resulting changes in local hemodynamics are monitored via impedance plethysmography (IPG) and photoplethysmography (PPG) sensors interfaced with custom analog electronics. Proof-of-concept measurements were conducted on three subjects using hot packs/ice bags to modulate the palmar skin temperature. From ensemble averaged and smoothed versions of pulsatile IPG and PPG signals, the effects of local changes in skin temperature on a series of parameters associated with neuro-vascular mechanisms (heart rate, blood volume, blood flow rate, blood volume pulse inflection point area ratio, and local pulse transit time) have been observed. The promising experimental results suggest that, with different active temperature modulation schemes (consisting of heating/cooling cycles covering different temperature ranges at different rates), it would be possible to enhance the depth and specificity of the information associated with neuro-vascular health by using biosensors that can fit inside a wearable device (such as a sleeve). This study sets the foundation for future studies on designing and testing such a wearable neuro-vascular health assessment system employing active sensing. PMID:26736951

  9. The Role of Pericytes in Neurovascular Unit Remodeling in Brain Disorders

    PubMed Central

    ElAli, Ayman; Thériault, Peter; Rivest, Serge

    2014-01-01

    Neurons are extremely vulnerable cells that tightly rely on the brain’s highly dynamic and complex vascular network that assures an accurate and adequate distribution of nutrients and oxygen. The neurovascular unit (NVU) couples neuronal activity to vascular function, controls brain homeostasis, and maintains an optimal brain microenvironment adequate for neuronal survival by adjusting blood-brain barrier (BBB) parameters based on brain needs. The NVU is a heterogeneous structure constituted by different cell types that includes pericytes. Pericytes are localized at the abluminal side of brain microvessels and contribute to NVU function. Pericytes play essential roles in the development and maturation of the neurovascular system during embryogenesis and stability during adulthood. Initially, pericytes were described as contractile cells involved in controlling neurovascular tone. However, recent reports have shown that pericytes dynamically respond to stress induced by injury upon brain diseases, by chemically and physically communicating with neighboring cells, by their immune properties and by their potential pluripotent nature within the neurovascular niche. As such, in this paper, we would like to review the role of pericytes in NVU remodeling, and their potential as targets for NVU repair strategies and consequently neuroprotection in two pathophysiologically distinct brain disorders: ischemic stroke and Alzheimer’s disease (AD). PMID:24743889

  10. Control of the neurovascular coupling by nitric oxide-dependent regulation of astrocytic Ca2+ signaling

    PubMed Central

    Muñoz, Manuel F.; Puebla, Mariela; Figueroa, Xavier F.

    2015-01-01

    Neuronal activity must be tightly coordinated with blood flow to keep proper brain function, which is achieved by a mechanism known as neurovascular coupling. Then, an increase in synaptic activity leads to a dilation of local parenchymal arterioles that matches the enhanced metabolic demand. Neurovascular coupling is orchestrated by astrocytes. These glial cells are located between neurons and the microvasculature, with the astrocytic endfeet ensheathing the vessels, which allows fine intercellular communication. The neurotransmitters released during neuronal activity reach astrocytic receptors and trigger a Ca2+ signaling that propagates to the endfeet, activating the release of vasoactive factors and arteriolar dilation. The astrocyte Ca2+ signaling is coordinated by gap junction channels and hemichannels formed by connexins (Cx43 and Cx30) and channels formed by pannexins (Panx-1). The neuronal activity-initiated Ca2+ waves are propagated among neighboring astrocytes directly via gap junctions or through ATP release via connexin hemichannels or pannexin channels. In addition, Ca2+ entry via connexin hemichannels or pannexin channels may participate in the regulation of the astrocyte signaling-mediated neurovascular coupling. Interestingly, nitric oxide (NO) can activate connexin hemichannel by S-nitrosylation and the Ca2+-dependent NO-synthesizing enzymes endothelial NO synthase (eNOS) and neuronal NOS (nNOS) are expressed in astrocytes. Therefore, the astrocytic Ca2+ signaling triggered in neurovascular coupling may activate NO production, which, in turn, may lead to Ca2+ influx through hemichannel activation. Furthermore, NO release from the hemichannels located at astrocytic endfeet may contribute to the vasodilation of parenchymal arterioles. In this review, we discuss the mechanisms involved in the regulation of the astrocytic Ca2+ signaling that mediates neurovascular coupling, with a special emphasis in the possible participation of NO in this process

  11. Ursolic Acid Inhibits the Initiation, Progression of Prostate Cancer and Prolongs the Survival of TRAMP Mice by Modulating Pro-Inflammatory Pathways

    PubMed Central

    Shanmugam, Muthu K.; Ong, Tina H.; Kumar, Alan Prem; Lun, Chang K.; Ho, Paul C.; Wong, Peter T. H.; Hui, Kam M.; Sethi, Gautam

    2012-01-01

    Prostate cancer is one of the leading causes of cancer death among men worldwide. In this study, using transgenic adenocarcinoma of mouse prostate (TRAMP) mice, the effect of diet enriched with 1% w/w ursolic acid (UA) was investigated to evaluate the stage specific chemopreventive activity against prostate cancer. We found that TRAMP mice fed with UA diet for 8 weeks (weeks 4 to 12) delayed formation of prostate intraepithelial neoplasia (PIN). Similarly, mice fed with UA diet for 6 weeks (weeks 12 to 18) inhibited progression of PIN to adenocarcinoma as determined by hematoxylin and eosin staining. Finally, TRAMP mice fed with UA diet for 12 weeks (weeks 24 to 36) demonstrated markedly reduced tumor growth without any significant effects on total body weight and prolonged overall survival. With respect to the molecular mechanism, we found that UA down-regulated activation of various pro-inflammatory mediators including, NF-κB, STAT3, AKT and IKKα/β phosphorylation in the dorsolateral prostate (DLP) tissues that correlated with the reduction in serum levels of TNF-α and IL-6. In addition, UA significantly down-regulated the expression levels of cyclin D1 and COX-2 but up-regulated the levels of caspase-3 as revealed by immunohistochemical analysis of tumor tissue sections. Finally, UA was detected in serum samples obtained from various mice groups fed with enriched diet in nanogram quantity indicating that it is well absorbed in the GI tract. Overall, our findings provide strong evidence that UA can be an excellent agent for both the prevention and treatment of prostate cancer. PMID:22427843

  12. Neurovascular changes in acute, sub-acute and chronic mouse models of Parkinson's disease.

    PubMed

    Sarkar, Sumit; Raymick, James; Mann, Dushyant; Bowyer, John F; Hanig, Joseph P; Schmued, Larry C; Paule, Merle G; Chigurupati, Srinivasulu

    2014-02-01

    Although selective neurodegeneration of nigro-striatal dopaminergic neurons is widely accepted as a cause of Parkinson's disease (PD), the role of vascular components in the brain in PD pathology is not well understood. However, the neurodegeneration seen in PD is known to be associated with neuroinflammatory-like changes that can affect or be associated with brain vascular function. Thus, dysfunction of the capillary endothelial cell component of neurovascular units present in the brain may contribute to the damage to dopaminergic neurons that occurs in PD. An animal model of PD employing acute, sub-acute and chronic exposures of mice to methyl-phenyl-tetrahydropyridine (MPTP) was used to determine the extent to which brain vasculature may be damaged in PD. Fluoro-Turquoise gelatin labeling of microvessels and endothelial cells was used to determine the extent of vascular damage produced by MPTP. In addition, tyrosine hydroxylase (TH) and NeuN were employed to detect and quantify dopaminergic neuron damage in the striatum (CPu) and substantia nigra (SNc). Gliosis was evaluated through GFAP immunohistochemistry. MPTP treatment drastically reduced TH immunoreactive neurons in the SNc (20.68 ± 2.83 in acute; 22.98 ± 2.14 in sub-acute; 10.20 ± 2.24 in chronic vs 34.88 ± 2.91 in controls; p<0.001). Similarly, TH immunoreactive terminals were dramatically reduced in the CPu of MPTP treated mice. Additionally, all three MPTP exposures resulted in a decrease in the intensity, length, and number of vessels in both CPu and SNc. Degenerative vascular changes such as endothelial cell 'clusters' were also observed after MPTP suggesting that vasculature damage may be modifying the availability of nutrients and exposing blood cells and/or toxic substances to neurons and glia. In summary, vascular damage and degeneration could be an additional exacerbating factor in the progression of PD, and therapeutics that protect and insure vascular integrity may be novel treatments for

  13. Brain endothelial TAK1 and NEMO safeguard the neurovascular unit

    PubMed Central

    Ridder, Dirk A.; Wenzel, Jan; Müller, Kristin; Töllner, Kathrin; Tong, Xin-Kang; Assmann, Julian C.; Stroobants, Stijn; Weber, Tobias; Niturad, Cristina; Fischer, Lisanne; Lembrich, Beate; Wolburg, Hartwig; Grand’Maison, Marilyn; Papadopoulos, Panayiota; Korpos, Eva; Truchetet, Francois; Rades, Dirk; Sorokin, Lydia M.; Schmidt-Supprian, Marc; Bedell, Barry J.; Pasparakis, Manolis; Balschun, Detlef; D’Hooge, Rudi; Löscher, Wolfgang; Hamel, Edith

    2015-01-01

    Inactivating mutations of the NF-κB essential modulator (NEMO), a key component of NF-κB signaling, cause the genetic disease incontinentia pigmenti (IP). This leads to severe neurological symptoms, but the mechanisms underlying brain involvement were unclear. Here, we show that selectively deleting Nemo or the upstream kinase Tak1 in brain endothelial cells resulted in death of endothelial cells, a rarefaction of brain microvessels, cerebral hypoperfusion, a disrupted blood–brain barrier (BBB), and epileptic seizures. TAK1 and NEMO protected the BBB by activating the transcription factor NF-κB and stabilizing the tight junction protein occludin. They also prevented brain endothelial cell death in a NF-κB–independent manner by reducing oxidative damage. Our data identify crucial functions of inflammatory TAK1–NEMO signaling in protecting the brain endothelium and maintaining normal brain function, thus explaining the neurological symptoms associated with IP. PMID:26347470

  14. Curcumin in inflammatory diseases.

    PubMed

    Shehzad, Adeeb; Rehman, Gauhar; Lee, Young Sup

    2013-01-01

    Curcumin (diferuloylmethane), a yellow coloring agent extracted from turmeric is also used as a remedy for the treatment and prevention of inflammatory diseases. Acute and chronic inflammation is a major factor in the progression of obesity, type II diabetes, arthritis, pancreatitis, cardiovascular, neurodegenerative and metabolic diseases, as well as certain types of cancer. Turmeric has a long history of use in Ayurvedic medicine for the treatment of inflammatory disorders. Recent studies on the efficacy and therapeutic applicability of turmeric have suggested that the active ingredient of tumeric is curcumin. Further, compelling evidence has shown that curcumin has the ability to inhibit inflammatory cell proliferation, invasion, and angiogenesis through multiple molecular targets and mechanisms of action. Curcumin is safe, non-toxic, and mediates its anti-inflammatory effects through the down-regulation of inflammatory transcription factors, cytokines, redox status, protein kinases, and enzymes that all promote inflammation. In addition, curcumin induces apoptosis through mitochondrial and receptor-mediated pathways, as well as activation of caspase cascades. In the current study, the anti-inflammatory effects of curcumin were evaluated relative to various chronic inflammatory diseases. Based on the available pharmacological data obtained from in vitro and in vivo research, as well as clinical trials, an opportunity exists to translate curcumin into clinics for the prevention of inflammatory diseases in the near future. PMID:23281076

  15. Neurovascular Compression Caused by Popliteus Muscle Enlargement Without Discrete Trauma

    PubMed Central

    2016-01-01

    Popliteal entrapment syndrome caused by isolated popliteus muscle enlargement is very rare, although its occurrence has been reported after discrete trauma. However, popliteal artery stenosis with combined peroneal and proximal tibial neuropathy caused by popliteus muscle enlargement without preceding trauma has not been reported. A 57-year-old man presented with a tingling sensation and pain in his left calf. He had no previous history of an injury. The symptoms were similar to those of lumbosacral radiculopathy. Calf pain became worse despite treatment, and the inability to flex his toes progressed. Computed tomography angiography and magnetic resonance imaging of the lower extremity showed popliteal artery stenosis caused by popliteus muscle enlargement and surrounding edema. An electrodiagnostic study confirmed combined peroneal and proximal tibial neuropathy at the popliteal fossa. Urgent surgical decompression was performed because of the progressive neurologic deficit and increasing neuropathic pain. The calf pain disappeared immediately after surgery, and he was discharged after the neurologic functions improved. PMID:27446794

  16. Neurovascular pathways to neurodegeneration in Alzheimer’s disease and other disorders

    PubMed Central

    Zlokovic, Berislav V.

    2014-01-01

    The neurovascular unit (NVU) comprises brain endothelial cells, pericytes or vascular smooth muscle cells, glia and neurons. The NVU controls blood–brain barrier (BBB) permeability and cerebral blood flow, and maintains the chemical composition of the neuronal ‘milieu’, which is required for proper functioning of neuronal circuits. Recent evidence indicates that BBB dysfunction is associated with the accumulation of several vasculotoxic and neurotoxic molecules within brain parenchyma, a reduction in cerebral blood flow, and hypoxia. Together, these vascular-derived insults might initiate and/or contribute to neuronal degeneration. This article examines mechanisms of BBB dysfunction in neurodegenerative disorders, notably Alzheimer’s disease, and highlights therapeutic opportunities relating to these neurovascular deficits. PMID:22048062

  17. Cerebellopontine angle and internal auditory canal: neurovascular anatomy on gas CT cisternograms

    SciTech Connect

    Bird, C.R.; Hasso, A.N.; Drayer, B.P.; Hinshaw, D.B. Jr.; Thompson, J.R.

    1985-03-01

    The authors reviewed 103 normal gas CT cisternograms to delineate the appearance of normal neurovascular structures in the cerebellopontine angle (CPA) and internal auditory canal (IAC). Cranial nerves VII and VIII were identified in the CPA in 97% of cases, either separately (53%) or as a bundle (44%). Intracanalicular branches of the VIIIth cranial nerve were identified in 20% of cases, and cranial nerve V was visualized in the CPA in 14%. The characteristic vascular loop, usually the anterior inferior cerebellar artery, was visible in 35% of cases, and, in 22% of visualized cases, was in an intracanalicular location. In 10% of cases, greater than 66% of the IAC was occupied by the neurovascular bundle. Familiarity with the normal anatomy and variations seen on gas CT cisternograms is necessary to prevent false-positive interpretations.

  18. Neurovascular and Immuno-Imaging: From Mechanisms to Therapies. Proceedings of the Inaugural Symposium

    PubMed Central

    Akassoglou, Katerina; Agalliu, Dritan; Chang, Christopher J.; Davalos, Dimitrios; Grutzendler, Jaime; Hillman, Elizabeth M. C.; Khakh, Baljit S.; Kleinfeld, David; McGavern, Dorian B.; Nelson, Sarah J.; Zlokovic, Berislav V.

    2016-01-01

    Breakthrough advances in intravital imaging have launched a new era for the study of dynamic interactions at the neurovascular interface in health and disease. The first Neurovascular and Immuno-Imaging Symposium was held at the Gladstone Institutes, University of California, San Francisco in March, 2015. This highly interactive symposium brought together a group of leading researchers who discussed how recent studies have unraveled fundamental biological mechanisms in diverse scientific fields such as neuroscience, immunology, and vascular biology, both under physiological and pathological conditions. These Proceedings highlight how advances in imaging technologies and their applications revolutionized our understanding of the communication between brain, immune, and vascular systems and identified novel targets for therapeutic intervention in neurological diseases. PMID:26941593

  19. EMCCD-Based High Resolution Dynamic X-Ray Detector for Neurovascular Interventions

    PubMed Central

    Sharma, P.; Vasan, S.N. Swetadri; Jain, A.; Panse, A.; Titus, A.H.; Cartwright, A. N.; Bednarek, D. R; Rudin, S.

    2012-01-01

    We have designed and developed from the discrete component level a high resolution dynamic detector for neurovascular interventions. The heart of the detector is a 1024 × 1024 pixel electron multiplying charge coupled device (EMCCD) with a pixel size of 13 × 13 μm2, bonded to a fiber optic plate (FOP), and optically coupled to a 350 μm micro-columnar CsI(TI) scintillator via a 3.3:1 fiber optic taper (FOT). The detector provides x-ray images of 9 cycles/mm resolution at 15 frames/sec and real time live video at 30 frames/sec with binning at a lower resolution, both independent of gain applied to EMCCD, as needed for region-of-interest (ROI) image guidance during neurovascular interventions. PMID:22256144

  20. New horizons in neurometabolic and neurovascular coupling from calibrated fMRI.

    PubMed

    Shu, C Y; Sanganahalli, B G; Coman, D; Herman, P; Hyder, F

    2016-01-01

    Neurovascular coupling relates changes in neuronal activity to constriction/dilation of microvessels. However neurometabolic coupling, which is less well known, relates alterations in neuronal activity with metabolic demands. The link between the blood oxygenation level dependent (BOLD) signal and neural activity opened doors for functional MRI (fMRI) to be a powerful neuroimaging tool in the neurosciences. But due to the complex makeup of BOLD contrast, researchers began to investigate the relationship between BOLD signal and blood flow and/or volume changes during functional brain activation, which together provided the tools to measure oxygen consumption on the basis of the biophysical model of BOLD. This field is called calibrated fMRI, thereby allowed probing of both neurometabolic and neurovascular couplings for a variety of health conditions in animals and humans. Calibrated fMRI may provide brain disorder biomarkers that could be used for monitoring effective therapies. PMID:27130413

  1. Neurovascular and Immuno-Imaging: From Mechanisms to Therapies. Proceedings of the Inaugural Symposium.

    PubMed

    Akassoglou, Katerina; Agalliu, Dritan; Chang, Christopher J; Davalos, Dimitrios; Grutzendler, Jaime; Hillman, Elizabeth M C; Khakh, Baljit S; Kleinfeld, David; McGavern, Dorian B; Nelson, Sarah J; Zlokovic, Berislav V

    2016-01-01

    Breakthrough advances in intravital imaging have launched a new era for the study of dynamic interactions at the neurovascular interface in health and disease. The first Neurovascular and Immuno-Imaging Symposium was held at the Gladstone Institutes, University of California, San Francisco in March, 2015. This highly interactive symposium brought together a group of leading researchers who discussed how recent studies have unraveled fundamental biological mechanisms in diverse scientific fields such as neuroscience, immunology, and vascular biology, both under physiological and pathological conditions. These Proceedings highlight how advances in imaging technologies and their applications revolutionized our understanding of the communication between brain, immune, and vascular systems and identified novel targets for therapeutic intervention in neurological diseases. PMID:26941593

  2. Identification of a neurovascular signaling pathway regulating seizures in mice

    PubMed Central

    Fredriksson, Linda; Stevenson, Tamara K; Su, Enming J; Ragsdale, Margaret; Moore, Shannon; Craciun, Stefan; Schielke, Gerald P; Murphy, Geoffrey G; Lawrence, Daniel A

    2015-01-01

    Objective A growing body of evidence suggests that increased blood–brain barrier (BBB) permeability can contribute to the development of seizures. The protease tissue plasminogen activator (tPA) has been shown to promote BBB permeability and susceptibility to seizures. In this study, we examined the pathway regulated by tPA in seizures. Methods An experimental model of kainate-induced seizures was used in genetically modified mice, including mice deficient in tPA (tPA−/−), its inhibitor neuroserpin (Nsp−/−), or both (Nsp:tPA−/−), and in mice conditionally deficient in the platelet-derived growth factor receptor alpha (PDGFRα). Results Compared to wild-type (WT) mice, Nsp−/− mice have significantly reduced latency to seizure onset and generalization; whereas tPA−/− mice have the opposite phenotype, as do Nsp:tPA−/− mice. Furthermore, interventions that maintain BBB integrity delay seizure propagation, whereas osmotic disruption of the BBB in seizure-resistant tPA−/− mice dramatically reduces the time to seizure onset and accelerates seizure progression. The phenotypic differences in seizure progression between WT, tPA−/−, and Nsp−/− mice are also observed in electroencephalogram recordings in vivo, but absent in ex vivo electrophysiological recordings where regulation of the BBB is no longer necessary to maintain the extracellular environment. Finally, we demonstrate that these effects on seizure progression are mediated through signaling by PDGFRα on perivascular astrocytes. Interpretation Together, these data identify a specific molecular pathway involving tPA-mediated PDGFRα signaling in perivascular astrocytes that regulates seizure progression through control of the BBB. Inhibition of PDGFRα signaling and maintenance of BBB integrity might therefore offer a novel clinical approach for managing seizures. PMID:26273685

  3. Neurovascular coupling during nociceptive processing in the primary somatosensory cortex of the rat.

    PubMed

    Jeffrey-Gauthier, Renaud; Guillemot, Jean-Paul; Piché, Mathieu

    2013-08-01

    Neuroimaging methods such as functional magnetic resonance imaging (fMRI) have been used extensively to investigate pain-related cerebral mechanisms. However, these methods rely on a tight coupling of neuronal activity to hemodynamic changes. Because pain may be associated with hemodynamic changes unrelated to local neuronal activity (eg, increased mean arterial pressure [MAP]), it is essential to determine whether the neurovascular coupling is maintained during nociceptive processing. In this study, local field potentials (LFP) and cortical blood flow (CBF) changes evoked by electrical stimulation of the left hind paw were recorded concomitantly in the right primary somatosensory cortex (SI) in 15 rats. LFP, CBF, and MAP changes were examined in response to stimulus intensities ranging from 3 to 30 mA. In addition, LFP, CBF, and MAP changes evoked by a 10-mA stimulation were examined during immersion of the tail in non-nociceptive or nociceptive hot water (counter-stimulation). SI neurovascular coupling was altered for stimuli of nociceptive intensities (P<0.001). This alteration was intensity-dependent and was strongly associated with MAP changes (r=0.98, P<0.001). However, when the stimulus intensity was kept constant, SI neurovascular coupling was not significantly affected by nociceptive counter-stimulation (P=0.4), which similarly affected the amplitude of shock-evoked LFP and CBF changes. It remains to be determined whether such neurovascular uncoupling occurs in humans, and whether it also affects other regions usually activated by painful stimuli. These results should be taken into account for accurate interpretation of fMRI studies that involve nociceptive stimuli associated with MAP changes. PMID:23707276

  4. Classification of neurovascular compression in glossopharyngeal neuralgia: Three-dimensional visualization of the glossopharyngeal nerve

    PubMed Central

    Tanrikulu, Levent; Hastreiter, Peter; Dörfler, Arnd; Buchfelder, Michael; Naraghi, Ramin

    2015-01-01

    Background: We introduce a method of noninvasive topographical analysis of the neurovascular relationships of the glossopharyngeal nerve (CN IX) by three-dimensional (3D) visualization. Patients with glossopharyngeal neuralgia (GN) resulting from neurovascular compression (NVC) were studied. Methods: 15 patients with GN were prospectively examined with 3D visualization using high-resolution magnetic resonance imaging with constructive interference in steady state (MR-CISS). The datasets were segmented and visualized with the real, individual neurovascular relationships by direct volume rendering. Segmentation and 3D visualization of the CN IX and corresponding blood vessels were performed. The 3D visualizations were interactively compared with the intraoperative setup during microvascular decompression (MVD) in order to verify the results by the observed surgical-anatomical findings. Results: 15 patients (female/male: 5/10) were examined. All of them underwent MVD (100%). Microvascular details were documented. The posterior inferior cerebellar artery (PICA) was the most common causative vessel in 12 of 15 patients (80%), the vertebral artery (VA) alone in one case (6.7%), and the combination of compression by the VA and PICA in 3 patients (13.3%). We identified three distinct types of NVC within the root entry zone of CN IX. Conclusion: 3D visualization by direct volume rendering of MR-CISS data offers the opportunity of noninvasive exploration and anatomical categorization of the CN IX. It proves to be advantageous in supporting to establish the diagnosis and microneurosurgical interventions by representing original, individual patient data in a 3D fashion. It provides an excellent global individual view over the entire neurovascular relationships of the brainstem and corresponding nerves in each case. PMID:26759734

  5. Early effects of high-fat diet on neurovascular function and focal ischemic brain injury.

    PubMed

    Li, Weiguo; Prakash, Roshini; Chawla, Dhruv; Du, Wenting; Didion, Sean P; Filosa, Jessica A; Zhang, Quanguang; Brann, Darrell W; Lima, Victor V; Tostes, Rita C; Ergul, Adviye

    2013-06-01

    Obesity is a risk factor for stroke, but the early effects of high-fat diet (HFD) on neurovascular function and ischemic stroke outcomes remain unclear. The goal of this study was to test the hypotheses that HFD beginning early in life 1) impairs neurovascular coupling, 2) causes cerebrovascular dysfunction, and 3) worsens short-term outcomes after cerebral ischemia. Functional hyperemia and parenchymal arteriole (PA) reactivity were measured in rats after 8 wk of HFD. The effect of HFD on basilar artery function after middle cerebral artery occlusion (MCAO) and associated O-GlcNAcylation were assessed. Neuronal cell death, infarct size, hemorrhagic transformation (HT) frequency/severity, and neurological deficit were evaluated after global ischemia and transient MCAO. HFD caused a 10% increase in body weight and doubled adiposity without a change in lipid profile, blood glucose, and blood pressure. Functional hyperemia and PA relaxation were decreased with HFD. Basilar arteries from stroked HFD rats were more sensitive to contractile factors, and acetylcholine-mediated relaxation was impaired. Vascular O-GlcNAcylated protein content was increased with HFD. This group also showed greater mortality rate, infarct volume, HT occurrence rate, and HT severity and poor functional outcome compared with the control diet group. These results indicate that HFD negatively affects neurovascular coupling and cerebrovascular function even in the absence of dyslipidemia. These early cerebrovascular changes may be the cause of greater cerebral injury and poor outcomes of stroke in these animals. PMID:23576615

  6. Glial cells dilate and constrict blood vessels: a mechanism of neurovascular coupling.

    PubMed

    Metea, Monica R; Newman, Eric A

    2006-03-15

    Neuronal activity evokes localized changes in blood flow. Although this response, termed neurovascular coupling, is widely used to monitor human brain function and diagnose pathology, the cellular mechanisms that mediate the response remain unclear. We investigated the contribution of glial cells to neurovascular coupling in the acutely isolated mammalian retina. We found that light stimulation and glial cell stimulation can both evoke dilation or constriction of arterioles. Light-evoked and glial-evoked vasodilations were blocked by inhibitors of cytochrome P450 epoxygenase, the synthetic enzyme for epoxyeicosatrienoic acids. Vasoconstrictions, in contrast, were blocked by an inhibitor of omega-hydroxylase, which synthesizes 20-hydroxyeicosatetraenoic acid. Nitric oxide influenced whether vasodilations or vasoconstrictions were produced in response to light and glial stimulation. Light-evoked vasoactivity was blocked when neuron-to-glia signaling was interrupted by a purinergic antagonist. These results indicate that glial cells contribute to neurovascular coupling and suggest that regulation of blood flow may involve both vasodilating and vasoconstricting components. PMID:16540563

  7. Early effects of high-fat diet on neurovascular function and focal ischemic brain injury

    PubMed Central

    Li, Weiguo; Prakash, Roshini; Chawla, Dhruv; Du, Wenting; Didion, Sean P.; Filosa, Jessica A.; Zhang, Quanguang; Brann, Darrell W.; Lima, Victor V.; Tostes, Rita C.

    2013-01-01

    Obesity is a risk factor for stroke, but the early effects of high-fat diet (HFD) on neurovascular function and ischemic stroke outcomes remain unclear. The goal of this study was to test the hypotheses that HFD beginning early in life 1) impairs neurovascular coupling, 2) causes cerebrovascular dysfunction, and 3) worsens short-term outcomes after cerebral ischemia. Functional hyperemia and parenchymal arteriole (PA) reactivity were measured in rats after 8 wk of HFD. The effect of HFD on basilar artery function after middle cerebral artery occlusion (MCAO) and associated O-GlcNAcylation were assessed. Neuronal cell death, infarct size, hemorrhagic transformation (HT) frequency/severity, and neurological deficit were evaluated after global ischemia and transient MCAO. HFD caused a 10% increase in body weight and doubled adiposity without a change in lipid profile, blood glucose, and blood pressure. Functional hyperemia and PA relaxation were decreased with HFD. Basilar arteries from stroked HFD rats were more sensitive to contractile factors, and acetylcholine-mediated relaxation was impaired. Vascular O-GlcNAcylated protein content was increased with HFD. This group also showed greater mortality rate, infarct volume, HT occurrence rate, and HT severity and poor functional outcome compared with the control diet group. These results indicate that HFD negatively affects neurovascular coupling and cerebrovascular function even in the absence of dyslipidemia. These early cerebrovascular changes may be the cause of greater cerebral injury and poor outcomes of stroke in these animals. PMID:23576615

  8. Modeling Neurovascular Coupling from Clustered Parameter Sets for Multimodal EEG-NIRS

    PubMed Central

    Talukdar, M. Tanveer; Frost, H. Robert; Diamond, Solomon G.

    2015-01-01

    Despite significant improvements in neuroimaging technologies and analysis methods, the fundamental relationship between local changes in cerebral hemodynamics and the underlying neural activity remains largely unknown. In this study, a data driven approach is proposed for modeling this neurovascular coupling relationship from simultaneously acquired electroencephalographic (EEG) and near-infrared spectroscopic (NIRS) data. The approach uses gamma transfer functions to map EEG spectral envelopes that reflect time-varying power variations in neural rhythms to hemodynamics measured with NIRS during median nerve stimulation. The approach is evaluated first with simulated EEG-NIRS data and then by applying the method to experimental EEG-NIRS data measured from 3 human subjects. Results from the experimental data indicate that the neurovascular coupling relationship can be modeled using multiple sets of gamma transfer functions. By applying cluster analysis, statistically significant parameter sets were found to predict NIRS hemodynamics from EEG spectral envelopes. All subjects were found to have significant clustered parameters (P < 0.05) for EEG-NIRS data fitted using gamma transfer functions. These results suggest that the use of gamma transfer functions followed by cluster analysis of the resulting parameter sets may provide insights into neurovascular coupling in human neuroimaging data. PMID:26089979

  9. The sectional anatomy of the carpal tunnel and its related neurovascular structures studied by using plastination.

    PubMed

    Sora, M-C; Genser-Strobl, B

    2005-05-01

    The aim of this study was to evaluate the morphology of the carpal tunnel and its related neurovascular structures. A slice anatomy study was performed on 12 right wrists of unfixed human cadavers by using the plastination technique. The measurements were performed at the level of the pisiform, hook of the hamate and in the middle between these structures. The diameters of the carpal tunnel and the median nerve were measured at the level of the hook of the hamate. The median nerve can be predicted to be 18 +/- 1.6 mm radial to the pisiform and the ulnar neurovascular bundle 6.8 +/- 1.4 mm radial to the pisiform. Between those structures there will be at least a 9-mm area, localized 8 mm radial to the pisiform, where the incision of the transverse carpal ligament could be performed risk-free. At the hamate hook the median nerve can be predicted at 9.24 +/- 1.18 mm and the ulnar artery lies usually 1.26 +/- 2.5 mm radial to the hook. An understanding of the contents and their positions, and relationships to each other allows an accurate identification of neurovascular structures in the carpal tunnel. Our findings can be used as anatomic landmarks of the carpal tunnel and could be helpful to physicians performing carpal tunnel investigations. PMID:15804269

  10. Inflammation and neurovascular changes in amyotrophic lateral sclerosis.

    PubMed

    Evans, M C; Couch, Y; Sibson, N; Turner, M R

    2013-03-01

    Neuroinflammation in now established as an important factor in the pathogenesis of many neurodegenerative diseases, including amyotrophic lateral sclerosis (ALS). At various time points, astrocytes and microglia are markedly activated, either producing neuroprotective or pro-inflammatory molecules, which can decrease or increase the rate of primary motor neuron degeneration respectively. Recent research has shown that this neuroinflammatory component is affected by the peripheral immune system; T lymphocytes in particular are able to cross into the brain and spinal cord parenchyma, where they interact with resident microglia, either inducing them to adopt an M1 (cytotoxic) or M2 (protective) phenotype, depending on the stage of disease. Clearly understanding the changes that occur to allow the interaction between peripheral and central immune responses will be essential in any attempt to manipulate the disease process via neuroinflammatory mechanisms. However, our understanding of the endothelial changes, which facilitate the infiltration of peripheral immune cells into the brain and spinal cord, is still in its infancy. There are suggestions, though, of up-regulation of cellular adhesion molecules, which are able to arrest circulating leukocytes and facilitate diapedesis into the brain parenchyma. In addition, tight junction proteins appear to be down-regulated, leading to an increase in vascular permeability, an effect that is amplified by vascular damage late in the disease process. This review summarises our current knowledge regarding neuroinflammation, peripheral immune involvement, and endothelial changes in ALS. This article is part of a Special Issue entitled 'Neuroinflammation in neurodegeneration and neurodysfunction'. PMID:23110760

  11. Impaired neurovascular coupling to ictal epileptic activity and spreading depolarization in a patient with subarachnoid hemorrhage: possible link to blood-brain barrier dysfunction.

    PubMed

    Winkler, Maren K L; Chassidim, Yoash; Lublinsky, Svetlana; Revankar, Gajanan S; Major, Sebastian; Kang, Eun-Jeung; Oliveira-Ferreira, Ana I; Woitzik, Johannes; Sandow, Nora; Scheel, Michael; Friedman, Alon; Dreier, Jens P

    2012-11-01

    Spreading depolarization describes a sustained neuronal and astroglial depolarization with abrupt ion translocation between intraneuronal and extracellular space leading to a cytotoxic edema and silencing of spontaneous activity. Spreading depolarizations occur abundantly in acutely injured human brain and are assumed to facilitate neuronal death through toxic effects, increased metabolic demand, and inverse neurovascular coupling. Inverse coupling describes severe hypoperfusion in response to spreading depolarization. Ictal epileptic events are less frequent than spreading depolarizations in acutely injured human brain but may also contribute to lesion progression through increased metabolic demand. Whether abnormal neurovascular coupling can occur with ictal epileptic events is unknown. Herein we describe a patient with aneurysmal subarachnoid hemorrhage in whom spreading depolarizations and ictal epileptic events were measured using subdural opto-electrodes for direct current electrocorticography and regional cerebral blood flow recordings with laser-Doppler flowmetry. Simultaneously, changes in tissue partial pressure of oxygen were recorded with an intraparenchymal oxygen sensor. Isolated spreading depolarizations and clusters of recurrent spreading depolarizations with persistent depression of spontaneous activity were recorded over several days followed by a status epilepticus. Both spreading depolarizations and ictal epileptic events where accompanied by hyperemic blood flow responses at one optode but mildly hypoemic blood flow responses at another. Of note, quantitative analysis of Gadolinium-diethylene-triamine-pentaacetic acid (DTPA)-enhanced magnetic resonance imaging detected impaired blood-brain barrier integrity in the region where the optode had recorded the mildly hypoemic flow responses. The data suggest that abnormal flow responses to spreading depolarizations and ictal epileptic events, respectively, may be associated with blood-brain barrier

  12. The Brain’s Heart – Therapeutic Opportunities for Patent Foramen Ovale (PFO) and Neurovascular Disease

    PubMed Central

    Ning, MingMing; Lo, Eng H.; Ning, Pei-Chen; Xu, Su-Yu; McMullin, David; Demirjian, Zareh; Inglessis, Ignacio; Dec, G William; Palacios, Igor; Buonanno, Ferdinando S.

    2013-01-01

    Patent foramen ovale (PFO), a common congenital cardiac abnormality, is a connection between the right and left atria in the heart. As a “back door to the brain”, PFO can serve as a conduit for paradoxical embolism, allowing venous thrombi to enter the arterial circulation, avoiding filtration by the lungs, and causing ischemic stroke. PFO-related strokes affect more than 150,000 people per year in the US, and PFO is present in up to 60% of migraine patients with aura, and in one out of four normal individuals. So, in such a highly prevalent condition, what are the best treatment and prevention strategies? Emerging studies show PFO-related neurovascular disease to be a multi-organ condition with varying individual risk factors that may require individualized therapeutic approaches – opening the field for new pharmacologic and therapeutic targets. The anatomy of PFO suggests that, in addition to thrombi, it can also allow harmful circulatory factors to travel directly from the venous to the arterial circulation, a concept important in finding novel therapeutic targets for PFO-related neurovascular injury. Here, we: 1) review emerging data on PFO-related injuries and clinical trials; 2) discuss potential mechanisms of PFO-related neurovascular disease in the context of multi-organ interaction and heart-brain signaling; and 3) discuss novel therapeutic targets and research frontiers. Clinical studies and molecular mapping of the circulatory landscape of this multi-organ disease will both be necessary in order to better individualize clinical treatment for a condition affecting more than a quarter of the world’s population. PMID:23528225

  13. Neurovascular and neuroimaging effects of the hallucinogenic serotonin receptor agonist psilocin in the rat brain.

    PubMed

    Spain, Aisling; Howarth, Clare; Khrapitchev, Alexandre A; Sharp, Trevor; Sibson, Nicola R; Martin, Chris

    2015-12-01

    The development of pharmacological magnetic resonance imaging (phMRI) has presented the opportunity for investigation of the neurophysiological effects of drugs in vivo. Psilocin, a hallucinogen metabolised from psilocybin, was recently reported to evoke brain region-specific, phMRI signal changes in humans. The present study investigated the effects of psilocin in a rat model using phMRI and then probed the relationship between neuronal and haemodynamic responses using a multimodal measurement preparation. Psilocin (2 mg/kg or 0.03 mg/kg i.v.) or vehicle was administered to rats (N=6/group) during either phMRI scanning or concurrent imaging of cortical blood flow and recording of local field potentials. Compared to vehicle controls psilocin (2 mg/kg) evoked phMRI signal increases in a number of regions including olfactory and limbic areas and elements of the visual system. PhMRI signal decreases were seen in other regions including somatosensory and motor cortices. Investigation of neurovascular coupling revealed that whilst neuronal responses (local field potentials) to sensory stimuli were decreased in amplitude by psilocin administration, concurrently measured haemodynamic responses (cerebral blood flow) were enhanced. The present findings show that psilocin evoked region-specific changes in phMRI signals in the rat, confirming recent human data. However, the results also suggest that the haemodynamic signal changes underlying phMRI responses reflect changes in both neuronal activity and neurovascular coupling. This highlights the importance of understanding the neurovascular effects of pharmacological manipulations for interpreting haemodynamic neuroimaging data. PMID:26192543

  14. Neurovascular and neuroimaging effects of the hallucinogenic serotonin receptor agonist psilocin in the rat brain

    PubMed Central

    Spain, Aisling; Howarth, Clare; Khrapitchev, Alexandre A.; Sharp, Trevor; Sibson, Nicola R.; Martin, Chris

    2015-01-01

    The development of pharmacological magnetic resonance imaging (phMRI) has presented the opportunity for investigation of the neurophysiological effects of drugs in vivo. Psilocin, a hallucinogen metabolised from psilocybin, was recently reported to evoke brain region-specific, phMRI signal changes in humans. The present study investigated the effects of psilocin in a rat model using phMRI and then probed the relationship between neuronal and haemodynamic responses using a multimodal measurement preparation. Psilocin (2 mg/kg or 0.03 mg/kg i.v.) or vehicle was administered to rats (N = 6/group) during either phMRI scanning or concurrent imaging of cortical blood flow and recording of local field potentials. Compared to vehicle controls psilocin (2 mg/kg) evoked phMRI signal increases in a number of regions including olfactory and limbic areas and elements of the visual system. PhMRI signal decreases were seen in other regions including somatosensory and motor cortices. Investigation of neurovascular coupling revealed that whilst neuronal responses (local field potentials) to sensory stimuli were decreased in amplitude by psilocin administration, concurrently measured haemodynamic responses (cerebral blood flow) were enhanced. The present findings show that psilocin evoked region-specific changes in phMRI signals in the rat, confirming recent human data. However, the results also suggest that the haemodynamic signal changes underlying phMRI responses reflect changes in both neuronal activity and neurovascular coupling. This highlights the importance of understanding the neurovascular effects of pharmacological manipulations for interpreting haemodynamic neuroimaging data. PMID:26192543

  15. Regional differences in neurovascular coupling in rat brain as determined by fMRI and electrophysiology.

    PubMed

    Sloan, H L; Austin, V C; Blamire, A M; Schnupp, J W H; Lowe, A S; Allers, K A; Matthews, P M; Sibson, N R

    2010-11-01

    Increases in neuronal activity induce local increases in cerebral perfusion. However, our understanding of the processes underlying this neurovascular coupling remains incomplete and, particularly, how these vary across the brain. Recent work supports an important role for astrocytes in neurovascular coupling, in large part via activation of their metabotropic glutamate receptors (mGluR). Here, using a combination of functional magnetic resonance imaging (fMRI) and electrophysiology we demonstrate regional heterogeneity in the mechanisms underlying neurovascular coupling. Direct electrical stimulation of the rat hindpaw sensorimotor cortex induces blood oxygenation level dependent (BOLD) and cerebral blood volume (CBV) fMRI responses in several anatomically distinct cortical and subcortical structures. Following intraperitoneal administration of the type 5 mGluR antagonist, MPEP, both BOLD and CBV responses to cortical stimulation were significantly reduced, whilst the local field potential (LFP) responses remained largely constant. Spatially, the degree of reduction in fMRI responses varied between cortical and subcortical regions (primary cortex approximately 18% vs. striatum approximately 66%), and also between primary and secondary cortical areas ( approximately 18% vs. approximately 55%). Similarly, greater decreases in response amplitude were seen in the contralateral secondary cortex ( approximately 91%) and ipsilateral striatum (approximately 70%), compared to the primary cortex (approximately 44%). Following MPEP, a negative component of the BOLD and CBV responses became more apparent, suggesting that different mechanisms mediate vasodilatory and vasoconstrictory responses. Interestingly, under baseline conditions the quantitative relationship between fMRI and LFP responses in cortical and subcortical regions was markedly different. Our data indicate that coupling between neuronal and fMRI responses is neither empirically nor mechanistically consistent

  16. Acute Resveratrol Consumption Improves Neurovascular Coupling Capacity in Adults with Type 2 Diabetes Mellitus

    PubMed Central

    Wong, Rachel H.X.; Raederstorff, Daniel; Howe, Peter R.C.

    2016-01-01

    Background: Poor cerebral perfusion may contribute to cognitive impairment in type 2 diabetes mellitus (T2DM). We conducted a randomized controlled trial to test the hypothesis that resveratrol can enhance cerebral vasodilator function and thereby alleviate the cognitive deficits in T2DM. We have already reported that acute resveratrol consumption improved cerebrovascular responsiveness (CVR) to hypercapnia. We now report the effects of resveratrol on neurovascular coupling capacity (CVR to cognitive stimuli), cognitive performance and correlations with plasma resveratrol concentrations. Methods: Thirty-six T2DM adults aged 40–80 years were randomized to consume single doses of resveratrol (0, 75, 150 and 300 mg) at weekly intervals. Transcranial Doppler ultrasound was used to monitor changes in blood flow velocity (BFV) during a cognitive test battery. The battery consisted of dual-tasking (finger tapping with both Trail Making task and Serial Subtraction 3 task) and a computerized multi-tasking test that required attending to four tasks simultaneously. CVR to cognitive tasks was calculated as the per cent increase in BFV from pre-test basal to peak mean blood flow velocity and also as the area under the curve for BFV. Results: Compared to placebo, 75 mg resveratrol significantly improved neurovascular coupling capacity, which correlated with plasma total resveratrol levels. Enhanced performance on the multi-tasking test battery was also evident following 75 mg and 300 mg of resveratrol. Conclusion: a single 75 mg dose of resveratrol was able to improve neurovascular coupling and cognitive performance in T2DM. Evaluation of benefits of chronic resveratrol supplementation is now warranted. PMID:27420093

  17. Myositis autoantibodies in Korean patients with inflammatory myositis: Anti-140-kDa polypeptide antibody is primarily associated with rapidly progressive interstitial lung disease independent of clinically amyopathic dermatomyositis

    PubMed Central

    2010-01-01

    Background To investigate the association between myositis autoantibodies and clinical subsets of inflammatory myositis in Korean patients. Methods Immunoprecipitation was performed using the sera of classic polymyositis (PM) (n = 11) and dermatomyositis (DM) (n = 38) patients who met the Bohan and Peter criteria for definite inflammatory myositis. A panel of defined myositis autoantibodies was surveyed to investigate the association between each autoantibody and clinical subsets of inflammatory myositis. Results Either MSAs, anti-p140, or anti-p155/140 antibodies were found in 63.3% (31/49) of the study subjects. Anti-140-kDa-polypeptide (anti-p140) (18.4%, 9/49) and anti-155/140-kDa polypeptide (anti-p155/140) (16.3%, 8/49) antibodies were the most common, followed by anti-Mi2 (14.3%, 7/49), anti-ARS (12.2%, 6/49) and anti-SRP (2.0%, 1/49) antibodies. All MSAs and anti-p140 and anti-p155/140 antibodies were mutually exclusive. Anti-p140 (23.7%, 9/38), anti-p155/140 (21.1%, 8/38), and anti-Mi2 (18.4%, 3/38) antibodies were found exclusively in DM patients. Anti-p140 antibody was associated with rapidly progressive interstitial lung disease (ILD) (p = 0.001), with a sensitivity of 100.0% (4/4) and a specificity of 85.3% (29/34) in DM patients. Anti-p155/140 antibody was associated with cancer-associated DM (p = 0.009), with a sensitivity of 55.6% (5/9) and a specificity of 89.7% (26/29). Cancer-associated survival was significantly worse when anti-p155/140 antibody was present (19.2 ± 7.6 vs. 65.0 ± 3.5 months, p = 0.032). Finally, anti-ARS antibodies were associated with stable or slowly progressive ILD in PM and DM patients (p = 0.005). Conclusions Anti-p140 and anti-p155/140 antibodies were commonly found autoantibodies in Korean patients with inflammatory myositis. Despite the lack of clinically amyopathic DM patients in the study subjects, a strong association was observed between anti-p140 antibody and rapidly progressive ILD. Anti-p155/140 antibody was

  18. Cocaine attenuates blood flow but not neuronal responses to stimulation while preserving neurovascular coupling for resting brain activity

    PubMed Central

    Chen, Wei; Liu, Peng; Volkow, Nora D.; Pan, Yingtian; Du, Congwu

    2016-01-01

    Cocaine affects neuronal activity and constricts cerebral blood vessels, making it difficult to determine whether cocaine-induced changes in cerebral blood flow (CBF) reflect neuronal activation or its vasoactive effects. Here we assessed the effects of acute cocaine on both resting-state and stimulation responses to investigate cocaine’s effects on neurovascular coupling and to differentiate its effects on neuronal activity from its vasoactive actions. We concurrently measured cortical field potentials via thinned skull EEG recordings and CBF with laser Doppler flowmetry in the rat’s somatosensory cortex for both resting state and forepaw stimulation prior to and following cocaine administration (1mg/kg, i.v.). Results show both resting-state field potentials and CBF were depressed after cocaine administration (19.8±4.7% and 52.1±13.4%, respectively) and these changes were strongly correlated with each other (r=0.81, p<0.001) indicating that cocaine did not affect neurovascular coupling at rest and that the reduction in resting CBF reflected reduction in synchronized spontaneous neuronal activity rather than vasoconstriction. In contrast, the forepaw-stimulation-evoked neuronal activity was not changed by cocaine (p=0.244) whereas the CBF to the stimulation was reduced 49.9±2.6% (p=0.028) gradually recovering ~20min post cocaine injection, indicating that neurovascular coupling during stimulation was temporarily disrupted by cocaine. Neurovascular uncoupling by cocaine during stimulation but not during rest indicates that distinct processes might underlie regulation of neurovascular coupling for spontaneous than for stimulation-induced activity. The greater reductions by cocaine to the stimulation-induced CBF increases than to the background CBF should be considered when interpreting fMRI studies comparing activation responses between controls and cocaine abusers. Neurovascular uncoupling could contribute to cocaine’s neurotoxicity particularly for

  19. Modified Bilateral Neurovascular Cheek Flap: Functional Reconstruction of Extensive Lower Lip Defects

    PubMed Central

    2016-01-01

    Background: Reconstruction of extensive lower lip defects is challenging, and functional outcomes are difficult to achieve. Methods: A modified bilateral neurovascular cheek (MBNC) flap has been described. The data of patients with cancer of the lower lip treated with wide excision and reconstructed with the MBNC flap in the Plastic Surgery Unit, Srinagarind Hospital, Khon Kaen University, from 1966 to 2012 were reviewed. Results: Of the total of 143 patients included, 90.91% were women, and their age ranged from 32 to 100 years. All defects involved 70% or greater of the lower lip, which included oral commissure, buccal mucosa, or cheek skin and upper lip. All 20 patients who were followed up demonstrated good outcomes of intercommissural distance, interlabial distance, sulcus depth, and 2-point discrimination compared with normal lip parameters according to age group and satisfaction with treatment. Conclusions: Reconstruction of extensive lower lip defects with the MBNC flap provided good oral competence and functional outcomes. The flap provided adequate lip height and width, with proper position of oral commissure and vermilion reconstruction. The awareness about neurovascular anatomy of the lip and cheek and gentle dissection preserve the lip function. The flap overcomes the drawbacks of Karapandzic technique, which is microstomia, and of Bernard technique, which is a tight adynamic lower lip. It can be used in defects of more than two-thirds of the lip, extending to the cheek, commissural reconstruction, and secondary reconstruction.

  20. Neurovascular coupling to D2/D3 dopamine receptor occupancy using simultaneous PET/functional MRI

    PubMed Central

    Sander, Christin Y.; Hooker, Jacob M.; Catana, Ciprian; Normandin, Marc D.; Alpert, Nathaniel M.; Knudsen, Gitte M.; Vanduffel, Wim; Rosen, Bruce R.; Mandeville, Joseph B.

    2013-01-01

    This study employed simultaneous neuroimaging with positron emission tomography (PET) and functional magnetic resonance imaging (fMRI) to demonstrate the relationship between changes in receptor occupancy measured by PET and changes in brain activity inferred by fMRI. By administering the D2/D3 dopamine receptor antagonist [11C]raclopride at varying specific activities to anesthetized nonhuman primates, we mapped associations between changes in receptor occupancy and hemodynamics [cerebral blood volume (CBV)] in the domains of space, time, and dose. Mass doses of raclopride above tracer levels caused increases in CBV and reductions in binding potential that were localized to the dopamine-rich striatum. Moreover, similar temporal profiles were observed for specific binding estimates and changes in CBV. Injection of graded raclopride mass doses revealed a monotonic coupling between neurovascular responses and receptor occupancies. The distinct CBV magnitudes between putamen and caudate at matched occupancies approximately matched literature differences in basal dopamine levels, suggesting that the relative fMRI measurements reflect basal D2/D3 dopamine receptor occupancy. These results can provide a basis for models that relate dopaminergic occupancies to hemodynamic changes in the basal ganglia. Overall, these data demonstrate the utility of simultaneous PET/fMRI for investigations of neurovascular coupling that correlate neurochemistry with hemodynamic changes in vivo for any receptor system with an available PET tracer. PMID:23723346

  1. Neurovascular coupling and the influence of luminal agonists via the endothelium.

    PubMed

    Dormanns, K; van Disseldorp, E M J; Brown, R G; David, T

    2015-01-01

    A numerical model of neurovascular coupling (NVC) is presented based on neuronal activity coupled to vasodilation/contraction models via the astrocytic mediated perivascular K(+) and the smooth muscle cell Ca(2+) pathway. Luminal agonists acting on P2Y receptors on the endothelial cell surface provide a flux of IP3 into the endothelial cytosol. This concentration of IP3 is transported via gap junctions between endothelial and smooth muscle cells providing a source of sacroplasmic derived Ca(2+) in the smooth muscle cell. The model is able to relate a neuronal input signal to the corresponding vessel reaction. Results indicate that blood flow mediated IP3 production via the agonist ATP has a substantial effect on the contraction/dilation dynamics of the SMC. The resulting variation in cytosolic Ca(2+) can enhance and inhibit the flow of blood to the cortical tissue. IP3 coupling between endothelial and smooth muscle cells seems to be important in the dynamics of the smooth muscle cell. The VOCC channels are, due to the hyperpolarisation from K(+) SMC efflux, almost entirely closed and do not seem to play a significant role during neuronal activity. The current model shows that astrocytic Ca(2+) is not necessary for neurovascular coupling to occur in contrast to a number of experiments outlining the importance of astrocytic Ca(2+) in NVC, however this Ca(2+) pathway is not the only one mediating NVC. Importantly agonists in flowing blood have a significant influence on the endothelial and smooth muscle cell dynamics. PMID:25167790

  2. A modular approach to create a neurovascular unit-on-a-chip.

    PubMed

    Achyuta, Anil Kumar H; Conway, Amy J; Crouse, Richard B; Bannister, Emilee C; Lee, Robin N; Katnik, Christopher P; Behensky, Adam A; Cuevas, Javier; Sundaram, Shivshankar S

    2013-02-21

    In this work, we describe the fabrication and working of a modular microsystem that recapitulates the functions of the "Neurovascular Unit". The microdevice comprised a vertical stack of a poly(dimethylsiloxane) (PDMS) neural parenchymal chamber separated by a vascular channel via a microporous polycarbonate (PC) membrane. The neural chamber housed a mixture of neurons (~4%), astrocytes (~95%), and microglia (~1%). The vascular channel was lined with a layer of rat brain microvascular endothelial cell line (RBE4). Cellular components in the neural chamber and vascular channel showed viability (>90%). The neural cells fired inhibitory as well as excitatory potentials following 10 days of culture. The endothelial cells showed diluted-acetylated low density lipoprotein (dil-a-LDL) uptake, expressed von Willebrand factor (vWF) and zonula occludens (ZO-1) tight junctions, and showed decreased Alexafluor™-conjugated dextran leakage across their barriers significantly compared with controls (p < 0.05). When the vascular layer was stimulated with TNF-α for 6 h, about 75% of resident microglia and astrocytes on the neural side were activated significantly (p < 0.05 compared to controls) recapitulating tissue-mimetic responses resembling neuroinflammation. The impact of this microsystem lies in the fact that this biomimetic neurovascular platform might not only be harnessed for obtaining mechanistic insights for neurodegenerative disorders, but could also serve as a potential screening tool for central nervous system (CNS) therapeutics in toxicology and neuroinfectious diseases. PMID:23108480

  3. Neurovascular coupling in normal aging: A combined optical, ERP and fMRI study

    PubMed Central

    Fabiani, Monica; Gordon, Brian A.; Maclin, Edward L.; Pearson, Melanie A.; Brumback-Peltz, Carrie R.; Low, Kathy A.; McAuley, Edward; Sutton, Bradley P.; Kramer, Arthur F.; Gratton, Gabriele

    2013-01-01

    Brain aging is characterized by changes in both hemodynamic and neuronal responses, which may be influenced by the cardiorespiratory fitness of the individual. To investigate the relationship between neuronal and hemodynamic changes, we studied the brain activity elicited by visual stimulation (checkerboard reversals at different frequencies) in younger adults and in older adults varying in physical fitness. Four functional brain measures were used to compare neuronal and hemodynamic responses obtained from BA17: two reflecting neuronal activity (the event-related optical signal, EROS, and the C1 response of the ERP), and two reflecting functional hemodynamic changes (functional magnetic resonance imaging, fMRI, and near-infrared spectroscopy, NIRS). The results indicated that both younger and older adults exhibited a quadratic relationship between neuronal and hemodynamic effects, with reduced increases of the hemodynamic response at high levels of neuronal activity. Although older adults showed reduced activation, similar neurovascular coupling functions were observed in the two age groups when fMRI and deoxy-hemoglobin measures were used. However, the coupling between oxy-and deoxy-hemoglobin changes decreased with age and increased with increasing fitness. These data indicate that departures from linearity in neurovascular coupling may be present when using hemodynamic measures to study neuronal function. PMID:23664952

  4. Pharmacologically-induced neurovascular uncoupling is associated with cognitive impairment in mice.

    PubMed

    Tarantini, Stefano; Hertelendy, Peter; Tucsek, Zsuzsanna; Valcarcel-Ares, M Noa; Smith, Nataliya; Menyhart, Akos; Farkas, Eszter; Hodges, Erik L; Towner, Rheal; Deak, Ferenc; Sonntag, William E; Csiszar, Anna; Ungvari, Zoltan; Toth, Peter

    2015-11-01

    There is increasing evidence that vascular risk factors, including aging, hypertension, diabetes mellitus, and obesity, promote cognitive impairment; however, the underlying mechanisms remain obscure. Cerebral blood flow (CBF) is adjusted to neuronal activity via neurovascular coupling (NVC) and this mechanism is known to be impaired in the aforementioned pathophysiologic conditions. To establish a direct relationship between impaired NVC and cognitive decline, we induced neurovascular uncoupling pharmacologically in mice by inhibiting the synthesis of vasodilator mediators involved in NVC. Treatment of mice with the epoxygenase inhibitor N-(methylsulfonyl)-2-(2-propynyloxy)-benzenehexanamide (MSPPOH), the NO synthase inhibitor l-NG-Nitroarginine methyl ester (L-NAME), and the COX inhibitor indomethacin decreased NVC by over 60% mimicking the aging phenotype, which was associated with significantly impaired spatial working memory (Y-maze), recognition memory (Novel object recognition), and impairment in motor coordination (Rotarod). Blood pressure (tail cuff) and basal cerebral perfusion (arterial spin labeling perfusion MRI) were unaffected. Thus, selective experimental disruption of NVC is associated with significant impairment of cognitive and sensorimotor function, recapitulating neurologic symptoms and signs observed in brain aging and pathophysiologic conditions associated with accelerated cerebromicrovascular aging. PMID:26174328

  5. A Novel In Vitro Model to Study Pericytes in the Neurovascular Unit of the Developing Cortex

    PubMed Central

    Zehendner, Christoph M.; Wedler, Hannah E.; Luhmann, Heiko J.

    2013-01-01

    Cortical function is impaired in various disorders of the central nervous system including Alzheimer’s disease, autism and schizophrenia. Some of these disorders are speculated to be associated with insults in early brain development. Pericytes have been shown to regulate neurovascular integrity in development, health and disease. Hence, precisely controlled mechanisms must have evolved in evolution to operate pericyte proliferation, repair and cell fate within the neurovascular unit (NVU). It is well established that pericyte deficiency leads to NVU injury resulting in cognitive decline and neuroinflammation in cortical layers. However, little is known about the role of pericytes in pathophysiological processes of the developing cortex. Here we introduce an in vitro model that enables to precisely study pericytes in the immature cortex and show that moderate inflammation and hypoxia result in caspase-3 mediated pericyte loss. Using heterozygous EYFP-NG2 mouse mutants we performed live imaging of pericytes for several days in vitro. In addition we show that pericytes maintain their capacity to proliferate which may allow cell-based therapies like reprogramming of pericytes into induced neuronal cells in the presented approach. PMID:24278454

  6. Chronic Inflammatory Demyelinating Polyneuropathy

    PubMed Central

    Dimachkie, Mazen M.; Barohn, Richard J.

    2014-01-01

    Opinion statement Chronic Inflammatory polyneuropathies are an important group of neuromuscular disorders that present chronically and progress over more than 8 weeks, being referred to as chronic inflammatory demyelinating polyneuropathy (CIDP). Despite tremendous progress in elucidating disease pathogenesis, the exact triggering event remains unknown. Our knowledge regarding diagnosis and management of CIDP and its variants continues to expand, resulting in improved opportunities for identification and treatment. Most clinical neurologists will be involved in the management of patients with these disorders, and should be familiar with available therapies for CIDP. We review the distinctive clinical, laboratory, and electro-diagnostic features that aid in diagnosis. We emphasize the importance of clinical patterns that define treatment responsiveness and the most appropriate therapies in order to improve prognosis. PMID:23564314

  7. Prostacyclin: An Inflammatory Paradox

    PubMed Central

    Stitham, Jeremiah; Midgett, Charles; Martin, Kathleen A.; Hwa, John

    2011-01-01

    Prostacyclin (PGI2) is a member of the prostaglandin family of bioactive lipids. Its best-characterized role is in the cardiovascular system, where it is released by vascular endothelial cells, serving as a potent vasodilator and inhibitor of platelet aggregation. In recent years, prostacyclin (PGI2) has also been shown to promote differentiation and inhibit proliferation in vascular smooth muscle cells. In addition to these well-described homeostatic roles within the cardiovascular system, prostacyclin (PGI2) also plays an important role as an inflammatory mediator. In this review, we focus on the contribution of prostacyclin (PGI2) as both a pathophysiological mediator and therapeutic agent in three major inflammatory-mediated disease processes, namely rheumatoid arthritis, where it promotes disease progression (“pro-inflammatory”), along with pulmonary vascular disease and atherosclerosis, where it inhibits disease progression (“anti-inflammatory”). The emerging role of prostacyclin (PGI2) in this context provides new opportunities for understanding the complex molecular basis for inflammatory-related diseases, and insights into the development of current and future anti-inflammatory treatments. PMID:21687516

  8. Single-Dose and Fractionated Irradiation Promote Initiation and Progression of Atherosclerosis and Induce an Inflammatory Plaque Phenotype in ApoE{sup -/-} Mice

    SciTech Connect

    Hoving, Saske; Heeneman, Sylvia; Gijbels, Marion J.J.; Poele, Johannes A.M. te; Russell, Nicola S.; Daemen, Mat J.A.P.; Stewart, Fiona A.

    2008-07-01

    Purpose: Increased risk of atherosclerosis and stroke has been demonstrated in patients receiving radiotherapy for Hodgkin's lymphoma and head-and-neck cancer. We previously showed that 14 Gy to the carotid arteries of hypercholesterolemic ApoE{sup -/-} mice resulted in accelerated development of macrophage-rich, inflammatory atherosclerotic lesions. Here we investigate whether clinically relevant fractionated irradiation schedules and lower single doses also predispose to an inflammatory plaque phenotype. Methods and Materials: ApoE{sup -/-} mice were given 8 or 14 Gy, or 20 x 2.0 Gy in 4 weeks to the neck, and the carotid arteries were subsequently examinated for presence of atherosclerotic lesions, plaque size, and phenotype. Results: At 4 weeks, early atherosclerotic lesions were found in 44% of the mice after single doses of 14 Gy but not in age-matched controls. At 22 to 30 weeks after irradiation there was a twofold increase in the mean number of carotid lesions (8-14 Gy and 20 x 2.0 Gy) and total plaque burden (single doses only), compared with age-matched controls. The majority of lesions seen at 30 to 34 weeks after fractionated irradiation or 14-Gy single doses were granulocyte rich (100% and 63%, respectively), with thrombotic features (90% and 88%), whereas these phenotypes were much less common in age-matched controls or after a single dose of 8 Gy. Conclusions: We showed that fractionated irradiation accelerated the development of atherosclerosis in ApoE{sup -/-} mice and predisposed to the formation of an inflammatory, thrombotic plaque phenotype.

  9. Neurovascular dysfunction, inflammation and endothelial activation: Implications for the pathogenesis of Alzheimer's disease

    PubMed Central

    2011-01-01

    Alzheimer's disease (AD) is an age-related disorder characterized by progressive cognitive decline and dementia. Alzheimer's disease is an increasingly prevalent disease with 5.3 million people in the United States currently affected. This number is a 10 percent increase from previous estimates and is projected to sharply increase to 8 million by 2030; it is the sixth-leading cause of death. In the United States the direct and indirect costs of Alzheimer's and other dementias to Medicare, Medicaid and businesses amount to more than $172 billion each year. Despite intense research efforts, effective disease-modifying therapies for this devastating disease remain elusive. At present, the few agents that are FDA-approved for the treatment of AD have demonstrated only modest effects in modifying clinical symptoms for relatively short periods and none has shown a clear effect on disease progression. New therapeutic approaches are desperately needed. Although the idea that vascular defects are present in AD and may be important in disease pathogenesis was suggested over 25 years ago, little work has focused on an active role for cerebrovascular mechanisms in the pathogenesis of AD. Nevertheless, increasing literature supports a vascular-neuronal axis in AD as shared risk factors for both AD and atherosclerotic cardiovascular disease implicate vascular mechanisms in the development and/or progression of AD. Also, chronic inflammation is closely associated with cardiovascular disease, as well as a broad spectrum of neurodegenerative diseases of aging including AD. In this review we summarize data regarding, cardiovascular risk factors and vascular abnormalities, neuro- and vascular-inflammation, and brain endothelial dysfunction in AD. We conclude that the endothelial interface, a highly synthetic bioreactor that produces a large number of soluble factors, is functionally altered in AD and contributes to a noxious CNS milieu by releasing inflammatory and neurotoxic species

  10. Anatomy of Mandibular Vital Structures. Part I: Mandibular Canal and Inferior Alveolar Neurovascular Bundle in Relation with Dental Implantology

    PubMed Central

    Wang, Hom-Lay; Sabalys, Gintautas

    2010-01-01

    ABSTRACT Objectives It is critical to determine the location and configuration of the mandibular canal and related vital structures during the implant treatment. The purpose of the present study was to review the literature concerning the mandibular canal and inferior alveolar neurovascular bundle anatomical variations related to the implant surgery. Material and Methods Literature was selected through the search of PubMed, Embase and Cochrane electronic databases. The keywords used for search were mandibular canal, inferior alveolar nerve, and inferior alveolar neurovascular bundle. The search was restricted to English language articles, published from 1973 to November 2009. Additionally, a manual search in the major anatomy, dental implant, prosthetic and periodontal journals and books were performed. Results In total, 46 literature sources were obtained and morphological aspects and variations of the anatomy related to implant treatment in posterior mandible were presented as two entities: intraosseous mandibular canal and associated inferior alveolar neurovascular bundle. Conclusions A review of morphological aspects and variations of the anatomy related to mandibular canal and mandibular vital structures are very important especially in implant therapy since inferior alveolar neurovascular bundle exists in different locations and possesses many variations. Individual, gender, age, race, assessing technique used and degree of edentulous alveolar bone atrophy largely influence these variations. It suggests that osteotomies in implant dentistry should not be developed in the posterior mandible until the position of the mandibular canal is established. PMID:24421958

  11. Protective effects of activated protein C on neurovascular unit in a rat model of intrauterine infection-induced neonatal white matter injury.

    PubMed

    Jin, Sheng-juan; Liu, Yan; Deng, Shi-hua; Lin, Tu-lian; Rashid, Abid; Liao, Li-hong; Ning, Qin; Luo, Xiao-ping

    2015-12-01

    Activated protein C (APC), a natural anticoagulant, has been reported to exert direct vasculoprotective, neural protective, anti-inflammatory, and proneurogenic activities in the central nervous system. This study was aimed to explore the neuroprotective effects and potential mechanisms of APC on the neurovascular unit of neonatal rats with intrauterine infection-induced white matter injury. Intraperitoneal injection of 300 μg/kg lipopolysaccharide (LPS) was administered consecutively to pregnant Sprague-Dawley rats at embryonic days 19 and 20 to establish the rat model of intrauterine infection- induced white matter injury. Control rats were injected with an equivalent amount of sterile saline on the same time. APC at the dosage of 0.2 mg/kg was intraperitoneally injected to neonatal rats immediately after birth. Brain tissues were collected at postnatal day 7 and stained with hematoxylin and eosin (H&E). Immunohistochemistry was used to evaluate myelin basic protein (MBP) expression in the periventricular white matter region. Blood-brain barrier (BBB) permeability and brain water content were measured using Evens Blue dye and wet/dry weight method. Double immunofluorescence staining and real-time quantitative PCR were performed to detect microglial activation and the expression of protease activated receptor 1 (PAR1). Typical pathological changes of white matter injury were observed in rat brains exposed to LPS, and MBP expression in the periventricular region was significantly decreased. BBB was disrupted and the brain water content was increased. Microglia were largely activated and the mRNA and protein levels of PAR1 were elevated. APC administration ameliorated the pathological lesions of the white matter and increased MBP expression. BBB permeability and brain water content were reduced. Microglia activation was inhibited and the PAR1 mRNA and protein expression levels were both down-regulated. Our results suggested that APC exerted neuroprotective effects

  12. Progression of luminal breast tumors is promoted by ménage à trois between the inflammatory cytokine TNFα and the hormonal and growth-supporting arms of the tumor microenvironment.

    PubMed

    Weitzenfeld, Polina; Meron, Nurit; Leibovich-Rivkin, Tal; Meshel, Tsipi; Ben-Baruch, Adit

    2013-01-01

    Breast cancer progression is strongly linked to inflammatory processes, aggravating disease course. The impacts of the inflammatory cytokine TNF α on breast malignancy are not fully substantiated, and they may be affected by cooperativity between TNF α and other protumoral mediators. Here, we show that together with representatives of other important arms of the tumor microenvironment, estrogen (hormonal) and EGF (growth-supporting), TNF α potently induced metastasis-related properties and functions in luminal breast tumor cells, representing the most common type of breast cancer. Jointly, TNFα + Estrogen + EGF had a stronger effect on breast cancer cells than each element alone, leading to the following: (1) extensive cell spreading and formation of FAK/paxillin-enriched cellular protrusions; (2) elevated proportion of tumor cells coexpressing high levels of CD44 and β 1 and VLA6; (3) EMT and cell migration; (4) resistance to chemotherapy; (5) release of protumoral factors (CXCL8, CCL2, MMPs). Importantly, the tumor cells used in this study are known to be nonmetastatic under all conditions; nevertheless, they have acquired high metastasizing abilities in vivo in mice, following a brief stimulation by TNFα + Estrogen + EGF. These dramatic findings indicate that TNF α can turn into a strong prometastatic factor, suggesting a paradigm shift in which clinically approved inhibitors of TNFα would be applied in breast cancer therapy. PMID:24369447

  13. A Neurovascular Perspective for Long-Term Changes After Brain Trauma

    PubMed Central

    Pop, V.; Badaut, J.

    2012-01-01

    Traumatic brain injury (TBI) affects all age groups in a population and is an injury generating scientific interest not only as an acute event, but also as a complex brain disease with several underlying neurobehavioral and neuropathological characteristics. We review early and long-term alterations after juvenile and adult TBI with a focus on changes in the neurovascular unit (NVU), including neuronal interactions with glia and blood vessels at the blood-brain barrier (BBB). Post-traumatic changes in cerebral blood-flow, BBB structures and function, as well as mechanistic pathways associated with brain aging and neurodegeneration are presented from clinical and experimental reports. Based on the literature, increased attention on BBB changes should be integrated in studies characterizing TBI outcome and may provide a meaningful therapeutic target to resolve detrimental post-traumatic dysfunction. PMID:22350620

  14. Development and pathological changes of neurovascular unit regulated by hypoxia response in the retina.

    PubMed

    Kurihara, T

    2016-01-01

    Retina is a highly vascularized tissue with a high oxygen and metabolic demand receiving light located in the back of the eye. The development and the maintenance of the retinal vasculature are important to regulate the homeostasis in the tissue. α Subunits of hypoxia-inducible factor (HIF) are key molecules in hypoxia response inducing genes required for cell survival such as vascular endothelial growth factor under hypoxia. Neurons, glia, and vascular endothelium cells interdependently form neurovascular unit in the retina tightly regulated by hypoxia response via HIF expression. A corruption of the precise hypoxia response in the developmental or matured retinal tissue may lead congenital vascular anomalies or adult neovascular ocular diseases. To regulate hypoxia response through HIF activity would be an ideal therapeutic target for these vision-threatening eye diseases. PMID:27130417

  15. Computational and Pharmacological Target of Neurovascular Unit for Drug Design and Delivery

    PubMed Central

    Islam, Md. Mirazul; Mohamed, Zahurin

    2015-01-01

    The blood-brain barrier (BBB) is a dynamic and highly selective permeable interface between central nervous system (CNS) and periphery that regulates the brain homeostasis. Increasing evidences of neurological disorders and restricted drug delivery process in brain make BBB as special target for further study. At present, neurovascular unit (NVU) is a great interest and highlighted topic of pharmaceutical companies for CNS drug design and delivery approaches. Some recent advancement of pharmacology and computational biology makes it convenient to develop drugs within limited time and affordable cost. In this review, we briefly introduce current understanding of the NVU, including molecular and cellular composition, physiology, and regulatory function. We also discuss the recent technology and interaction of pharmacogenomics and bioinformatics for drug design and step towards personalized medicine. Additionally, we develop gene network due to understand NVU associated transporter proteins interactions that might be effective for understanding aetiology of neurological disorders and new target base protective therapies development and delivery. PMID:26579539

  16. Investigating Human Neurovascular Coupling Using Functional Neuroimaging: A Critical Review of Dynamic Models

    PubMed Central

    Huneau, Clément; Benali, Habib; Chabriat, Hugues

    2015-01-01

    The mechanisms that link a transient neural activity to the corresponding increase of cerebral blood flow (CBF) are termed neurovascular coupling (NVC). They are possibly impaired at early stages of small vessel or neurodegenerative diseases. Investigation of NVC in humans has been made possible with the development of various neuroimaging techniques based on variations of local hemodynamics during neural activity. Specific dynamic models are currently used for interpreting these data that can include biophysical parameters related to NVC. After a brief review of the current knowledge about possible mechanisms acting in NVC we selected seven models with explicit integration of NVC found in the literature. All these models were described using the same procedure. We compared their physiological assumptions, mathematical formalism, and validation. In particular, we pointed out their strong differences in terms of complexity. Finally, we discussed their validity and their potential applications. These models may provide key information to investigate various aspects of NVC in human pathology. PMID:26733782

  17. Hemostatic hydrodissection of the neurovascular bundles during robotic assisted laparoscopic radical prostatectomy: safety and efficacy trial

    NASA Astrophysics Data System (ADS)

    Parekattil, Sijo J.; Dahm, Philipp; Vieweg, Johannes W.

    2009-02-01

    Preservation of continence and potency after Robotic Assisted Laparoscopic Radical Prostatectomy (RALP) are two key outcome measures that patients consider when comparing different treatment options for localized prostate cancer. Ensuring that positive surgical margins are as low as possible provides oncologic control. Various techniques to optimize these outcomes have been employed. This study presents the early outcomes for Hemostatic Hydrodissection of the Neurovascular Bundles during 86 consecutive RALPs. Positive margin rates were 12.5% overall (9% for pT2 and 28.6% for pT3); continence at 6 months was 100%, at 3 months 90% and at 1 month 66%. In patients with no preoperative erectile dysfunction (preoperative SHIM of 25), 79% had return of erections sufficient for intercourse by 6 months. 2 of these patients were able to have intercourse 2 weeks after surgery. These preliminary findings appear promising.

  18. Correlation of histomorphologic findings and partial neurovascular bundle preservation during laparoscopic and robotic radical prostatectomy.

    PubMed

    Andino, Lizmarie; Davis, John W; Wei, Wei; Prokhorova, Ina N; Troncoso, Patricia; Matin, Surena F

    2013-03-01

    The objective of this work was to compare the amount of residual periprostatic tissue for radical prostatectomy performed by the partial NS (PNS) technique with that performed by the nerve-sparing (NS) or wide-resection (WR) techniques. Retrospective histomorphologic evaluation of radical prostatectomy specimens (RPSs) from patients undergoing laparoscopic radical prostatectomy (LRP) or robot-assisted radical prostatectomy (RARP) was performed. The posterolateral regions corresponding to the neurovascular bundle in RPSs from 48 patients who had undergone NS, PNS, or WR during LRP (n = 30) or RARP (n = 18) were examined by two pathologists unaware of the technique used. The RPSs were evaluated at the base, mid-gland, and apex. The amount of periprostatic tissue at each site was recorded. Measurements were analyzed by use of a linear mixed model. For both LRP and RARP, each gradation of nerve-preservation was associated with periprostatic tissue, except PNS and WR did not differ for LRP at the apex and base or for RARP at the apex, mid-gland, and base. For LRP, a greater amount of tissue was on the left side of the prostate than on the right at the mid-gland level (P = 0.004) whereas for RARP the opposite was found (P = 0.024). Of 18 separate analyses, 13 were significantly associated. The study is limited by its retrospective design. The amount of periprostatic tissue in the neurovascular bundle area correlates well with the nerve-preservation approach used during LRP and RARP, providing anatomic evidence supporting the PNS approach. We also describe a novel finding of laterality bias at the mid-gland level in LRP and RARP specimens. PMID:27000885

  19. Mechanistic Mathematical Modeling Tests Hypotheses of the Neurovascular Coupling in fMRI

    PubMed Central

    Lundengård, Karin; Cedersund, Gunnar; Sten, Sebastian; Leong, Felix; Smedberg, Alexander; Elinder, Fredrik

    2016-01-01

    Functional magnetic resonance imaging (fMRI) measures brain activity by detecting the blood-oxygen-level dependent (BOLD) response to neural activity. The BOLD response depends on the neurovascular coupling, which connects cerebral blood flow, cerebral blood volume, and deoxyhemoglobin level to neuronal activity. The exact mechanisms behind this neurovascular coupling are not yet fully investigated. There are at least three different ways in which these mechanisms are being discussed. Firstly, mathematical models involving the so-called Balloon model describes the relation between oxygen metabolism, cerebral blood volume, and cerebral blood flow. However, the Balloon model does not describe cellular and biochemical mechanisms. Secondly, the metabolic feedback hypothesis, which is based on experimental findings on metabolism associated with brain activation, and thirdly, the neurotransmitter feed-forward hypothesis which describes intracellular pathways leading to vasoactive substance release. Both the metabolic feedback and the neurotransmitter feed-forward hypotheses have been extensively studied, but only experimentally. These two hypotheses have never been implemented as mathematical models. Here we investigate these two hypotheses by mechanistic mathematical modeling using a systems biology approach; these methods have been used in biological research for many years but never been applied to the BOLD response in fMRI. In the current work, model structures describing the metabolic feedback and the neurotransmitter feed-forward hypotheses were applied to measured BOLD responses in the visual cortex of 12 healthy volunteers. Evaluating each hypothesis separately shows that neither hypothesis alone can describe the data in a biologically plausible way. However, by adding metabolism to the neurotransmitter feed-forward model structure, we obtained a new model structure which is able to fit the estimation data and successfully predict new, independent validation data

  20. Effects of natural free radical scavengers on peripheral nerve and neurovascular function in diabetic rats.

    PubMed

    Cotter, M A; Love, A; Watt, M J; Cameron, N E; Dines, K C

    1995-11-01

    Increased generation of reactive oxygen species, coupled with impaired endogenous scavenging mechanisms, plays a prominent role in the aetiology of neurovascular abnormalities in experimental diabetes mellitus. We examined the efficacy of the natural anti-oxidants vitamins C, E and beta-carotene in preventing nerve conduction and nutritive blood flow deficits in streptozotocin-diabetic rats. One month of diabetes caused a 19.1% reduction in sciatic motor conduction velocity (p < 0.001). This was approximately prevented 80-90% by high-dose (1000 mg.kg-1.day-1) vitamin E and beta-carotene treatments (p < 0.001). Vitamin C had lesser effects; the maximum protection found for motor conduction velocity was 36% using a dose of 150 mg.kg-1.day-1 (p < 0.001). High dose (500 mg.kg-1.day-1 (p < 0.001). High dose (500 mg.kg-1.day-1) vitamin C had a lesser effect on conduction than intermediate doses. Joint vitamin C and lower dose (500 mg.kg-1.day-1) vitamin E treatment had a predominantly additive preventive effect against nerve dysfunction. Resistance to hypoxic conduction failure for sciatic nerve in vitro was markedly increased by diabetes and this remained relatively unaffected by treatment. Sciatic nutritive endoneurial blood flow, measured using microelectrode polarography and hydrogen clearance, was reduced 46.1% by 1 month of diabetes (p < 0.001). This was prevented to the extent of 87%, 36% and 98% by vitamins E, C and beta-carotene, respectively (p < 0.01). These data emphasize the role of oxidative stress in the development of early neurovascular changes in experimental diabetes and show that naturally available scavengers have a neuroprotective action. PMID:8582537

  1. Sensitivity evaluation of DSA-based parametric imaging using Doppler ultrasound in neurovascular phantoms

    NASA Astrophysics Data System (ADS)

    Balasubramoniam, A.; Bednarek, D. R.; Rudin, S.; Ionita, C. N.

    2016-03-01

    An evaluation of the relation between parametric imaging results obtained from Digital Subtraction Angiography (DSA) images and blood-flow velocity measured using Doppler ultrasound in patient-specific neurovascular phantoms is provided. A silicone neurovascular phantom containing internal carotid artery, middle cerebral artery and anterior communicating artery was embedded in a tissue equivalent gel. The gel prevented movement of the vessels when blood mimicking fluid was pumped through it to obtain Colour Doppler images. The phantom was connected to a peristaltic pump, simulating physiological flow conditions. To obtain the parametric images, water was pumped through the phantom at various flow rates (100, 120 and 160 ml/min) and 10 ml contrast boluses were injected. DSA images were obtained at 10 frames/sec from the Toshiba C-arm and DSA image sequences were input into LabVIEW software to get parametric maps from time-density curves. The parametric maps were compared with velocities determined by Doppler ultrasound at the internal carotid artery. The velocities measured by the Doppler ultrasound were 38, 48 and 65 cm/s for flow rates of 100, 120 and 160 ml/min, respectively. For the 20% increase in flow rate, the percentage change of blood velocity measured by Doppler ultrasound was 26.3%. Correspondingly, there was a 20% decrease of Bolus Arrival Time (BAT) and 14.3% decrease of Mean Transit Time (MTT), showing strong inverse correlation with Doppler measured velocity. The parametric imaging parameters are quite sensitive to velocity changes and are well correlated to the velocities measured by Doppler ultrasound.

  2. Mechanistic Mathematical Modeling Tests Hypotheses of the Neurovascular Coupling in fMRI.

    PubMed

    Lundengård, Karin; Cedersund, Gunnar; Sten, Sebastian; Leong, Felix; Smedberg, Alexander; Elinder, Fredrik; Engström, Maria

    2016-06-01

    Functional magnetic resonance imaging (fMRI) measures brain activity by detecting the blood-oxygen-level dependent (BOLD) response to neural activity. The BOLD response depends on the neurovascular coupling, which connects cerebral blood flow, cerebral blood volume, and deoxyhemoglobin level to neuronal activity. The exact mechanisms behind this neurovascular coupling are not yet fully investigated. There are at least three different ways in which these mechanisms are being discussed. Firstly, mathematical models involving the so-called Balloon model describes the relation between oxygen metabolism, cerebral blood volume, and cerebral blood flow. However, the Balloon model does not describe cellular and biochemical mechanisms. Secondly, the metabolic feedback hypothesis, which is based on experimental findings on metabolism associated with brain activation, and thirdly, the neurotransmitter feed-forward hypothesis which describes intracellular pathways leading to vasoactive substance release. Both the metabolic feedback and the neurotransmitter feed-forward hypotheses have been extensively studied, but only experimentally. These two hypotheses have never been implemented as mathematical models. Here we investigate these two hypotheses by mechanistic mathematical modeling using a systems biology approach; these methods have been used in biological research for many years but never been applied to the BOLD response in fMRI. In the current work, model structures describing the metabolic feedback and the neurotransmitter feed-forward hypotheses were applied to measured BOLD responses in the visual cortex of 12 healthy volunteers. Evaluating each hypothesis separately shows that neither hypothesis alone can describe the data in a biologically plausible way. However, by adding metabolism to the neurotransmitter feed-forward model structure, we obtained a new model structure which is able to fit the estimation data and successfully predict new, independent validation data

  3. Acute two-photon imaging of the neurovascular unit in the cortex of active mice

    PubMed Central

    Tran, Cam Ha T.; Gordon, Grant R.

    2015-01-01

    In vivo two-photon scanning fluorescence imaging is a powerful technique to observe physiological processes from the millimeter to the micron scale in the intact animal. In neuroscience research, a common approach is to install an acute cranial window and head bar to explore neocortical function under anesthesia before inflammation peaks from the surgery. However, there are few detailed acute protocols for head-restrained and fully awake animal imaging of the neurovascular unit during activity. This is because acutely performed awake experiments are typically untenable when the animal is naïve to the imaging apparatus. Here we detail a method that achieves acute, deep-tissue two-photon imaging of neocortical astrocytes and microvasculature in behaving mice. A week prior to experimentation, implantation of the head bar alone allows mice to train for head-immobilization on an easy-to-learn air-supported ball treadmill. Following just two brief familiarization sessions to the treadmill on separate days, an acute cranial window can subsequently be installed for immediate imaging. We demonstrate how running and whisking data can be captured simultaneously with two-photon fluorescence signals with acceptable movement artifacts during active motion. We also show possible applications of this technique by (1) monitoring dynamic changes to microvascular diameter and red blood cells in response to vibrissa sensory stimulation, (2) examining responses of the cerebral microcirculation to the systemic delivery of pharmacological agents using a tail artery cannula during awake imaging, and (3) measuring Ca2+ signals from synthetic and genetically encoded Ca2+ indicators in astrocytes. This method will facilitate acute two-photon fluorescence imaging in awake, active mice and help link cellular events within the neurovascular unit to behavior. PMID:25698926

  4. Morroniside Improves Microvascular Functional Integrity of the Neurovascular Unit after Cerebral Ischemia

    PubMed Central

    Sun, Fang-Ling; Cheng, Hua; Wang, Ying; Li, Lei; Xue, Jin-Long; Wang, Xiao-feng; Ai, Hou-Xi; Zhang, Li; Xu, Jing-dong

    2014-01-01

    Treating the vascular elements within the neurovascular unit is essential for protecting and repairing the brain after stroke. Acute injury on endothelial systems results in the disruption of blood-brain barrier (BBB), while post-ischemic angiogenesis plays an important role in delayed functional recovery. Here, we considered alterations in microvessel integrity to be targets for brain recovery, and tested the natural compound morroniside as a therapeutic approach to restore the vascular elements of injured tissue in a rat model of focal cerebral ischemia. Sprague-Dawley rats were subjected to middle cerebral artery occlusion (MCAO) model, and morroniside was then administered intragastrically once a day at doses of 30, 90, and 270 mg/kg. BBB integrity and associated factors were analyzed to identify cerebrovascular permeability 3 days after MCAO. The recruitment of endothelial progenitor cells (EPCs), the expression of angiogenic factors and the new vessel formation in the peri-infarct cortex of rats were examined 7 days after MCAO to identify the angiogenesis. We demonstrated that at 3 days post-ischemia, morroniside preserved neurovascular unit function by ameliorating BBB injury. By 7 days post-ischemia, morroniside amplified angiogenesis, in part by enhancing endothelial progenitor cell proliferation and expression of angiogenic factors. Morever, the increase in the amount of vWF+ vessels induced by ischemia could be extended to 28 days after administration of morroniside, indicating the crucial role of morroniside in angiogenesis during the chronic phase. Taken together, our findings suggested that morroniside might offer a novel therapeutic approach for promoting microvascular integrity recovery and provide a thoroughly new direction for stroke therapy. PMID:24979385

  5. Three-Dimensional Visualization of Developing Neurovascular Architecture in the Craniofacial Region of Embryonic Mice.

    PubMed

    Sugimoto, Toshiaki; Taya, Yuji; Shimazu, Yoshihito; Soeno, Yuuichi; Sato, Kaori; Aoba, Takaaki

    2015-11-01

    Recent studies have highlighted the mechanism of vascular and axonal guidance to ensure proper morphogenesis and organogenesis. We aimed to perform global mapping of developing neurovascular networks during craniofacial development of embryonic mice. To this end, we developed histology-based three-dimensional (3D) reconstructions using paraffin-embedded serial sections obtained from mouse embryos. All serial sections were dual-immunolabeled with Pecam1 and Pgp9.5/Gap43 cocktail antibodies. All immunolabeled serial sections were digitized with virtual microscopy to acquire high spatial resolution images. The 3D reconstructs warranted superior positional accuracy to trace the long-range connectivity of blood vessels and individual cranial nerve axons. It was feasible to depict simultaneously the details of angiogenic sprouting and axon terminal arborization and to assess quantitatively the locoregional proximity between blood vessels and cranial nerve axons. Notably, 3D views of the craniofacial region revealed the following: Branchial arch arteries and blood capillary plexi were formed without accompanying nerves at embryonic day (E) 9.5. Cranial nerve axons began to grow into the branchial arches, developing a labyrinth of small blood vessels at E10.5. Vascular remodeling occurred, and axon terminals of the maxillary, mandibular, chorda tympani, and hypoglossal nerve axons had arborized around the lateral lingual swellings at E11.5. The diverged patterning of trigeminal nerves and the arterial branches from the carotid artery became congruent at E11.5. The overall results support the advantage of dual-immunolabeling and 3D reconstruction technology to document the architecture and wiring of the developing neurovascular networks in mouse embryos. PMID:26054056

  6. Developmental Switch in Neurovascular Coupling in the Immature Rodent Barrel Cortex

    PubMed Central

    Zehendner, Christoph M.; Tsohataridis, Simeon; Luhmann, Heiko J.; Yang, Jenq-Wei

    2013-01-01

    Neurovascular coupling (NVC) in the adult central nervous system (CNS) is a mechanism that provides regions of the brain with more oxygen and glucose upon increased levels of neural activation. Hemodynamic changes that go along with neural activation evoke a blood oxygen level-dependent (BOLD) signal in functional magnetic resonance imaging (fMRI) that can be used to study brain activity non-invasively. A correct correlation of the BOLD signal to neural activity is pivotal to understand this signal in neuronal development, health and disease. However, the function of NVC during development is largely unknown. The rodent whisker-to-barrel cortex is an experimentally well established model to study neurovascular interdependences. Using extracellular multi-electrode recordings and laser-Doppler-flowmetry (LDF) we show in the murine barrel cortex of postnatal day 7 (P7) and P30 mice in vivo that NVC undergoes a physiological shift during the first month of life. In the mature CNS it is well accepted that cortical sensory processing results in a rise in regional cerebral blood flow (rCBF). We show in P7 animals that rCBF decreases during prolonged multi-whisker stimulation and goes along with multi unit activity (MUA) fatigue. In contrast at P30, MUA remains stable during repetitive stimulation and is associated with an increase in rCBF. Further we characterize in both age groups the responses in NVC to single sensory stimuli. We suggest that the observed shift in NVC is an important process in cortical development that may be of high relevance for the correct interpretation of brain activity e.g. in fMRI studies of the immature central nervous system (CNS). PMID:24224059

  7. Hydrogen sulfide mitigates matrix metalloproteinase-9 activity and neurovascular permeability in hyperhomocysteinemic mice*

    PubMed Central

    Tyagi, Neetu; Givvimani, Srikanth; Qipshidze, Natia; Kundu, Soumi; Kapoor, Shray; Vacek, Jonathan C.; Tyagi, Suresh C.

    2010-01-01

    An elevated level of homocysteine (Hcy), known as hyperhomocysteinmia (HHcy), was associated with neurovascular diseases. At physiological levels, hydrogen sulfide (H2S) protected the neurovascular system. Because Hcy was also a precursor of hydrogen sulfide (H2S), we sought to test whether the H2S protected the brain during HHcy. Cystathionine-β-synthase heterozygous (CBS+/−) and wild type (WT) mice were supplemented with or without NaHS (30 µM/L, H2S donor) in drinking water. Blood flow and cerebral microvascular permeability in pial vessels were measured by intravital microscopy in WT, WT+NaHS, CBS−/+ and CBS−/+ + NaHS treated mice. The brain tissues were analyzed for matrix metalloproteinase (MMP) and tissue inhibitor of metalloproteinase (TIMP) by Western blot and RT-PCR. The mRNA levels of CBS and cystathionine gamma lyase (CSE, enzyme responsible for conversion of Hcy to H2S) genes were measured by RT-PCR. The results showed a significant increase in MMP-2, MMP-9, TIMP-3 protein and mRNA in CBS (−/+) mice, while H2S treatment mitigated this increase. Interstitial localization of MMPs was also apparent through Immunohistochemistry. A decrease in protein and mRNA expression of TIMP-4 was observed in CBS (−/+) mice. Microscopy data revealed increase in permeability in CBS (−/+) mice. These effects were ameliorated by H2S and suggested that physiological levels of H2S supplementation may have therapeutic potential against HHcy-induced microvascular permeability, in part, by normalizing the MMP/TIMP ratio in the brain. PMID:19913585

  8. Blood circulating microparticle species in relapsing–remitting and secondary progressive multiple sclerosis. A case–control, cross sectional study with conventional MRI and advanced iron content imaging outcomes

    PubMed Central

    Alexander, J.S.; Chervenak, R.; Weinstock-Guttman, B.; Tsunoda, I.; Ramanathan, M.; Martinez, N.E.; Omura, S.; Sato, F.; Chaitanya, G.V.; Minagar, A.; McGee, J.; Jennings, M.H.; Monceaux, C.; Becker, F.; Cvek, U.; Trutschl, M.; Zivadinov, R.

    2015-01-01

    Background Although multiple sclerosis (MS) is thought to represent an excessive and inappropriate immune response to several central nervous system (CNS) autoantigens, increasing evidence also suggests that MS may also be a neurovascular inflammatory disease, characterized by endothelial activation and shedding of cell membrane microdomains known as ‘microparticles’ into the circulation. Objective To investigate the relationships between these endothelial biomarkers and MS. Methods We examined the relative abundance of CD31+/PECAM-1, CD51+CD61+ (αV–β3) and CD54+ (ICAM-1) bearing microparticles in sera of healthy individuals, patients with relapsing–remitting MS, and secondary-progressive MS. We also investigated the correlation among circulating levels of different microparticle species in MS with conventional MRI (T2- and T1-lesion volumes and brain atrophy), as well as novel MR modalities [assessment of iron content on susceptibility-weighted imaging (SWI)-filtered phase]. Results Differences in circulating microparticle levels were found among MS groups, and several microparticle species (CD31+/CD51+/CD61+/CD54+) were found to correlate with conventional MRI and SWI features of MS. Conclusion These results indicate that circulating microparticles’ profiles in MS may support mechanistic roles for microvascular stress and injury which is an underlying contributor not only to MS initiation and progression, but also to pro-inflammatory responses. PMID:26073484

  9. Combined inhibition of PDE4 and PI3Kδ modulates the inflammatory component involved in the progression of chronic obstructive pulmonary disease.

    PubMed

    Dinavahi, S S; Nyayapathy, S; Perumal, Y; Dharmarajan, S; Viswanadha, S

    2014-04-01

    Chronic Obstructive Pulmonary Disease (COPD) represents a group of disorders with several underlying causes that hamper airflow into the lungs. Despite current intervention therapies, COPD remains a disease with a significant unmet medical need. Treatment with Phosphodiesterase (PDE) 4 inhibitors results in modest efficacy at clinically relevant doses. The objective of the current study is to evaluate the combination of a PDE4 (Roflumilast) and a Phosphoinositide-3-kinase (PI3K) δ (IC87114) inhibitor for their therapeutic potential in diminishing the inflammatory response associated with COPD. Due to their divergent and independent pathways, we hypothesize that the combination would be efficacious at low concentrations in an in vitro setting. Inhibition of TNFα, pAkt, MMP-9 in differentiated U937 macrophages upon stimulation with LPS/CSE was determined. Neutrophil functionality manifested by a modulation of elastase activity was estimated. Protective effect of drug combination on CSE induced apoptosis of lung epithelial cells was also determined. Data demonstrated that the combination of Roflumilast and IC87114 reduced TNFα, pAkt and MMP-9 at nanomolar concentrations and was several fold potent than either of the compounds alone. Inhibition of neutrophil elastase was also increased significantly with the combination along with a better protection against CSE induced apoptosis in alveolar epithelial cells, thereby providing a rationale for their evaluation in COPD patients. PMID:24105104

  10. Skimmin, a Coumarin from Hydrangea paniculata, Slows down the Progression of Membranous Glomerulonephritis by Anti-Inflammatory Effects and Inhibiting Immune Complex Deposition

    PubMed Central

    Xin, Hongqi; Li, Yan; Zhang, Dongming; Shi, Jing; Yang, Jingzhi

    2013-01-01

    Skimmin is one of the major pharmacologically active molecules present in Hydrangea paniculata, a medical herb used in the traditional Chinese medicine as an anti-inflammatory agent. In the current study, we attempted to investigate its renoprotective activity and underlying mechanisms in a rat model of membranous glomerulonephritis induced by cationic bovine serum albumin (c-BSA). Sprague-Dawley (SD) rats were divided into five groups, including normal control, model control, Mycophenolate Mofetil-treated group, and two skimming-treated groups (15 mg/kg and 30 mg/kg). Our research showed that treatment with skimmin significantly reduced the levels of blood urea nitrogen (BUN), urinary albumin excretion (UAE), and serum creatinine (Scr) as compared with model control after experimental induction of membranous glomerulonephritis (P < 0.01). Moreover, glomerular hypercellularity, tubulointerstitial injury, and glomerular deposition of IgG were less intense after skimmin treatment. By immunochemistry analysis, we demonstrated that skimmin could significantly inhibit interleukin-1β (IL1β) and IL-6 expression (P < 0.05), reduce the loss of nephrin and podocin, and suppress the infiltration of renal interstitium by CD3-positive T cell and CD20-positive B cell. These results suggest that treatment with skimmin can significantly improve renal function and suppress the IgG deposition as well as the development of glomerular lesions in a rat model of membranous glomerulonephritis. PMID:23990847

  11. Chronic Trypanosoma cruzi infection potentiates adipose tissue macrophage polarization toward an anti-inflammatory M2 phenotype and contributes to diabetes progression in a diet-induced obesity model

    PubMed Central

    Cabalén, María E.; Cabral, María F.; Sanmarco, Liliana M.; Andrada, Marta C.; Onofrio, Luisina I.; Ponce, Nicolás E.; Aoki, María P.; Gea, Susana; Cano, Roxana C.

    2016-01-01

    Chronic obesity and Chagas disease (caused by the protozoan Trypanosoma cruzi) represent serious public health concerns. The interrelation between parasite infection, adipose tissue, immune system and metabolism in an obesogenic context, has not been entirely explored. A novel diet-induced obesity model (DIO) was developed in C57BL/6 wild type mice to examine the effect of chronic infection (DIO+I) on metabolic parameters and on obesity-related disorders. Dyslipidemia, hyperleptinemia, and cardiac/hepatic steatosis were strongly developed in DIO mice. Strikingly, although these metabolic alterations were collectively improved by infection, plasmatic apoB100 levels remain significantly increased in DIO+I, suggesting the presence of pro-atherogenic small and dense LDL particles. Moreover, acute insulin resistance followed by chronic hyperglycemia with hypoinsulinemia was found, evidencing an infection-related-diabetes progression. These lipid and glucose metabolic changes seemed to be highly dependent on TLR4 expression since TLR4−/− mice were protected from obesity and its complications. Notably, chronic infection promoted a strong increase in MCP-1 producing macrophages with a M2 (F4/80+CD11c-CD206+) phenotype associated to oxidative stress in visceral adipose tissue of DIO+I mice. Importantly, infection reduced lipid content but intensified inflammatory infiltrates in target tissues. Thus, parasite persistence in an obesogenic environment and the resulting host immunometabolic dysregulation may contribute to diabetes/atherosclerosis progression. PMID:26921251

  12. Inflammatory mechanisms of endometritis.

    PubMed

    Woodward, E M; Troedsson, M H T

    2015-07-01

    Transient post breeding endometritis is a normal physiological reaction in the mare, as it is believed that an inflammatory response is necessary for the effective removal of contaminating bacteria and excess spermatozoa introduced into the uterus. While most mares can clear endometritis within a reasonable amount of time, persistent endometritis caused by either bacteria or spermatozoa can threaten the success of a pregnancy. A subpopulation of mares is susceptible to persistent endometritis, and these mares are a concern in equine reproductive medicine. Research has identified several factors that contribute to susceptibility; however, the exact mechanisms of the progression of the disease are still being elucidated. Current research focuses on endometrial gene expression during endometritis in an attempt to understand the timing of specific inflammatory processes involved with the development of susceptibility to persistent endometritis. With an increased understanding of the mechanisms involved with the disease, current treatments can be improved upon, and new treatments can be developed to target affected pathways. PMID:25537084

  13. Eicosanoid Profiling in an Orthotopic Model of Lung Cancer Progression by Mass Spectrometry Demonstrates Selective Production of Leukotrienes by Inflammatory Cells of the Microenvironment

    PubMed Central

    Poczobutt, Joanna M.; Gijon, Miguel; Amin, Jay; Hanson, Dwight; Li, Howard; Walker, Deandra; Weiser-Evans, Mary; Lu, Xian; Murphy, Robert C.; Nemenoff, Raphael A.

    2013-01-01

    Eicosanoids are bioactive lipid mediators derived from arachidonic acid1 (AA), which is released by cytosolic phospholipase A2 (cPLA2). AA is metabolized through three major pathways, cyclooxygenase (COX), lipoxygenase (LO) and cytochrome P450, to produce a family of eicosanoids, which individually have been shown to have pro- or anti-tumorigenic activities in cancer. However, cancer progression likely depends on complex changes in multiple eicosanoids produced by cancer cells and by tumor microenvironment and a systematic examination of the spectrum of eicosanoids in cancer has not been performed. We used liquid chromatography coupled with tandem mass spectrometry (LC/MS/MS) to quantitate eicosanoids produced during lung tumor progression in an orthotopic immunocompetent mouse model of lung cancer, in which Lewis lung carcinoma (LLC) cells are injected into lungs of syngeneic mice. The presence of tumor increased products of both the cyclooxygenase and the lipoxygenase pathways in a time-dependent fashion. Comparing tumors grown in cPLA2 knockout vs wild-type mice, we demonstrated that prostaglandins (PGE2, PGD2 and PGF2a) were produced by both cancer cells and the tumor microenvironment (TME), but leukotriene (LTB4, LTC4, LTD4, LTE4) production required cPLA2 expression in the TME. Using flow cytometry, we recovered tumor-associated neutrophils and 2 types of tumor-associated macrophages from tumor-bearing lungs and we defined their distinct eicosanoid profiles by LC/MS/MS. The combination of flow cytometry and LC/MS/MS unravels the complexity of eicosanoid production in lung cancer and provides a rationale to develop therapeutic strategies that target select cell populations to inhibit specific classes of eicosanoids. PMID:24244531

  14. Microstructural abnormalities of the trigeminal nerve by diffusion-tensor imaging in trigeminal neuralgia without neurovascular compression.

    PubMed

    Neetu, Soni; Sunil, Kumar; Ashish, Awasthi; Jayantee, Kalita; Usha Kant, Misra

    2016-02-01

    Microstructural changes of the trigeminal nerve in trigeminal neuralgia due to neurovascular compression have been reported by using diffusion tensor imaging. Other aetiologies such as primary demyelinating lesions, brain stem infarction and nerve root infiltration by tumour affecting the trigeminal pathway may also present as trigeminal neuralgia. The aim of this study was to evaluate the microstructural tissue abnormalities in the trigeminal nerve in symptomatic trigeminal neuralgia not related to neurovascular compression using diffusion tensor imaging. Mean values of the quantitative diffusion parameters of trigeminal nerve, fractional anisotropy and apparent diffusion coefficient, were measured in a group of four symptomatic trigeminal neuralgia patients without neurovascular compression who showed focal non-enhancing T2-hyperintense lesions in the pontine trigeminal pathway. These diffusion parameters were compared between the affected and unaffected sides in the same patient and with four age-matched healthy controls. Cranial magnetic resonance imaging revealed hyperintense lesions in the dorsolateral part of the pons along the central trigeminal pathway on T2-fluid-attenuated inversion recovery sequences. The mean fractional anisotropy value on the affected side was significantly decreased (P = 0.001) compared to the unaffected side and healthy controls. Similarly, the mean apparent diffusion coefficient value was significantly higher (P = 0.001) on the affected side compared to the unaffected side and healthy controls. The cause of trigeminal neuralgia in our patients was abnormal pontine lesions affecting the central trigeminal pathway. The diffusion tensor imaging results suggest that microstructural tissue abnormalities of the trigeminal nerve also exist even in non-neurovascular compression-related trigeminal neuralgia. PMID:26678753

  15. The absolute CBF response to activation is preserved during elevated perfusion: Implications for neurovascular coupling measures

    PubMed Central

    Whittaker, Joseph R.; Driver, Ian D.; Bright, Molly G.; Murphy, Kevin

    2016-01-01

    Functional magnetic resonance imaging (fMRI) techniques in which the blood oxygenation level dependent (BOLD) and cerebral blood flow (CBF) response to a neural stimulus are measured, can be used to estimate the fractional increase in the cerebral metabolic rate of oxygen consumption (CMRO2) that accompanies evoked neural activity. A measure of neurovascular coupling is obtained from the ratio of fractional CBF and CMRO2 responses, defined as n, with the implicit assumption that relative rather than absolute changes in CBF and CMRO2 adequately characterise the flow-metabolism response to neural activity. The coupling parameter n is important in terms of its effect on the BOLD response, and as potential insight into the flow-metabolism relationship in both normal and pathological brain function. In 10 healthy human subjects, BOLD and CBF responses were measured to test the effect of baseline perfusion (modulated by a hypercapnia challenge) on the coupling parameter n during graded visual stimulation. A dual-echo pulsed arterial spin labelling (PASL) sequence provided absolute quantification of CBF in baseline and active states as well as relative BOLD signal changes, which were used to estimate CMRO2 responses to the graded visual stimulus. The absolute CBF response to the visual stimuli were constant across different baseline CBF levels, meaning the fractional CBF responses were reduced at the hyperperfused baseline state. For the graded visual stimuli, values of n were significantly reduced during hypercapnia induced hyperperfusion. Assuming the evoked neural responses to the visual stimuli are the same for both baseline CBF states, this result has implications for fMRI studies that aim to measure neurovascular coupling using relative changes in CBF. The coupling parameter n is sensitive to baseline CBF, which would confound its interpretation in fMRI studies where there may be significant differences in baseline perfusion between groups. The absolute change in

  16. Neurovascular risks of sacral screws with bicortical purchase: an anatomical study

    PubMed Central

    Ergur, Ipek; Kiray, Amac; Kosay, Can; Tayefi, Hamid

    2007-01-01

    The aim of this cadaver study is to define the anatomic structures on anterior sacrum, which are under the risk of injury during bicortical screw application to the S1 and S2 pedicles. Thirty formaldehyde-preserved human male cadavers were studied. Posterior midline incision was performed, and soft tissues and muscles were dissected from the posterior part of the lumbosacral region. A 6 mm pedicle screw was inserted between the superior facet of S1 and the S1 foramen. The entry point of the S2 pedicle screw was located between S1 and S2 foramina. S1 and S2 screws were placed on both right and the left sides of all cadavers. Then, all cadavers were turned into supine position. All abdominal and pelvic organs were moved away and carefully observed for any injury. The tips of the sacral screws were marked and the relations with the anatomic structures were defined. The position of the sacral screws relative to the middle and lateral sacral arteries and veins, and the sacral sympathetic trunk were measured. There was no injury to the visceral organs. In four cases, S1 screw tip was in direct contact with middle sacral artery. In two cases, S1 screw tip was in direct contact with middle sacral vein. It was observed that the S1 screw tips were in close proximity to sacral sympathetic trunk on both right and the left sides. The tip of the S2 screw was in contact with middle sacral artery on the left side only in one case. It is found that the tip of the S2 screw was closely located with the middle sacral vein in two cases. The tip of the S2 pedicle screw was in contact with the sacral sympathetic trunk in eight cases on the right side and seven cases on the left side. Lateral sacral vein was also observed to be disturbed by the S1 and S2 screws. As a conclusion, anterior cortical penetration during sacral screw insertion carries a risk of neurovascular injury. The risk of sacral sympathetic trunk and minor vascular structures together with the major neurovascular

  17. Astrocyte Ca2+ Signaling Drives Inversion of Neurovascular Coupling after Subarachnoid Hemorrhage

    PubMed Central

    Pappas, Anthony C.; Koide, Masayo

    2015-01-01

    Physiologically, neurovascular coupling (NVC) matches focal increases in neuronal activity with local arteriolar dilation. Astrocytes participate in NVC by sensing increased neurotransmission and releasing vasoactive agents (e.g., K+) from perivascular endfeet surrounding parenchymal arterioles. Previously, we demonstrated an increase in the amplitude of spontaneous Ca2+ events in astrocyte endfeet and inversion of NVC from vasodilation to vasoconstriction in brain slices obtained from subarachnoid hemorrhage (SAH) model rats. However, the role of spontaneous astrocyte Ca2+ signaling in determining the polarity of the NVC response remains unclear. Here, we used two-photon imaging of Fluo-4-loaded rat brain slices to determine whether altered endfoot Ca2+ signaling underlies SAH-induced inversion of NVC. We report a time-dependent emergence of endfoot high-amplitude Ca2+ signals (eHACSs) after SAH that were not observed in endfeet from unoperated animals. Furthermore, the percentage of endfeet with eHACSs varied with time and paralleled the development of inversion of NVC. Endfeet with eHACSs were present only around arterioles exhibiting inversion of NVC. Importantly, depletion of intracellular Ca2+ stores using cyclopiazonic acid abolished SAH-induced eHACSs and restored arteriolar dilation in SAH brain slices to two mediators of NVC (a rise in endfoot Ca2+ and elevation of extracellular K+). These data indicate a causal link between SAH-induced eHACSs and inversion of NVC. Ultrastructural examination using transmission electron microscopy indicated that a similar proportion of endfeet exhibiting eHACSs also exhibited asymmetrical enlargement. Our results demonstrate that subarachnoid blood causes a delayed increase in the amplitude of spontaneous intracellular Ca2+ release events leading to inversion of NVC. SIGNIFICANCE STATEMENT Aneurysmal subarachnoid hemorrhage (SAH)—strokes involving cerebral aneurysm rupture and release of blood onto the brain surface

  18. Astrocyte Ca2+ Signaling Drives Inversion of Neurovascular Coupling after Subarachnoid Hemorrhage.

    PubMed

    Pappas, Anthony C; Koide, Masayo; Wellman, George C

    2015-09-30

    Physiologically, neurovascular coupling (NVC) matches focal increases in neuronal activity with local arteriolar dilation. Astrocytes participate in NVC by sensing increased neurotransmission and releasing vasoactive agents (e.g., K(+)) from perivascular endfeet surrounding parenchymal arterioles. Previously, we demonstrated an increase in the amplitude of spontaneous Ca(2+) events in astrocyte endfeet and inversion of NVC from vasodilation to vasoconstriction in brain slices obtained from subarachnoid hemorrhage (SAH) model rats. However, the role of spontaneous astrocyte Ca(2+) signaling in determining the polarity of the NVC response remains unclear. Here, we used two-photon imaging of Fluo-4-loaded rat brain slices to determine whether altered endfoot Ca(2+) signaling underlies SAH-induced inversion of NVC. We report a time-dependent emergence of endfoot high-amplitude Ca(2+) signals (eHACSs) after SAH that were not observed in endfeet from unoperated animals. Furthermore, the percentage of endfeet with eHACSs varied with time and paralleled the development of inversion of NVC. Endfeet with eHACSs were present only around arterioles exhibiting inversion of NVC. Importantly, depletion of intracellular Ca(2+) stores using cyclopiazonic acid abolished SAH-induced eHACSs and restored arteriolar dilation in SAH brain slices to two mediators of NVC (a rise in endfoot Ca(2+) and elevation of extracellular K(+)). These data indicate a causal link between SAH-induced eHACSs and inversion of NVC. Ultrastructural examination using transmission electron microscopy indicated that a similar proportion of endfeet exhibiting eHACSs also exhibited asymmetrical enlargement. Our results demonstrate that subarachnoid blood causes a delayed increase in the amplitude of spontaneous intracellular Ca(2+) release events leading to inversion of NVC. Significance statement: Aneurysmal subarachnoid hemorrhage (SAH)--strokes involving cerebral aneurysm rupture and release of blood onto the

  19. Simultaneous real-time 3D photoacoustic tomography and EEG for neurovascular coupling study in an animal model of epilepsy

    NASA Astrophysics Data System (ADS)

    Wang, Bo; Xiao, Jiaying; Jiang, Huabei

    2014-08-01

    Objective. Neurovascular coupling in epilepsy is poorly understood; its study requires simultaneous monitoring of hemodynamic changes and neural activity in the brain. Approach. Here for the first time we present a combined real-time 3D photoacoustic tomography (PAT) and electrophysiology/electroencephalography (EEG) system for the study of neurovascular coupling in epilepsy, whose ability was demonstrated with a pentylenetetrazol (PTZ) induced generalized seizure model in rats. Two groups of experiments were carried out with different wavelengths to detect the changes of oxy-hemoglobin (HbO2) and deoxy-hemoglobin (HbR) signals in the rat brain. We extracted the average PAT signals of the superior sagittal sinus (SSS), and compared them with the EEG signal. Main results. Results showed that the seizure process can be divided into three stages. A ‘dip’ lasting for 1-2 min in the first stage and the following hyperfusion in the second stage were observed. The HbO2 signal and the HbR signal were generally negatively correlated. The change of blood flow was also estimated. All the acquired results here were in accordance with other published results. Significance. Compared to other existing functional neuroimaging tools, the method proposed here enables reliable tracking of hemodynamic signal with both high spatial and high temporal resolution in 3D, so it is more suitable for neurovascular coupling study of epilepsy.

  20. Toward the Era of a One-Stop Imaging Service Using an Angiography Suite for Neurovascular Disorders

    PubMed Central

    Hung, Sheng-Che; Lin, Chung-Jung; Chang, Feng-Chi; Luo, Chao-Bao; Teng, Michael Mu-Huo; Chang, Cheng-Yen

    2013-01-01

    Transportation of patients requiring multiple diagnostic and imaging-guided therapeutic modalities is unavoidable in current radiological practice. This clinical scenario causes time delays and increased risk in the management of stroke and other neurovascular emergencies. Since the emergence of flat-detector technology in imaging practice in recent decades, studies have proven that flat-detector X-ray angiography in conjunction with contrast medium injection and specialized reconstruction algorithms can provide not only high-quality and high-resolution CT-like images but also functional information. This improvement in imaging technology allows quantitative assessment of intracranial hemodynamics and, subsequently in the same imaging session, provides treatment guidance for patients with neurovascular disorders by using only a flat-detector angiographic suite—a so-called one-stop quantitative imaging service (OSIS). In this paper, we review the recent developments in the field of flat-detector imaging and share our experience of applying this technology in neurovascular disorders such as acute ischemic stroke, cerebral aneurysm, and stenoocclusive carotid diseases. PMID:23762863

  1. New aspects of the topographical anatomy of the mammary gland regarding its neurovascular supply along a regular ligamentous suspension.

    PubMed

    Wueringer, Elisabeth; Tschabitscher, Manfred

    2002-07-01

    The exact location of the main nerves and vessels to the breast and the nipple-areola complex has always been obscure. We found that the course of the rich neurovascular supply to the nipple runs along a regularly-located, suspensory apparatus and can therefore be predicted exactly. It consists of a horizontal fibrous septum originating at the pectoral fascia along the 5th rib, merging into vertical ligaments along the sternum medially and along the lateral border of pectoralis minor laterally. Cranially, and in an anterior direction, the vertical ligaments are connected by the superficial fascia. In the current anatomical study, we seek to demonstrate the vascular supply provided by these structures more impressively. For this purpose we dissected the ligamentous suspension after intraarterial injection with colored latex in both breasts of 10 female cadavers. The large vessels, guided by this circle of fibrous attachments could then be seen clearly. In a further 4 female cadavers, a similar procedure was performed after intraarterial injection of surgical ink. This stained the vascular layers even more intensely. This topographical knowledge has clinical relevance. The rich and constant neurovascular supply to the nipple areola complex may be maintained in a new breast-reduction technique, which allows safe postoperative viability and sensibility of the nipple. The clinical results act as a striking evidence of our anatomical findings. Further procedures taking advantage of the easy determination and access to the neurovascular supply may be seen in future. PMID:14566611

  2. Early and late stimulus-evoked cortical hemodynamic responses provide insight into the neurogenic nature of neurovascular coupling

    PubMed Central

    Kennerley, Aneurin J; Harris, Sam; Bruyns-Haylett, Michael; Boorman, Luke; Zheng, Ying; Jones, Myles; Berwick, Jason

    2012-01-01

    Understanding neurovascular coupling is a prerequisite for the interpretation of results obtained from modern neuroimaging techniques. This study investigated the hemodynamic and neural responses in rat somatosensory cortex elicited by 16 seconds electrical whisker stimuli. Hemodynamics were measured by optical imaging spectroscopy and neural activity by multichannel electrophysiology. Previous studies have suggested that the whisker-evoked hemodynamic response contains two mechanisms, a transient ‘backwards' dilation of the middle cerebral artery, followed by an increase in blood volume localized to the site of neural activity. To distinguish between the mechanisms responsible for these aspects of the response, we presented whisker stimuli during normocapnia (‘control'), and during a high level of hypercapnia. Hypercapnia was used to ‘predilate' arteries and thus possibly ‘inhibit' aspects of the response related to the ‘early' mechanism. Indeed, hemodynamic data suggested that the transient stimulus-evoked response was absent under hypercapnia. However, evoked neural responses were also altered during hypercapnia and convolution of the neural responses from both the normocapnic and hypercapnic conditions with a canonical impulse response function, suggested that neurovascular coupling was similar in both conditions. Although data did not clearly dissociate early and late vascular responses, they suggest that the neurovascular coupling relationship is neurogenic in origin. PMID:22126914

  3. Keratoconus: an inflammatory disorder?

    PubMed

    Galvis, V; Sherwin, T; Tello, A; Merayo, J; Barrera, R; Acera, A

    2015-07-01

    Keratoconus has been classically defined as a progressive, non-inflammatory condition, which produces a thinning and steepening of the cornea. Its pathophysiological mechanisms have been investigated for a long time. Both genetic and environmental factors have been associated with the disease. Recent studies have shown a significant role of proteolytic enzymes, cytokines, and free radicals; therefore, although keratoconus does not meet all the classic criteria for an inflammatory disease, the lack of inflammation has been questioned. The majority of studies in the tears of patients with keratoconus have found increased levels of interleukin-6 (IL-6), tumor necrosis factor-α(TNF-α), and matrix metalloproteinase (MMP)-9. Eye rubbing, a proven risk factor for keratoconus, has been also shown recently to increase the tear levels of MMP-13, IL-6, and TNF-α. In the tear fluid of patients with ocular rosacea, IL-1α and MMP-9 have been reported to be significantly elevated, and cases of inferior corneal thinning, resembling keratoconus, have been reported. We performed a literature review of published biochemical changes in keratoconus that would support that this could be, at least in part, an inflammatory condition. PMID:25931166

  4. Keratoconus: an inflammatory disorder?

    PubMed Central

    Galvis, V; Sherwin, T; Tello, A; Merayo, J; Barrera, R; Acera, A

    2015-01-01

    Keratoconus has been classically defined as a progressive, non-inflammatory condition, which produces a thinning and steepening of the cornea. Its pathophysiological mechanisms have been investigated for a long time. Both genetic and environmental factors have been associated with the disease. Recent studies have shown a significant role of proteolytic enzymes, cytokines, and free radicals; therefore, although keratoconus does not meet all the classic criteria for an inflammatory disease, the lack of inflammation has been questioned. The majority of studies in the tears of patients with keratoconus have found increased levels of interleukin-6 (IL-6), tumor necrosis factor-α(TNF-α), and matrix metalloproteinase (MMP)-9. Eye rubbing, a proven risk factor for keratoconus, has been also shown recently to increase the tear levels of MMP-13, IL-6, and TNF-α. In the tear fluid of patients with ocular rosacea, IL-1α and MMP-9 have been reported to be significantly elevated, and cases of inferior corneal thinning, resembling keratoconus, have been reported. We performed a literature review of published biochemical changes in keratoconus that would support that this could be, at least in part, an inflammatory condition. PMID:25931166

  5. SIV-induced impairment of neurovascular repair: a potential role for VEGF

    PubMed Central

    Ebenezer, Gigi J.; McArthur, Justin C.; Polydefkis, Michael; Dorsey, Jamie L.; O'Donnell, Ryan; Hauer, Peter; Adams, Robert J.

    2013-01-01

    Peripheral nerves and blood vessels travel together closely during development but little is known about their interactions post-injury. The SIV-infected pigtailed macaque model of human immunodeficiency virus (HIV) recapitulates peripheral nervous system pathology of HIV infection. In this study, we assessed the effect of SIV infection on neurovascular regrowth using a validated excisional axotomy model. Six uninfected and five SIV-infected macaques were studied 14 and 70 days after axotomy to characterize regenerating vessels and axons. Blood vessel extension preceded the appearance of regenerating nerve fibers suggesting that vessels serve as scaffolding to guide regenerating axons through extracellular matrix. Vascular endothelial growth factor (VEGF) was expressed along vascular silhouettes by endothelial cells, pericytes, and perivascular cells. VEGF expression correlated with dermal nerve (r=0.68, p= 0.01) and epidermal nerve fiber regrowth (r=0.63, p=0.02). No difference in blood vessel growth was observed between SIV-infected and control macaques. In contrast, SIV-infected animals demonstrated altered length, pruning and arborization of nerve fibers as well as alteration of VEGF expression. These results reinforce earlier human primate findings that vessel growth precedes and influences axonal regeneration. The consistency of these observations across human and non-human primates validates the use of the pigtailed-macaque as a preclinical model. PMID:22549763

  6. Testing methodologies for the nonlinear analysis of causal relationships in neurovascular coupling.

    PubMed

    Lüdtke, Niklas; Logothetis, Nikos K; Panzeri, Stefano

    2010-10-01

    We investigated the use and implementation of a nonlinear methodology for establishing which changes in neurophysiological signals cause changes in the blood oxygenation level-dependent (BOLD) contrast measured in functional magnetic resonance imaging. Unlike previous analytical approaches, which used linear correlation to establish covariations between neural activity and BOLD, we propose a directed information-theoretic measure, the transfer entropy, which can elucidate even highly nonlinear causal relationships between neural activity and BOLD signal. In this study we investigated the practicality of such an analysis given the limited data samples that can be collected experimentally due to the low temporal resolution of BOLD signals. We implemented several algorithms for the estimation of transfer entropy and we tested their effectiveness using simulated local field potentials (LFPs) and BOLD data constructed to match the main statistical properties of real LFP and BOLD signals measured simultaneously in monkey primary visual cortex. We found that using the advanced methods of entropy estimation implemented and described here, a transfer entropy analysis of neurovascular coupling based on experimentally attainable data sets is feasible. PMID:20409664

  7. Brain regional angiogenic potential at the neurovascular unit during normal aging

    PubMed Central

    Murugesan, Nivetha; Demarest, Tyler G.; Madri, Joseph A.; Pachter, Joel S.

    2011-01-01

    Given strong regional specialization of the brain, cerebral angiogenesis may be regionally modified during normal aging. To test this hypothesis, expression of a broad cadre of angiogenesis-associated genes was assayed at the neurovascular unit (NVU) in discrete brain regions of young vs. aged mice by laser capture microdissection coupled to quantitative real-time PCR. Complementary quantitative capillary density/branching studies were performed as well. Effects of physical exercise were also assayed to determine if age-related trends could be reversed. Additionally, gene response to hypoxia was probed to highlight age-associated weaknesses in adapting to this angiogenic stress. Aging impacted resting expression of angiogenesis-associated genes at the NVU in a region-dependent manner. Physical exercise reversed some of these age-associated gene trends, as well as positively influenced cerebral capillary density/branching in a region-dependent way. Lastly, hypoxia revealed a weaker angiogenic response in aged brain. These results suggest heterogeneous changes in angiogenic capacity of the brain during normal aging, and imply a therapeutic benefit of physical exercise that acts at the level of the NVU. PMID:22019053

  8. A 3D neurovascular bundles segmentation method based on MR-TRUS deformable registration

    NASA Astrophysics Data System (ADS)

    Yang, Xiaofeng; Rossi, Peter; Jani, Ashesh B.; Mao, Hui; Ogunleye, Tomi; Curran, Walter J.; Liu, Tian

    2015-03-01

    In this paper, we propose a 3D neurovascular bundles (NVB) segmentation method for ultrasound (US) image by integrating MR and transrectal ultrasound (TRUS) images through MR-TRUS deformable registration. First, 3D NVB was contoured by a physician in MR images, and the 3D MRdefined NVB was then transformed into US images using a MR-TRUS registration method, which models the prostate tissue as an elastic material, and jointly estimates the boundary deformation and the volumetric deformations under the elastic constraint. This technique was validated with a clinical study of 6 patients undergoing radiation therapy (RT) treatment for prostate cancer. The accuracy of our approach was assessed through the locations of landmarks, as well as previous ultrasound Doppler images of patients. MR-TRUS registration was successfully performed for all patients. The mean displacement of the landmarks between the post-registration MR and TRUS images was less than 2 mm, and the average NVB volume Dice Overlap Coefficient was over 89%. This NVB segmentation technique could be a useful tool as we try to spare the NVB in prostate RT, monitor NVB response to RT, and potentially improve post-RT potency outcomes.

  9. Free neurovascular flap from the first web of the foot in hand reconstruction.

    PubMed

    May, J W; Chait, L A; Cohen, B E; O'Brien, B M

    1977-09-01

    To identify an anatomically reliable and functionally acceptable neurovascular free flap for use in hand reconstruction, 50 fresh cadaver feet were dissected under the operating microscope, with particular attention paid to the anatomy of the first web area. A distal communicating artery was seen in 100% of dissections, allowing either dorsal or plantar donor artery inflow to nourish the entire flap area. Because of the ease of dissection, the first dorsal metatarsal or dorsalis pedis is suggested as the donor artery, and a dorsal branch of the greater saphenous venous system is suggested as the donor vein. The deep peroneal nerve was seen to consistently innervate the first web and, along with the plantar digital nerves, is suggested as an anatomically identifiable donor nerve. Either part of the foot first web may be used alone or together as a free flap. When indicated further dorsal skin may be incorporated into the web flap to expand its application. Two-point discrimination studies of the lateral plantar surface of the great toe in 50 normal individuals showed an average of 11.2 mm. This was significantly better as a potential donor flap than the medial dorsum of the foot where the average was 32 mm. A single case demonstrating the application of this flap in hand reconstruction is presented. PMID:332757

  10. Neuronal networks and mediators of cortical neurovascular coupling responses in normal and altered brain states.

    PubMed

    Lecrux, C; Hamel, E

    2016-10-01

    Brain imaging techniques that use vascular signals to map changes in neuronal activity, such as blood oxygenation level-dependent functional magnetic resonance imaging, rely on the spatial and temporal coupling between changes in neurophysiology and haemodynamics, known as 'neurovascular coupling (NVC)'. Accordingly, NVC responses, mapped by changes in brain haemodynamics, have been validated for different stimuli under physiological conditions. In the cerebral cortex, the networks of excitatory pyramidal cells and inhibitory interneurons generating the changes in neural activity and the key mediators that signal to the vascular unit have been identified for some incoming afferent pathways. The neural circuits recruited by whisker glutamatergic-, basal forebrain cholinergic- or locus coeruleus noradrenergic pathway stimulation were found to be highly specific and discriminative, particularly when comparing the two modulatory systems to the sensory response. However, it is largely unknown whether or not NVC is still reliable when brain states are altered or in disease conditions. This lack of knowledge is surprising since brain imaging is broadly used in humans and, ultimately, in conditions that deviate from baseline brain function. Using the whisker-to-barrel pathway as a model of NVC, we can interrogate the reliability of NVC under enhanced cholinergic or noradrenergic modulation of cortical circuits that alters brain states.This article is part of the themed issue 'Interpreting BOLD: a dialogue between cognitive and cellular neuroscience'. PMID:27574304

  11. Model of the transient neurovascular response based on prompt arterial dilation.

    PubMed

    Kim, Jung Hwan; Khan, Reswanul; Thompson, Jeffrey K; Ress, David

    2013-09-01

    Brief neural stimulation results in a stereotypical pattern of vascular and metabolic response that is the basis for popular brain-imaging methods such as functional magnetic resonance imagine. However, the mechanisms of transient oxygen transport and its coupling to cerebral blood flow (CBF) and oxygen metabolism (CMRO2) are poorly understood. Recent experiments show that brief stimulation produces prompt arterial vasodilation rather than venous vasodilation. This work provides a neurovascular response model for brief stimulation based on transient arterial effects using one-dimensional convection-diffusion transport. Hemoglobin oxygen dissociation is included to enable predictions of absolute oxygen concentrations. Arterial CBF response is modeled using a lumped linear flow model, and CMRO2 response is modeled using a gamma function. Using six parameters, the model successfully fit 161/166 measured extravascular oxygen time courses obtained for brief visual stimulation in cat cerebral cortex. Results show how CBF and CMRO2 responses compete to produce the observed features of the hemodynamic response: initial dip, hyperoxic peak, undershoot, and ringing. Predicted CBF and CMRO2 response amplitudes are consistent with experimental measurements. This model provides a powerful framework to quantitatively interpret oxygen transport in the brain; in particular, its intravascular oxygen concentration predictions provide a new model for fMRI responses. PMID:23756690

  12. Regulation of cerebrospinal fluid (CSF) flow in neurodegenerative, neurovascular and neuroinflammatory disease.

    PubMed

    Simon, Matthew J; Iliff, Jeffrey J

    2016-03-01

    Cerebrospinal fluid (CSF) circulation and turnover provides a sink for the elimination of solutes from the brain interstitium, serving an important homeostatic role for the function of the central nervous system. Disruption of normal CSF circulation and turnover is believed to contribute to the development of many diseases, including neurodegenerative conditions such as Alzheimer's disease, ischemic and traumatic brain injury, and neuroinflammatory conditions such as multiple sclerosis. Recent insights into CSF biology suggesting that CSF and interstitial fluid exchange along a brain-wide network of perivascular spaces termed the 'glymphatic' system suggest that CSF circulation may interact intimately with glial and vascular function to regulate basic aspects of brain function. Dysfunction within this glial vascular network, which is a feature of the aging and injured brain, is a potentially critical link between brain injury, neuroinflammation and the development of chronic neurodegeneration. Ongoing research within this field may provide a powerful new framework for understanding the common links between neurodegenerative, neurovascular and neuroinflammatory disease, in addition to providing potentially novel therapeutic targets for these conditions. This article is part of a Special Issue entitled: Neuro Inflammation edited by Helga E. de Vries and Markus Schwaninger. PMID:26499397

  13. Three-Dimensional Blood-Brain Barrier Model for in vitro Studies of Neurovascular Pathology.

    PubMed

    Cho, Hansang; Seo, Ji Hae; Wong, Keith H K; Terasaki, Yasukazu; Park, Joseph; Bong, Kiwan; Arai, Ken; Lo, Eng H; Irimia, Daniel

    2015-01-01

    Blood-brain barrier (BBB) pathology leads to neurovascular disorders and is an important target for therapies. However, the study of BBB pathology is difficult in the absence of models that are simple and relevant. In vivo animal models are highly relevant, however they are hampered by complex, multi-cellular interactions that are difficult to decouple. In vitro models of BBB are simpler, however they have limited functionality and relevance to disease processes. To address these limitations, we developed a 3-dimensional (3D) model of BBB on a microfluidic platform. We verified the tightness of the BBB by showing its ability to reduce the leakage of dyes and to block the transmigration of immune cells towards chemoattractants. Moreover, we verified the localization at endothelial cell boundaries of ZO-1 and VE-Cadherin, two components of tight and adherens junctions. To validate the functionality of the BBB model, we probed its disruption by neuro-inflammation mediators and ischemic conditions and measured the protective function of antioxidant and ROCK-inhibitor treatments. Overall, our 3D BBB model provides a robust platform, adequate for detailed functional studies of BBB and for the screening of BBB-targeting drugs in neurological diseases. PMID:26503597

  14. Three-Dimensional Blood-Brain Barrier Model for in vitro Studies of Neurovascular Pathology

    NASA Astrophysics Data System (ADS)

    Cho, Hansang; Seo, Ji Hae; Wong, Keith H. K.; Terasaki, Yasukazu; Park, Joseph; Bong, Kiwan; Arai, Ken; Lo, Eng H.; Irimia, Daniel

    2015-10-01

    Blood-brain barrier (BBB) pathology leads to neurovascular disorders and is an important target for therapies. However, the study of BBB pathology is difficult in the absence of models that are simple and relevant. In vivo animal models are highly relevant, however they are hampered by complex, multi-cellular interactions that are difficult to decouple. In vitro models of BBB are simpler, however they have limited functionality and relevance to disease processes. To address these limitations, we developed a 3-dimensional (3D) model of BBB on a microfluidic platform. We verified the tightness of the BBB by showing its ability to reduce the leakage of dyes and to block the transmigration of immune cells towards chemoattractants. Moreover, we verified the localization at endothelial cell boundaries of ZO-1 and VE-Cadherin, two components of tight and adherens junctions. To validate the functionality of the BBB model, we probed its disruption by neuro-inflammation mediators and ischemic conditions and measured the protective function of antioxidant and ROCK-inhibitor treatments. Overall, our 3D BBB model provides a robust platform, adequate for detailed functional studies of BBB and for the screening of BBB-targeting drugs in neurological diseases.

  15. Imaging the Perivascular Space as a Potential Biomarker of Neurovascular and Neurodegenerative Diseases.

    PubMed

    Ramirez, Joel; Berezuk, Courtney; McNeely, Alicia A; Gao, Fuqiang; McLaurin, JoAnne; Black, Sandra E

    2016-03-01

    Although the brain lacks conventional lymphatic vessels found in peripheral tissue, evidence suggests that the space surrounding the vasculature serves a similar role in the clearance of fluid and metabolic waste from the brain. With aging, neurodegeneration, and cerebrovascular disease, these microscopic perivascular spaces can become enlarged, allowing for visualization and quantification on structural MRI. The purpose of this review is to: (i) describe some of the recent pre-clinical findings from basic science that shed light on the potential neurophysiological mechanisms driving glymphatic and perivascular waste clearance, (ii) review some of the pathobiological etiologies that may lead to MRI-visible enlarged perivascular spaces (ePVS), (iii) describe the possible clinical implications of ePVS, (iv) evaluate existing qualitative and quantitative techniques used for measuring ePVS burden, and (v) propose future avenues of research that may improve our understanding of this potential clinical neuroimaging biomarker for fluid and metabolic waste clearance dysfunction in neurodegenerative and neurovascular diseases. PMID:26993511

  16. Three-Dimensional Blood-Brain Barrier Model for in vitro Studies of Neurovascular Pathology

    PubMed Central

    Cho, Hansang; Seo, Ji Hae; Wong, Keith H. K.; Terasaki, Yasukazu; Park, Joseph; Bong, Kiwan; Arai, Ken; Lo, Eng H.; Irimia, Daniel

    2015-01-01

    Blood–brain barrier (BBB) pathology leads to neurovascular disorders and is an important target for therapies. However, the study of BBB pathology is difficult in the absence of models that are simple and relevant. In vivo animal models are highly relevant, however they are hampered by complex, multi-cellular interactions that are difficult to decouple. In vitro models of BBB are simpler, however they have limited functionality and relevance to disease processes. To address these limitations, we developed a 3-dimensional (3D) model of BBB on a microfluidic platform. We verified the tightness of the BBB by showing its ability to reduce the leakage of dyes and to block the transmigration of immune cells towards chemoattractants. Moreover, we verified the localization at endothelial cell boundaries of ZO-1 and VE-Cadherin, two components of tight and adherens junctions. To validate the functionality of the BBB model, we probed its disruption by neuro-inflammation mediators and ischemic conditions and measured the protective function of antioxidant and ROCK-inhibitor treatments. Overall, our 3D BBB model provides a robust platform, adequate for detailed functional studies of BBB and for the screening of BBB-targeting drugs in neurological diseases. PMID:26503597

  17. Aging exacerbates obesity-induced cerebromicrovascular rarefaction, neurovascular uncoupling, and cognitive decline in mice.

    PubMed

    Tucsek, Zsuzsanna; Toth, Peter; Tarantini, Stefano; Sosnowska, Danuta; Gautam, Tripti; Warrington, Junie P; Giles, Cory B; Wren, Jonathan D; Koller, Akos; Ballabh, Praveen; Sonntag, William E; Ungvari, Zoltan; Csiszar, Anna

    2014-11-01

    Epidemiological studies show that obesity has deleterious effects on the brain and cognitive function in the elderly population. However, the specific mechanisms through which aging and obesity interact to promote cognitive decline remain unclear. To test the hypothesis that aging exacerbates obesity-induced cerebromicrovascular impairment, we compared young (7 months) and aged (24 months) high-fat diet-fed obese C57BL/6 mice. We found that aging exacerbates the obesity-induced decline in microvascular density both in the hippocampus and in the cortex. The extent of hippocampal microvascular rarefaction and the extent of impairment of hippocampal-dependent cognitive function positively correlate. Aging exacerbates obesity-induced loss of pericyte coverage on cerebral microvessels and alters hippocampal angiogenic gene expression signature, which likely contributes to microvascular rarefaction. Aging also exacerbates obesity-induced oxidative stress and induction of NADPH oxidase and impairs cerebral blood flow responses to whisker stimulation. Collectively, obesity exerts deleterious cerebrovascular effects in aged mice, promoting cerebromicrovascular rarefaction and neurovascular uncoupling. The morphological and functional impairment of the cerebral microvasculature in association with increased blood-brain barrier disruption and neuroinflammation (Tucsek Z, Toth P, Sosnowsk D, et al. Obesity in aging exacerbates blood-brain barrier disruption, neuroinflammation and oxidative stress in the mouse hippocampus: effects on expression of genes involved in beta-amyloid generation and Alzheimer's disease. J Gerontol Biol Med Sci. 2013. In press, PMID: 24269929) likely contribute to obesity-induced cognitive decline in aging. PMID:24895269

  18. Reconstruction of fingertip defects with the neurovascular tranquilli-leali flap.

    PubMed

    Loréa, P; Chahidi, N; Marchesi, S; Ezzedine, R; Marin Braun, F; Dury, M

    2006-06-01

    For many years, bipedicled palmar advancement flaps were used rarely in fingers because they sacrificed the dorsal branches of the digital arteries, risking dorsal skin necrosis. In 1995, a short bipedicled neurovascular VY advancement flap raised distally to the PIP flexion crease, which spared the dorsal blood supply, was described by Elliot et al. (1995). This paper includes an anatomical study on 28 fresh cadaver fingers to evaluate the advancement potential of this flap. It also reviews 22 fingertip reconstructions in 22 patients using this flap. The mean advancement of the flap in the cadaver study was 14 (range 10-16) mm. This procedure gave good clinical results in respect of healing, sensibility, bone cover and appearance. Complications occurred in four fingers (18%), viz. two infections, one neuroma and one stiff proximal interphalangeal joint. Our study suggests that this flap can be used to treat fingertip defects of a size of approximately half of the pulp of the distal phalangeal segment of the finger. PMID:16403425

  19. Inflammatory glaucoma

    PubMed Central

    Bodh, Sonam A.; Kumar, Vasu; Raina, Usha K.; Ghosh, B.; Thakar, Meenakshi

    2011-01-01

    Glaucoma is seen in about 20% of the patients with uveitis. Anterior uveitis may be acute, subacute, or chronic. The mechanisms by which iridocyclitis leads to obstruction of aqueous outflow include acute, usually reversible forms (e.g., accumulation of inflammatory elements in the intertrabecular spaces, edema of the trabecular lamellae, or angle closure due to ciliary body swelling) and chronic forms (e.g., scar formation or membrane overgrowth in the anterior chamber angle). Careful history and follow-up helps distinguish steroid-induced glaucoma from uveitic glaucoma. Treatment of combined iridocyclitis and glaucoma involves steroidal and nonsteroidal antiinflammatory agents and antiglaucoma drugs. However, glaucoma drugs can often have an unpredictable effect on intraocular pressure (IOP) in the setting of uveitis. Surgical intervention is required in case of medical failure. Method of Literature Search: Literature on the Medline database was searched using the PubMed interface. PMID:21713239

  20. Sphingolipid metabolites in inflammatory disease

    PubMed Central

    Maceyka, Michael; Spiegel, Sarah

    2015-01-01

    Sphingolipids are ubiquitous building blocks of eukaryotic cell membranes. Progress in our understanding of sphingolipid metabolism, state-of-the-art sphingolipidomic approaches and animal models have generated a large body of evidence demonstrating that sphingolipid metabolites, particularly ceramide and sphingosine-1-phosphate, are signalling molecules that regulate a diverse range of cellular processes that are important in immunity, inflammation and inflammatory disorders. Recent insights into the molecular mechanisms of action of sphingolipid metabolites and new perspectives on their roles in regulating chronic inflammation have been reported. The knowledge gained in this emerging field will aid in the development of new therapeutic options for inflammatory disorders. PMID:24899305

  1. Citalopram Enhances Neurovascular Regeneration and Sensorimotor Functional Recovery after Ischemic Stroke in Mice

    PubMed Central

    Espinera, Alyssa R.; Ogle, Molly E.; Gu, Xiaohuan; Wei, Ling

    2013-01-01

    Recent clinical trials have demonstrated that treatment with selective serotonin reuptake inhibitors (SSRIs) after stroke enhances motor functional recovery; however, the underlying mechanisms remain to be further elucidated. We hypothesized that daily administration of the clinical drug citalopram would produce these functional benefits via enhancing neurovascular repair in the ischemic peri-infarct region. To test this hypothesis, focal ischemic stroke was induced in male C57/B6 mice by permanent ligation of distal branches of the middle cerebral artery to the barrel cortex and 7-min occlusion of the bilateral common carotid arteries. Citalopram (10 mg/kg, i.p.) was injected 24 hrs after stroke and daily thereafter. To label proliferating cells, bromo-deoxyuridine was injected daily beginning 3 days after stroke. Immunohistochemical and functional assays were performed to elucidate citalopram-mediated cellular and sensorimotor changes after stroke. Citalopram treatment had no significant effect on infarct formation or edema 3 days after stroke; however, citalopram-treated mice had better functional recovery than saline-treated controls 3 and 14 days after stroke in the adhesive removal test. Increased expression of brain derived neurotrophic factor was detected in the peri-infarct region 7 days after stroke in citalopram-treated animals. The number of proliferating neural progenitor cells and the distance of neuroblast migration from the sub-ventricular zone towards the ischemic cortex were significantly greater in citalopram-treated mice at 7 days after stroke. Immunohistochemical staining and co-localization analysis showed that citalopram-treated animals generated more new neurons and microvessels in the peri-infarct region 21 and 28 days after stroke. Taken together, these results suggest that citalopram promotes post-stroke sensorimotor recovery likely via enhancing neurogenesis, neural cell migration and the microvessel support in the peri-infarct region of

  2. Failed microvascular decompression surgery for hemifacial spasm due to persistent neurovascular compression: an analysis of reoperations.

    PubMed

    Bigder, Mark Gregory; Kaufmann, Anthony M

    2016-01-01

    OBJECT Microvascular decompression (MVD) surgery for hemifacial spasm (HFS) is potentially curative. The findings at repeat MVD in patients with persistent or recurrent HFS were analyzed with the aim to identify factors that may improve surgical outcomes. METHODS Intraoperative findings were determined from review of dictated operative reports and operative diagrams for patients who underwent repeat MVD after prior surgery elsewhere. Clinical follow-up was obtained from the hospital and clinic records, as well as telephone questionnaires. RESULTS Among 845 patients who underwent MVD performed by the senior author, 12 had been referred after prior MVD for HFS performed elsewhere. Following repeat MVD, all patients improved and complete spasm resolution was described by 11 of 12 patients after a mean follow-up of 91 ± 55 months (range 28-193). Complications were limited to 1 patient with aggravation of preexisting hearing loss and mild facial weakness and 1 patient with aseptic meningitis without sequelae. Significant factors that may have contributed to the failure of the first surgery included retromastoid craniectomies that did not extend laterally to the sigmoid sinus or inferiorly to the posterior fossa floor in 11 of 12 patients and a prior surgical approach that focused on the cisternal portion of the facial nerve in 9 of 12 patients. In all cases, significant persistent neurovascular compression (NVC) was evident and alleviated more proximally on the facial root exit zone (fREZ). CONCLUSIONS Most HFS patients will achieve spasm relief with thorough alleviation of NVC of the fREZ, which extends from the pontomedullary sulcus root exit point to the Obersteiner-Redlich transition zone. PMID:26295916

  3. NADPH-diaphorase activity and neurovascular coupling in the rat cerebral cortex.

    PubMed

    Vlasenko, O V; Maisky, V A; Maznychenko, A V; Pilyavskii, A I

    2008-01-01

    The distribution of NADPH-diaphorase-reactive (NADPH-dr) neurons and neuronal processes in the cerebral cortex and basal forebrain and their association with parenchymal vessels were studied in normal adult rats using NADPH-d histochemical protocol. The intensely stained cortical interneurons and reactive subcortically originating afferents, and stained microvessels were examined through a light microscope at law (x250) and high (x630) magnifications. NADPH-dr interneurons were concentrated in layers 2-6 of the M1 and M2 areas. However, clear predominance in their concentration (14 +/- 0.8 P < 0.05 per section) was found in layer 6. A mean number of labeled neurons in auditory (AuV), granular and agranular (GI, AIP) areas of the insular cortex was calculated to reach 12.3 +/- 0.7, 18.5 +/- 1.0 and 23.3 +/- 1.7 units per section, respectively (P < 0.05). The distinct apposition of labelled neurons to intracortical vessels was found in the M1, M2. The order of frequency of neurovascular coupling in different zones of the cerebral cortex was as following sequence: AuV (31.2%, n = 1040) > GI (18.0%, n = 640) > S1 (13.3%, n = 720) > M1 (6.3%, n = 1360). A large number of structural associations between labeled cells and vessels in the temporal and insular cortex indicate that NADPH-d-reactive interneurons can contribute to regulation of the cerebral regional blood flow in these areas. PMID:18416183

  4. Recreating blood-brain barrier physiology and structure on chip: A novel neurovascular microfluidic bioreactor

    PubMed Central

    Brown, Jacquelyn A.; Pensabene, Virginia; Markov, Dmitry A.; Allwardt, Vanessa; Neely, M. Diana; Shi, Mingjian; Britt, Clayton M.; Hoilett, Orlando S.; Yang, Qing; Brewer, Bryson M.; Samson, Philip C.; McCawley, Lisa J.; May, James M.; Webb, Donna J.; Li, Deyu; Bowman, Aaron B.; Reiserer, Ronald S.; Wikswo, John P.

    2015-01-01

    The blood-brain barrier (BBB) is a critical structure that serves as the gatekeeper between the central nervous system and the rest of the body. It is the responsibility of the BBB to facilitate the entry of required nutrients into the brain and to exclude potentially harmful compounds; however, this complex structure has remained difficult to model faithfully in vitro. Accurate in vitro models are necessary for understanding how the BBB forms and functions, as well as for evaluating drug and toxin penetration across the barrier. Many previous models have failed to support all the cell types involved in the BBB formation and/or lacked the flow-created shear forces needed for mature tight junction formation. To address these issues and to help establish a more faithful in vitro model of the BBB, we have designed and fabricated a microfluidic device that is comprised of both a vascular chamber and a brain chamber separated by a porous membrane. This design allows for cell-to-cell communication between endothelial cells, astrocytes, and pericytes and independent perfusion of both compartments separated by the membrane. This NeuroVascular Unit (NVU) represents approximately one-millionth of the human brain, and hence, has sufficient cell mass to support a breadth of analytical measurements. The NVU has been validated with both fluorescein isothiocyanate (FITC)-dextran diffusion and transendothelial electrical resistance. The NVU has enabled in vitro modeling of the BBB using all human cell types and sampling effluent from both sides of the barrier. PMID:26576206

  5. Effect of acute nitrate supplementation on neurovascular coupling and cognitive performance in hypoxia.

    PubMed

    Lefferts, Wesley K; Hughes, William E; White, Corey N; Brutsaert, Tom D; Heffernan, Kevin S

    2016-02-01

    The matching of oxygen supply to neural demand (i.e., neurovascular coupling (NVC)) is an important determinant of cognitive performance. The impact of hypoxia on NVC remains poorly characterized. NVC is partially modulated by nitric oxide (NO), which may initially decrease in hypoxia. This study investigated the effect of acute NO-donor (nitrate) supplementation on NVC and cognitive function in hypoxia. Twenty healthy men participated in this randomized, double-blind, crossover design study. Following normoxic cognitive/NVC testing, participants consumed either nitrate (NIT) or a NIT-depleted placebo (PLA). Participants then underwent 120 min of hypoxia (11.6% ± 0.1% O2) and all cognitive/NVC testing was repeated. NVC was assessed as change in middle cerebral artery (MCA) blood flow during a cognitive task (incongruent Stroop) using transcranial Doppler. Additional computerized cognitive testing was conducted separately to assess memory, executive function, attention, sensorimotor, and social cognition domains. Salivary nitrite significantly increased following supplementation in hypoxia for NIT (+2.6 ± 1.0 arbitrary units (AU)) compared with PLA (+0.2 ± 0.3 AU; p < 0.05). Memory performance (-6 ± 13 correct) significantly decreased (p < 0.05) in hypoxia while all other cognitive domains were unchanged in hypoxia for both PLA and NIT conditions (p > 0.05). MCA flow increased during Stroop similarly in normoxia (PLA +5 ± 6 cm·s(-1), NIT +7 ± 7 cm·s(-1)) and hypoxia (PLA +5 ± 9 cm·s(-1), NIT +6 ± 7 cm·s(-1)) (p < 0.05) and this increase was not altered by PLA or NIT (p > 0.05). In conclusion, acute hypoxia resulted in significant reductions in memory concomitant with preservation of executive function, attention, and sensorimotor function. Hypoxia had no effect on NVC. Acute NIT supplementation had no effect on NVC or cognitive performance in hypoxia. PMID:26751937

  6. Neurovascular bundle dissection for Nesbit procedure in congenital penile curvature patients: medial or lateral?

    PubMed

    Akbulut, Fatih; Akman, Tolga; Salabas, Emre; Dincer, Murat; Ortac, Mazhar; Kadioglu, Ates

    2014-01-01

    The objective of this study was to compare the outcomes of the modified Nesbit procedure using different techniques for dissecting the neurovascular bundle (NVB) to correct ventral congenital penile curvatures (CPCs). The bundle was mobilized using the medial and lateral dissection technique in 21 (Group 1) and 13 (Group 2) patients, respectively. In the medial technique, Buck's fascia is opened at the dorsal side of the penis, the deep dorsal vein is removed at the most prominent site of the curvature and a diamond-shaped tunica albuginea (TA) is excised from the midline of the penis. In the lateral technique, the bundle is mobilized using a longitudinal lateral incision of the Buck's fascia above the urethra at the 5 and 7 o'clock positions via a bilateral approach. The localization and degree of curvature was evaluated using the combined intracavernous injection stimulation test or from the patients' photographs. The mean patient age and degree of curvature were similar between groups. The mean operation time was longer for Group 2 (P = 0.01). In Group 1, nine patients (42.8%) required one diamond excision, 10 (47.6%) required two diamond excisions and two (9.5%) required more than two excisions; in Group 2, six patients (46.2%) required two diamond excisions and seven patients (53.8%) required more than two diamond excisions (P = 0.019). The differences in penile shortening, penile straightening and numbness of the glans penis were not statistically significant. Medial dissection of the bundle for the modified Nesbit procedure reduces the number of diamond-shaped removals of TA and thus shortens operation time in comparison with its lateral counterpart. PMID:24625879

  7. Progress and frustration in inflammatory bowel disease.

    PubMed Central

    Brooke, B. N.

    1980-01-01

    Advances -- and lack of them -- in our understanding of the aetiology, nature, and treatment of ulcerative colitis and Crohn's disease during the past 30 years are reviewed with special reference to personal experience. PMID:7002013

  8. Other noninfectious inflammatory disorders.

    PubMed

    Rovira, Álex; Auger, Cristina; Rovira, Antoni

    2016-01-01

    Idiopathic inflammatory-demyelinating diseases (IIDDs) represent a broad spectrum of central nervous system (CNS) disorders, including monophasic, multiphasic, and progressive disorders that range from highly localized forms to multifocal or diffuse variants. In addition to the classic multiple sclerosis (MS) phenotypes, several MS variants have been described, which can be differentiated on the basis of severity, clinical course, and lesion distribution. Other forms of IIDD are now recognized as distinct entities and not MS variants, such as acute disseminated encephalomyelitis, and neuromyelitis optica spectrum disorders. The CNS can also be affected by a variety of inflammatory diseases. These include primary angiitis of the CNS (PACNS), a rare disorder specifically targeting the CNS vasculature, and various systemic conditions which, among other organs and systems, can also affect the CNS, such as systemic vasculitis and sarcoidosis. The diagnosis of PACNS is difficult, as this condition may be confused with reversible cerebral vasoconstriction syndrome (RCVS), a term comprising a group of conditions characterized by prolonged but reversible vasoconstriction of the cerebral arteries. Magnetic resonance imaging of the brain and spine is the radiologic technique of choice for diagnosing these disorders, and, together with the clinical and laboratory findings, enables a prompt and accurate diagnosis. PMID:27432677

  9. Autoantibodies in inflammatory arthritis.

    PubMed

    Conigliaro, P; Chimenti, M S; Triggianese, P; Sunzini, F; Novelli, L; Perricone, C; Perricone, R

    2016-07-01

    Rheumatoid arthritis (RA) is a systemic chronic inflammatory disease characterized by extensive synovitis resulting in erosions of articular cartilage and marginal bone with joint destruction. The lack of immunological tolerance in RA represents the first step toward the development of autoimmunity. Susceptible individuals, under the influence of environmental factors, such as tobacco smoke, and silica exposure, develop autoimmune phenomena that result in the presence of autoantibodies. HLA and non-HLA haplotypes play a major role in determining the development of specific autoantibodies differentiating anti-citrullinated antibodies (ACPA)-positive and negative RA patients. Rheumatoid factor (RF) and ACPA are the serological markers for RA, and during the preclinical immunological phase, autoantibody titers increase with a progressive spread of ACPA antigens repertoire. The presence of ACPA represents an independent risk factor for developing RA in patients with undifferentiated arthritis or arthralgia. Moreover, anti-CarP antibodies have been identified in patients with RA as well as in individuals before the onset of clinical symptoms of RA. Several autoantibodies mainly targeting post-translational modified proteins have been investigated as possible biomarkers to improve the early diagnosis, prognosis and response to therapy in RA patients. Psoriatic arthritis (PsA) is distinguished from RA by infrequent positivity for RF and ACPA, together with other distinctive clinical features. Actually, specific autoantibodies have not been described. Recently, anti-CarP antibodies have been reported in sera from PsA patients with active disease. Further investigations on autoantibodies showing high specificity and sensibility as well as relevant correlation with disease severity, progression, and response to therapy are awaited in inflammatory arthritides. PMID:26970491

  10. Effects of cerebral ischemia on human neurovascular coupling, CO2 reactivity, and dynamic cerebral autoregulation.

    PubMed

    Salinet, Angela S M; Robinson, Thompson G; Panerai, Ronney B

    2015-01-15

    Cerebral blood flow (CBF) regulation can be impaired in acute ischemic stroke but the combined effects of dynamic cerebral autoregulation (CA), CO2 cerebrovascular reactivity (CVR), and neurovascular coupling (NVC), obtained from simultaneous measurements, have not been described. CBF velocity in the middle cerebral artery (MCA) (CBFv, transcranial Doppler), blood pressure (BP, Finometer), and end-tidal Pco2 (PetCO2 , infrared capnography) were recorded during a 1-min passive movement of the arm in 27 healthy controls [mean age (SD) 61.4 (6.0) yr] and 27 acute stroke patients [age 63 (11.7) yr]. A multivariate autoregressive-moving average model was used to separate the contributions of BP, arterial Pco2 (PaCO2 ), and the neural activation to the CBFv responses. CBFv step responses for the BP, CO2, and stimulus inputs were also obtained. The contribution of the stimulus to the CBFv response was highly significant for the difference between the affected side [area under the curve (AUC) 104.5 (4.5)%] and controls [AUC 106.9 (4.3)%; P = 0.008]. CBFv step responses to CO2 [affected hemisphere 0.39 (0.7), unaffected 0.55 (0.8), controls 1.39 (0.9)%/mmHg; P = 0.01, affected vs. controls; P = 0.025, unaffected vs. controls] and motor stimulus inputs [affected hemisphere 0.20 (0.1), unaffected 0.22 (0.2), controls 0.37 (0.2) arbitrary units; P = 0.009, affected vs. controls; P = 0.02, unaffected vs. controls] were reduced in the stroke group compared with controls. The CBFv step responses to the BP input at baseline and during the paradigm were not different between groups (P = 0.07), but PetCO2 was lower in the stroke group (P < 0.05). These results provide new insights into the interaction of CA, CVR, and NVC in both health and disease states. PMID:25593216

  11. Positive Outcome After a Small-Caliber Gunshot Fracture of the Upper Cervical Spine without Neurovascular Damage

    PubMed Central

    Walter, Thula; Schwabe, Philipp; Schaser, Klaus-Dieter; Maurer, Martin

    2016-01-01

    Summary Background Gunshot wounds to the cervical spine most frequently concur with serious injuries to the spinal cord and cervical vessels and often have a fatal outcome. Case Report We describe the case of a 35-year-old male with a complex fracture of the C2 vertebra body and a mandibular fracture after a penetration gunshot to the cervical spine. Computed tomography (CT) at admission revealed the exact extent of the fractures and the small caliber bullet lodged next to the C2 vertebra. In this rare and extremely lucky case no collateral vascular or neurological damage was detected. Eighteen months after surgical bullet removal and posterior C1–C3 fusion complete bone healing of the C2 vertebra was achieved and there were no secondary neurovascular deficits. Conclusions Immediate surgical C1–C3 fixation resulted in an excellent outcome without secondary neurovascular deficits in this rare case of traumatic complex C2 vertebral fracture caused by a gunshot injury. PMID:27081417

  12. 3-D Imaging Reveals Participation of Donor Islet Schwann Cells and Pericytes in Islet Transplantation and Graft Neurovascular Regeneration

    PubMed Central

    Juang, Jyuhn-Huarng; Kuo, Chien-Hung; Peng, Shih-Jung; Tang, Shiue-Cheng

    2015-01-01

    The primary cells that participate in islet transplantation are the endocrine cells. However, in the islet microenvironment, the endocrine cells are closely associated with the neurovascular tissues consisting of the Schwann cells and pericytes, which form sheaths/barriers at the islet exterior and interior borders. The two cell types have shown their plasticity in islet injury, but their roles in transplantation remain unclear. In this research, we applied 3-dimensional neurovascular histology with cell tracing to reveal the participation of Schwann cells and pericytes in mouse islet transplantation. Longitudinal studies of the grafts under the kidney capsule identify that the donor Schwann cells and pericytes re-associate with the engrafted islets at the peri-graft and perivascular domains, respectively, indicating their adaptability in transplantation. Based on the morphological proximity and cellular reactivity, we propose that the new islet microenvironment should include the peri-graft Schwann cell sheath and perivascular pericytes as an integral part of the new tissue. PMID:26137552

  13. The effects of sodium-2-mercaptoethanesulfonate application on the neural and neurovascular tissues: An experimental animal study

    PubMed Central

    Ant, Ayca; Karamert, Recep; Kulduk, Gamze; Ekinci, Özgür; Tutar, Hakan; Göksu, Nebil

    2015-01-01

    Background: Sodium-2-mercaptoethanesulfonate (MESNA) is a protective agent that is also used as “a chemical dissector” in various surgical fields. The aim of this study is to evaluate the toxic effects of MESNA on neural and neurovascular structures based on a morphological analysis and examine its safety in neurotological applications. Methods: Three groups of guinea pigs were used as subjects. MESNA solution (50 and 100%) and saline solution were applied to the subarachnoid space over the brain tissue via a middle fossa approach of study and control groups, respectively. Effects of MESNA were assessed by means of light microscope. McNemar Chi-square test was used to evaluate the histopathological findings. Statistical significance of P < 0.05 was taken as criterion. Results: No morphological changes were observed on vascular and neural structures in the study groups in both concentrations, compared to the control group. Conclusions: On a morphological basis, a single application of MESNA does not cause any morphological changes that indicate a toxicity in neural and neurovascular structures. PMID:26487975

  14. 3-D Imaging Reveals Participation of Donor Islet Schwann Cells and Pericytes in Islet Transplantation and Graft Neurovascular Regeneration.

    PubMed

    Juang, Jyuhn-Huarng; Kuo, Chien-Hung; Peng, Shih-Jung; Tang, Shiue-Cheng

    2015-02-01

    The primary cells that participate in islet transplantation are the endocrine cells. However, in the islet microenvironment, the endocrine cells are closely associated with the neurovascular tissues consisting of the Schwann cells and pericytes, which form sheaths/barriers at the islet exterior and interior borders. The two cell types have shown their plasticity in islet injury, but their roles in transplantation remain unclear. In this research, we applied 3-dimensional neurovascular histology with cell tracing to reveal the participation of Schwann cells and pericytes in mouse islet transplantation. Longitudinal studies of the grafts under the kidney capsule identify that the donor Schwann cells and pericytes re-associate with the engrafted islets at the peri-graft and perivascular domains, respectively, indicating their adaptability in transplantation. Based on the morphological proximity and cellular reactivity, we propose that the new islet microenvironment should include the peri-graft Schwann cell sheath and perivascular pericytes as an integral part of the new tissue. PMID:26137552

  15. Caspase-3 Contributes to ZO-1 and Cl-5 Tight-Junction Disruption in Rapid Anoxic Neurovascular Unit Damage

    PubMed Central

    de Curtis, Marco; Kuhlmann, Christoph R. W.; Luhmann, Heiko J.

    2011-01-01

    Background Tight-junction (TJ) protein degradation is a decisive step in hypoxic blood-brain barrier (BBB) breakdown in stroke. In this study we elucidated the impact of acute cerebral ischemia on TJ protein arrangement and the role of the apoptotic effector protease caspase-3 in this context. Methodology/Principal Findings We used an in vitro model of the neurovascular unit and the guinea pig whole brain preparation to analyze with immunohistochemical methods the BBB properties and neurovascular integrity. In both methodological approaches we observed rapid TJ protein disruptions after 30 min of oxygen and glucose deprivation or middle cerebral artery occlusion, which were accompanied by strong caspase-3 activation in brain endothelial cells (BEC). Surprisingly only few DNA-fragmentations were detected with TUNEL stainings in BEC. Z-DEVD-fmk, an irreversible caspase-3 inhibitor, partly blocked TJ disruptions and was protective on trans-endothelial electrical resistance. Conclusions/Significance Our data provide evidence that caspase-3 is rapidly activated during acute cerebral ischemia predominantly without triggering DNA-fragmentation in BEC. Further we detected fast TJ protein disruptions which could be partly blocked by caspase-3 inhibition with Z-DEVD-fmk. We suggest that the basis for clinically relevant BBB breakdown in form of TJ disruptions is initiated within minutes during ischemia and that caspase-3 contributes to this process. PMID:21364989

  16. Inflammatory bowel disease: Pathogenesis

    PubMed Central

    Zhang, Yi-Zhen; Li, Yong-Yu

    2014-01-01

    Inflammatory bowel disease (IBD), including Crohn’s disease and ulcerative colitis, is characterized by chronic relapsing intestinal inflammation. It has been a worldwide health-care problem with a continually increasing incidence. It is thought that IBD results from an aberrant and continuing immune response to the microbes in the gut, catalyzed by the genetic susceptibility of the individual. Although the etiology of IBD remains largely unknown, it involves a complex interaction between the genetic, environmental or microbial factors and the immune responses. Of the four components of IBD pathogenesis, most rapid progress has been made in the genetic study of gut inflammation. The latest internationally collaborative studies have ascertained 163 susceptibility gene loci for IBD. The genes implicated in childhood-onset and adult-onset IBD overlap, suggesting similar genetic predispositions. However, the fact that genetic factors account for only a portion of overall disease variance indicates that microbial and environmental factors may interact with genetic elements in the pathogenesis of IBD. Meanwhile, the adaptive immune response has been classically considered to play a major role in the pathogenesis of IBD, as new studies in immunology and genetics have clarified that the innate immune response maintains the same importance in inducing gut inflammation. Recent progress in understanding IBD pathogenesis sheds lights on relevant disease mechanisms, including the innate and adaptive immunity, and the interactions between genetic factors and microbial and environmental cues. In this review, we provide an update on the major advances that have occurred in above areas. PMID:24415861

  17. PI3K/Akt Pathway Contributes to Neurovascular Unit Protection of Xiao-Xu-Ming Decoction against Focal Cerebral Ischemia and Reperfusion Injury in Rats

    PubMed Central

    Xiang, Jun; Zhang, Yong; Wang, Guo-Hua; Bao, Jie; Li, Wen-Wei; Zhang, Wen; Xu, Li-Li; Cai, Ding-Fang

    2013-01-01

    In the present study, we used a focal cerebral ischemia and reperfusion rat model to investigate the protective effects of Xiao-Xu-Ming decoction (XXMD) on neurovascular unit and to examine the role of PI3K (phosphatidylinositol 3-kinase)/Akt pathway in this protection. The cerebral ischemia was induced by 90 min of middle cerebral artery occlusion. Cerebral infarct area was measured by tetrazolium staining, and neurological function was observed at 24 h after reperfusion. DNA fragmentation assay, combined with immunofluorescence, was performed to evaluate apoptosis of neuron, astrocyte, and vascular endothelial cell which constitute neurovascular unit. The expression levels of proteins involved in PI3K/Akt pathway were detected by Western blot. The results showed that XXMD improved neurological function, decreased cerebral infarct area and neuronal damage, and attenuated cellular apoptosis in neurovascular unit, while these effects were abolished by inhibition of PI3K/Akt with LY294002. We also found that XXMD upregulated p-PDKl, p-Akt, and p-GSK3β expression levels, which were partly reversed by LY294002. In addition, the increases of p-PTEN and p-c-Raf expression levels on which LY294002 had no effect were also observed in response to XXMD treatment. The data indicated the protective effects of XXMD on neurovascular unit partly through the activation of PI3K/Akt pathway. PMID:23781261

  18. Neurovascular free-muscle transfer for the treatment of established facial paralysis following ablative surgery in the parotid region.

    PubMed

    Takushima, Akihiko; Harii, Kiyonori; Asato, Hirotaka; Ueda, Kazuki; Yamada, Atsushi

    2004-05-01

    Neurovascular free-muscle transfer for facial reanimation was performed as a secondary reconstructive procedure for 45 patients with facial paralysis resulting from ablative surgery in the parotid region. This intervention differs from neurovascular free-muscle transfer for treatment of established facial paralysis resulting from conditions such as congenital dysfunction, unresolved Bell palsy, Hunt syndrome, or intracranial morbidity, with difficulties including selection of recipient vessels and nerves, and requirements for soft-tissue augmentation. This article describes the authors' operative procedure for neurovascular free-muscle transfer after ablative surgery in the parotid region. Gracilis muscle (n = 24) or latissimus dorsi muscle (n = 21) was used for transfer. With gracilis transfer, recipient vessels comprised the superficial temporal vessels in 12 patients and the facial vessels in 12. For latissimus dorsi transfer, recipient vessels comprised the facial vessels in 16 patients and the superior thyroid artery and superior thyroid or internal jugular vein in four. Facial vessels on the contralateral side were used with interpositional graft of radial vessels in the remaining patient with latissimus dorsi transfer. Cross-face nerve grafting was performed before muscle transfer in 22 patients undergoing gracilis transfer. In the remaining two gracilis patients, the ipsilateral facial nerve stump was used as the primary recipient nerve. Dermal fat flap overlying the gracilis muscle was used for cheek augmentation in one patient. In the other 23 patients, only the gracilis muscle was used. With latissimus dorsi transfer, the ipsilateral facial nerve stump was used as the recipient nerve in three patients, and a cross-face nerve graft was selected as the recipient nerve in six. The contralateral facial nerve was selected as the recipient nerve in 12 patients, and a thoracodorsal nerve from the latissimus dorsi muscle segment was crossed through the upper lip

  19. Two-photon microscopy as a tool to study blood flow and neurovascular coupling in the rodent brain

    PubMed Central

    Shih, Andy Y; Driscoll, Jonathan D; Drew, Patrick J; Nishimura, Nozomi; Schaffer, Chris B; Kleinfeld, David

    2012-01-01

    The cerebral vascular system services the constant demand for energy during neuronal activity in the brain. Attempts to delineate the logic of neurovascular coupling have been greatly aided by the advent of two-photon laser scanning microscopy to image both blood flow and the activity of individual cells below the surface of the brain. Here we provide a technical guide to imaging cerebral blood flow in rodents. We describe in detail the surgical procedures required to generate cranial windows for optical access to the cortex of both rats and mice and the use of two-photon microscopy to accurately measure blood flow in individual cortical vessels concurrent with local cellular activity. We further provide examples on how these techniques can be applied to the study of local blood flow regulation and vascular pathologies such as small-scale stroke. PMID:22293983

  20. Exposure of the superior gluteal neurovascular bundle for the safe application of acetabular reinforcement cages in complex revisions.

    PubMed

    Smitham, Peter J; Kosuge, Dennis; Howie, Donald W; Solomon, Lucian B

    2016-05-16

    The posterior approach to the hip is the most common extensile approach used, however exposure is limited superiorly by the superior gluteal neurovascular bundle (SGNB). The extra-pelvic course of the SGNB demonstrates variability between individuals, occasionally located only 1 cm from the acetabular rim. In complex acetabular reconstructions where the application of a reinforcement cage maybe required protecting the SGNB is challenging. The flanges of these cages are designed to sit on the ilium superior to the acetabular rim and to receive screws for fixation. The application of such cages may result in iatrogenic injury to the SGNB by way of forceful retraction or entrapment. We describe a technique that involves exposure and release of the SGNB such that the flanges of cage constructs may be safely applied. PMID:27079287

  1. Helium preconditioning protects the brain against hypoxia/ischemia injury via improving the neurovascular niche in a neonatal rat model.

    PubMed

    Li, Yi; Zhang, Peixi; Liu, Ying; Liu, Wenwu; Yin, Na

    2016-11-01

    This study aimed to investigate whether helium preconditioning (He-PC) is able to exert neuroprotective effects via improving focal neurovascular niche in a neonatal rat hypoxia/ischemia (HI) brain injury model. Seven day old rat pups were divided into control group, HI group and He-PC group. HI was induced by exposure to 8% oxygen for 90min one day after preconditioning with 70% helium-30% oxygen for three 5-min periods. At 3 and 7 days, the brain was collected for the detection of inflammation related factors (tumor necrosis factor α [TNF-α], interleukin-1β [IL-1β], IL-10) and growth/neurotrophic factors (brain-derived neurotrophic factor [BDNF], basic fibroblast growth factor [bFGF] and nerve growth factor [NGF]); at 7 days, neurobehaviors were evaluated, and the brain was collected for the detection of mRNA expression of vascular endothelial growth factor (VEGF) and angiopoietin-1 (Ang-1) by PCR, protein expression of angiogenesis related molecules (VEGF, Ang-1, Tie-2 and Flt-1) by Western blotting and microvessel density (MCD) by immunohistochemistry for vWF. Results showed He-PC was able to reduce TNF-α and IL-1β, further increase IL-10, BDNF, bFGF and NGF, elevate the mRNA expression of VEGF and Ang-1, increase the protein expression of VEGF, Ang-1, Tie-2 and Flt-1, promote angiogenesis and improve neurobehaviors as compared to HI group. These findings suggest that He-PC may improve the post-stroke neurovascular niche to exert neuroprotective effects on neonatal HI brain injury. PMID:27515290

  2. Dietary supplementation with omega-3 polyunsaturated fatty acids robustly promotes neurovascular restorative dynamics and improves neurological functions after stroke.

    PubMed

    Zhang, Wenting; Wang, Hailian; Zhang, Hui; Leak, Rehana K; Shi, Yejie; Hu, Xiaoming; Gao, Yanqin; Chen, Jun

    2015-10-01

    Stroke is a devastating neurological disease with no satisfactory therapies to preserve long-term neurological function, perhaps due to the sole emphasis on neuronal survival in most preclinical studies. Recent studies have revealed the importance of protecting multiple cell types in the injured brain, such as oligodendrocytes and components of the neurovascular unit, before long-lasting recovery of function can be achieved. For example, revascularization in the ischemic penumbra is critical to provide various neurotrophic factors that enhance the survival and activity of neurons and other progenitor cells, such as oligodendrocyte precursor cells. In the present study, we hypothesized that chronic dietary supplementation with fish oil promotes post-stroke angiogenesis, neurogenesis, and oligodendrogenesis, thereby leading to long-term functional improvements. Mice received dietary supplementation with n-3 PUFA-enriched fish oil for three months before and up to one month after stroke. As expected, dietary n-3 PUFAs significantly increased levels of n-3 PUFAs in the brain and improved long-term behavioral outcomes after cerebral ischemia. n-3 PUFAs also robustly improved revascularization and angiogenesis and boosted the survival of NeuN/BrdU labeled newborn neurons up to 35days after stroke injury. Furthermore, these pro-neurogenic effects were accompanied by robust oligodendrogenesis. Thus, this is the first study to demonstrate that chronic dietary intake of n-3 PUFAs is an effective prophylactic measure not only to protect against ischemic injury for the long term but also to actively promote neurovascular restorative dynamics and brain repair. PMID:25771800

  3. Functional MRI during hyperbaric oxygen: Effects of oxygen on neurovascular coupling and BOLD fMRI signals.

    PubMed

    Cardenas, Damon P; Muir, Eric R; Huang, Shiliang; Boley, Angela; Lodge, Daniel; Duong, Timothy Q

    2015-10-01

    Hyperbaric oxygen (HBO) therapy is used to treat a number of ailments. Improved understanding of how HBO affects neuronal activity, cerebral blood flow (CBF) and blood-oxygenation-level dependent (BOLD) changes could shed light on the role of oxygen in neurovascular coupling and help guide HBO treatments. The goal of this study was to test two hypotheses: i) activation-induced CBF fMRI response is not dependent on hemoglobin deoxygenation, and ii) activation-induced BOLD fMRI is markedly attenuated under HBO. CBF and BOLD fMRI of forepaw stimulation in anesthetized rats under HBO at 3 atmospheres absolute (ATA) were compared with normobaric air. Robust BOLD and CBF fMRI were detected under HBO. Inflow effects and spin-density changes did not contribute significantly to the BOLD fMRI signal under HBO. Analysis of the T2(⁎)-weighted signal at normobaric air and 1, 2 and 3ATA oxygen in the tissue and the superior sagittal sinus showed a strong dependence on increasing inhaled [O2]. Spontaneous electrophysiological activity and evoked local-field potentials were reduced under HBO. The differences between normobaric air and HBO in basal and evoked electrical activity could not fully account for the strong BOLD responses under HBO. We concluded that activation-induced CBF regulation in the brain does not operate through an oxygen-sensing mechanism and that stimulus-evoked BOLD responses and the venous T2(⁎)-weighted signals still have room to increase under 3ATA HBO. To our knowledge, this is the first fMRI study under HBO, providing insights into the effects of HBO on neural activity, neurovascular coupling, tissue oxygenation, and the BOLD signal. PMID:26143203

  4. Inflammatory demyelinating neuropathies.

    PubMed

    Muley, Suraj Ashok; Parry, Gareth J

    2009-05-01

    Early and effective treatment of chronic inflammatory demyelinating polyneuropathy (CIDP) is important to minimize axonal degeneration that occurs secondary to demyelination. The disease course is invariably chronic, so long-term treatment is often required, and adverse effects and costs are important considerations in devising a treatment plan. CIDP responds to prednisone, but long-term treatment can result in significant adverse effects. Azathioprine, mycophenolate mofetil, and cyclosporine can be used as steroid-sparing agents and may facilitate more rapid and successful tapering of prednisone. Intravenous immunoglobulin (IVIg) and plasma exchange are also effective in the treatment of CIDP and can be used in patients who are unresponsive to prednisone or develop steroid-related adverse effects. IVIg may also be used as a first-line treatment, but its cost can be a limiting factor. A few uncontrolled studies have suggested that pulsed weekly methylprednisolone is both effective and well tolerated in the long-term treatment of CIDP. Treatments based on rituximab or cyclophosphamide have also been used in resistant disease. Variants of CIDP have been described on the basis of their association with specific antibodies or immunoglobulins and their response to specific immunomodulatory treatments. Multifocal motor neuropathy with conduction block responds to IVIg in the majority of patients. However, weakness may slowly worsen over time, and some patients become unresponsive. Anecdotal reports suggest that rituximab may be useful in patients who develop progressive disease. Placebo-controlled trials in anti-myelin-associated glycoprotein neuropathy suggest that rituximab is effective and, with a combination of prednisone and cyclophosphamide, numbness and strength may improve. Other treatments that may be effective include plasma exchange and IVIg. Treatment is generally started with prednisone, IVIg, or plasma exchange. Rituximab and cyclophosphamide are used only

  5. Inflammatory markers in coronary artery disease.

    PubMed

    Ikonomidis, Ignatios; Michalakeas, Christos A; Parissis, John; Paraskevaidis, Ioannis; Ntai, Konstantina; Papadakis, Ioannis; Anastasiou-Nana, Maria; Lekakis, John

    2012-01-01

    Coronary artery disease (CAD) is one of the most common manifestations of atherosclerosis. Inflammation is considered one of the major processes that contribute to atherogenesis. Inflammation plays an important role not only on the initiation and progression of atherosclerosis but also on plaque rupture, an event that leads to acute vascular events. Various biomarkers express different pathways and pathophysiologic mechanisms of cardiovascular disease, and inflammatory biomarkers express different parts of the atherogenic process, regarding the initiation and progression of atherosclerosis or the destabilization of the atherosclerotic plaque. Therefore, inflammatory biomarkers may prove to be useful in the detection, staging, and prognosis of patients with CAD. Furthermore, the fact that inflammatory processes are essential steps in the course of the disease offers future therapeutic targets for the interruption of the atherogenic process or for the management of acute events. PMID:22628054

  6. Overcoming radiation resistance in inflammatory breast cancer.

    PubMed

    Woodward, Wendy A; Debeb, Bisrat G; Xu, Wei; Buchholz, Thomas A

    2010-06-01

    The clinical-pathological features of inflammatory breast cancer include enrichment of factors that have been previously associated with radioresistant disease, including negative hormone receptor status and a phenotype enriched for relatively radioresistant breast cancer stem/progenitor cells. The risks and benefits of accelerated postmastectomy radiation treatment regimens in the multimodality management of inflammatory breast cancer were reviewed at the first International Inflammatory Breast Cancer Conference at The University of Texas M. D. Anderson Cancer Center. The biological basis for radiation resistance and strategies to radiosensitize these tumors were also presented. The prevalent basal phenotype of inflammatory breast cancer makes it an ideal clinical model to examine stem cell hypotheses, which the authors believe can help guide future trials to continue making incremental progress against this aggressive disease. PMID:20503417

  7. The importance of balanced pro-inflammatory and anti-inflammatory mechanisms in diffuse lung disease

    PubMed Central

    Keane, Michael P; Strieter, Robert M

    2002-01-01

    The lung responds to a variety of insults in a remarkably consistent fashion but with inconsistent outcomes that vary from complete resolution and return to normal to the destruction of normal architecture and progressive fibrosis. Increasing evidence indicates that diffuse lung disease results from an imbalance between the pro-inflammatory and anti-inflammatory mechanisms, with a persistent imbalance that favors pro-inflammatory mediators dictating the development of chronic diffuse lung disease. This review focuses on the mediators that influence this imbalance. PMID:11806840

  8. Anti-inflammatory and immunomodulatory properties of Carica papaya.

    PubMed

    Pandey, Saurabh; Cabot, Peter J; Shaw, P Nicholas; Hewavitharana, Amitha K

    2016-07-01

    Chronic inflammation is linked with the generation and progression of various diseases such as cancer, diabetes and atherosclerosis, and anti-inflammatory drugs therefore have the potential to assist in the treatment of these conditions. Carica papaya is a tropical plant that is traditionally used in the treatment of various ailments including inflammatory conditions. A literature search was conducted by using the keywords "papaya", "anti-inflammatory and inflammation" and "immunomodulation and immune" along with cross-referencing. Both in vitro and in vivo investigation studies were included. This is a review of all studies published since 2000 on the anti-inflammatory activity of papaya extracts and their effects on various immune-inflammatory mediators. Studies on the anti-inflammatory activities of recognized phytochemicals present in papaya are also included. Although in vitro and in vivo studies have shown that papaya extracts and papaya-associated phytochemicals possess anti-inflammatory and immunomodulatory properties, clinical studies are lacking. PMID:27416522

  9. Inflammatory Mediators of Hepatic Steatosis

    PubMed Central

    Hijona, Elizabeth; Hijona, Lander; Arenas, Juan I.; Bujanda, Luis

    2010-01-01

    Nonalcoholic fatty liver disease (NAFLD) is rapidly becoming a world-wide public health problem. NAFLD represents a spectrum of disease ranging from “simple steatosis”, which is considered relatively benign, to nonalcoholic steatohepatitis and to NAFLD-associated cirrhosis and end-stage liver disease. The etiology of NAFLD and its progression is complex and remains incompletely understood. The progression of the disease involves many factors. Apart from the two hits, the accumulation of TG and the development of fibrosis and necroinflammatory processes, exit numerous molecules associated with these two hits. Among them we can highlight the pro-inflammatory molecules and adiponectins. This review focuses on the growing evidence from both experimental and human studies suggesting a central role of cytokines in the pathogenesis of NAFLD. We review the role of cytokines as key regulators of insulin sensitivity and hepatic lipid overloading, liver injury and inflammation, and fibrosis with an emphasis on potential therapeutic implications. PMID:20300479

  10. The “Neurovascular Unit approach” to Evaluate Mechanisms of Dysfunctional Autoregulation in Asphyxiated Newborns in the era of Hypothermia Therapy

    PubMed Central

    Chalak, Lina F.; Tarumi, Takashi; Zhang, Rong

    2014-01-01

    Despite improvements in obstetrical and neonatal care, and introduction of hypothermia as a neuroprotective therapy, perinatal brain injury remains a frequent cause of cerebral palsy, mental retardation and epilepsy. The recognition of dysfunction of cerebral autoregulation is essential for a real time measure of efficacy to identify those who are at highest risk for brain injury. This article will focus on the “neurovascular unit” approach to the care of asphyxiated neonates to review 1) potential mechanisms of dysfunctional cerebral blood flow (CBF) regulation, 2) optimal monitoring methodology such as NIRS (near infrared spectroscopy), and TCD (transcutaneous Doppler), and 3) clinical implications of monitoring in the neonatal intensive care setting in asphyxiated newborns undergoing hypothermia and rewarming. Critical knowledge of the functional regulation of the neurovascular unit may lead to improved ability to predict outcomes in real time during hypothermia, as well as differentiate nonresponders who might benefit from additional therapies. PMID:25062804