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Sample records for progressive neurovascular inflammatory

  1. Recent progress in translational research on neurovascular and neurodegenerative disorders

    PubMed Central

    Demuth, Hans-Ulrich; Dijkhuizen, Rick M.; Farr, Tracy D.; Gelderblom, Mathias; Horsburgh, Karen; Iadecola, Costantino; Mcleod, Damian D.; Michalski, Dominik; Murphy, Tim H.; Orbe, Josune; Otte, Willem M.; Petzold, Gabor C.; Plesnila, Nikolaus; Reiser, Georg; Reymann, Klaus G.; Rueger, Maria A.; Saur, Dorothee; Savitz, Sean I.; Schilling, Stephan; Spratt, Neil J.; Turner, Renée J.; Vemuganti, Raghu; Vivien, Denis; Yepes, Manuel; Zille, Marietta; Boltze, Johannes; Bauer, Adam Q.; Giffard, Rona G.; Gounis, Matthew J.; Gröger, Victoria; Henrich-Noack, Petra; Von Hörsten, Stephan; Howells, David D.; Kempski, Oliver; Kim, Yun-Hee; Lambertsen, Kate L.; Lee, Jin-Moo; Leonard, Anna; Liesz, Arthur; Macrae, I Mhairi; Mays, Robert W.; Mcleod, Damian D.; Neumann, Jens; Nudo, Randolph J.; Offner, Halina; Rossner, Steffen; Selim, Magdy; Sohrabji, Farida; Yin, Kejie; Walter, Jochen; Ziemann, Ulf

    2017-01-01

    The already established and widely used intravenous application of recombinant tissue plasminogen activator as a re-opening strategy for acute vessel occlusion in ischemic stroke was recently added by mechanical thrombectomy, representing a fundamental progress in evidence-based medicine to improve the patient’s outcome. This has been paralleled by a swift increase in our understanding of pathomechanisms underlying many neurovascular diseases and most prevalent forms of dementia. Taken together, these current advances offer the potential to overcome almost two decades of marginally successful translational research on stroke and dementia, thereby spurring the entire field of translational neuroscience. Moreover, they may also pave the way for the renaissance of classical neuroprotective paradigms. This review reports and summarizes some of the most interesting and promising recent achievements in neurovascular and dementia research. It highlights sessions from the 9th International Symposium on Neuroprotection and Neurorepair that have been discussed from April 19th to 22nd in Leipzig, Germany. To acknowledge the emerging culture of interdisciplinary collaboration and research, special emphasis is given on translational stories ranging from fundamental research on neurode- and -regeneration to late stage translational or early stage clinical investigations. PMID:28059802

  2. Recent progress in translational research on neurovascular and neurodegenerative disorders.

    PubMed

    Demuth, Hans-Ulrich; Dijkhuizen, Rick M; Farr, Tracy D; Gelderblom, Mathias; Horsburgh, Karen; Iadecola, Costantino; Mcleod, Damian D; Michalski, Dominik; Murphy, Tim H; Orbe, Josune; Otte, Willem M; Petzold, Gabor C; Plesnila, Nikolaus; Reiser, Georg; Reymann, Klaus G; Rueger, Maria A; Saur, Dorothee; Savitz, Sean I; Schilling, Stephan; Spratt, Neil J; Turner, Renée J; Vemuganti, Raghu; Vivien, Denis; Yepes, Manuel; Zille, Marietta; Boltze, Johannes

    2017-01-01

    The already established and widely used intravenous application of recombinant tissue plasminogen activator as a re-opening strategy for acute vessel occlusion in ischemic stroke was recently added by mechanical thrombectomy, representing a fundamental progress in evidence-based medicine to improve the patient's outcome. This has been paralleled by a swift increase in our understanding of pathomechanisms underlying many neurovascular diseases and most prevalent forms of dementia. Taken together, these current advances offer the potential to overcome almost two decades of marginally successful translational research on stroke and dementia, thereby spurring the entire field of translational neuroscience. Moreover, they may also pave the way for the renaissance of classical neuroprotective paradigms.This review reports and summarizes some of the most interesting and promising recent achievements in neurovascular and dementia research. It highlights sessions from the 9th International Symposium on Neuroprotection and Neurorepair that have been discussed from April 19th to 22nd in Leipzig, Germany. To acknowledge the emerging culture of interdisciplinary collaboration and research, special emphasis is given on translational stories ranging from fundamental research on neurode- and -regeneration to late stage translational or early stage clinical investigations.

  3. Metabolic consequences of inflammatory disruption of the blood-brain barrier in an organ-on-chip model of the human neurovascular unit.

    PubMed

    Brown, Jacquelyn A; Codreanu, Simona G; Shi, Mingjian; Sherrod, Stacy D; Markov, Dmitry A; Neely, M Diana; Britt, Clayton M; Hoilett, Orlando S; Reiserer, Ronald S; Samson, Philip C; McCawley, Lisa J; Webb, Donna J; Bowman, Aaron B; McLean, John A; Wikswo, John P

    2016-12-12

    Understanding blood-brain barrier responses to inflammatory stimulation (such as lipopolysaccharide mimicking a systemic infection or a cytokine cocktail that could be the result of local or systemic inflammation) is essential to understanding the effect of inflammatory stimulation on the brain. It is through the filter of the blood-brain barrier that the brain responds to outside influences, and the blood-brain barrier is a critical point of failure in neuroinflammation. It is important to note that this interaction is not a static response, but one that evolves over time. While current models have provided invaluable information regarding the interaction between cytokine stimulation, the blood-brain barrier, and the brain, these approaches-whether in vivo or in vitro-have often been only snapshots of this complex web of interactions. We utilize new advances in microfluidics, organs-on-chips, and metabolomics to examine the complex relationship of inflammation and its effects on blood-brain barrier function ex vivo and the metabolic consequences of these responses and repair mechanisms. In this study, we pair a novel dual-chamber, organ-on-chip microfluidic device, the NeuroVascular Unit, with small-volume cytokine detection and mass spectrometry analysis to investigate how the blood-brain barrier responds to two different but overlapping drivers of neuroinflammation, lipopolysaccharide and a cytokine cocktail of IL-1β, TNF-α, and MCP1,2. In this study, we show that (1) during initial exposure to lipopolysaccharide, the blood-brain barrier is compromised as expected, with increased diffusion and reduced presence of tight junctions, but that over time, the barrier is capable of at least partial recovery; (2) a cytokine cocktail also contributes to a loss of barrier function; (3) from this time-dependent cytokine activation, metabolic signature profiles can be obtained for both the brain and vascular sides of the blood-brain barrier model; and (4) collectively, we

  4. Rituximab-Associated Inflammatory Progressive Multifocal Leukoencephalopathy

    PubMed Central

    Schofield, Christina; Harris, Penelope

    2016-01-01

    Progressive multifocal leukoencephalopathy (PML) is a rare disease of the immunosuppression that results from neurotropic invasion of the JC virus which leads to demyelination of oligodendrocytes. Immune reconstitution inflammatory syndrome (IRIS), on the other hand, is a condition of inflammation that develops as the immune system reconstitutes. This case report describes a case of a 35-year-old HIV-negative male who presented with three weeks of right lower extremity paresthesias as well as right upper extremity apraxia. He was diagnosed with PML complicated by IRIS secondary to Rituximab, which he had completed four months prior to presentation. Despite the condition's poor prognosis, the patient recovered with only minor deficits. PMID:27965904

  5. NLRP3 deficiency ameliorates neurovascular damage in experimental ischemic stroke.

    PubMed

    Yang, Fan; Wang, Ziying; Wei, Xinbing; Han, Huirong; Meng, Xianfang; Zhang, Yan; Shi, Weichen; Li, Fengli; Xin, Tao; Pang, Qi; Yi, Fan

    2014-04-01

    Although the innate immune response to induce postischemic inflammation is considered as an essential step in the progression of cerebral ischemia injury, the role of innate immunity mediator NLRP3 in the pathogenesis of ischemic stroke is unknown. In this study, focal ischemia was induced by middle cerebral artery occlusion in NLRP3(-/-), NOX2(-/-), or wild-type (WT) mice. By magnetic resonance imaging (MRI), Evans blue permeability, and electron microscopic analyses, we found that NLRP3 deficiency ameliorated cerebral injury in mice after ischemic stroke by reducing infarcts and blood-brain barrier (BBB) damage. We further showed that the contribution of NLRP3 to neurovascular damage was associated with an autocrine/paracrine pattern of NLRP3-mediated interleukin-1β (IL-1β) release as evidenced by increased brain microvessel endothelial cell permeability and microglia-mediated neurotoxicity. Finally, we found that NOX2 deficiency improved outcomes after ischemic stroke by mediating NLRP3 signaling. This study for the first time shows the contribution of NLRP3 to neurovascular damage and provides direct evidence that NLRP3 as an important target molecule links NOX2-mediated oxidative stress to neurovascular damage in ischemic stroke. Pharmacological targeting of NLRP3-mediated inflammatory response at multiple levels may help design a new approach to develop therapeutic strategies for prevention of deterioration of cerebral function and for the treatment of stroke.

  6. 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.

  7. 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

  8. Neurovascular complications of cocaine.

    PubMed

    Daras, M; Tuchman, A J; Koppel, B S; Samkoff, L M; Weitzner, I; Marc, J

    1994-08-01

    Use of cocaine in the USA, has reached epidemic proportions since 1983, when "crack" was introduced, its higher potency compared with cocaine HCl has been associated with a tremendous increase in the incidence of strokes. This study reports our experience with 55 cases of neurovascular events (25 ischemic and 30 hemorrhagic) related to cocaine use in 54 patients. Only 15 patients had other risk factors for stroke. Twenty six patients smoked "crack", 10 snorted cocaine and 12 injected it intravenously. Strokes occurred within 3 h of cocaine use in 15 patients with infarcts and 17 with hemorrhages. Ten infarcts occurred after an overnight binge. Of the hemorrhage group 9 were subarachnoid, 16 intracerebral (8 basal ganglia, 7 hemispheric and one brain stem) and 5 intraventricular. Computerized tomography (CT) showed an aneurysm of the anterior communicating artery, as well as one of the vein of Galen. Four aneurysms and 3 AVMs were identified on angiography. CT revealed 15 infarcts; it was normal in 7 patients with pure motor hemiparesis and in 3 with findings consistent with anterior spinal artery infarction. Several mechanisms may be responsible for the cerebrovascular complications. A sudden rise in systemic arterial pressure may cause hemorrhages, frequently in association with an underlying aneurysm or AVM. Vasospasm, arteritis, myocardial infarction with cardiac arrhythmias and increased platelet aggregation may provoke infarcts.

  9. [Stent for neurovascular diseases].

    PubMed

    Sakai, Nobuyuki; Sakai, Chiaki

    2009-09-01

    A stent is a medical device that can provide scaffolding to vessels and organ walls to keep the arteries open. Different types of stents have been used in the filed of neurovascular diseases, such as atherosclerosis and aneurysms. Carotid artery stenting (CAS) was approved in 2007 in Japan, and it has been widely used as an alternative to carotid endarterectomy (CEA) for treating severe carotid artery stenosis. According to current approval, the indications of carotid artery stenting are observed in high-surgical-risk patients, patients with more than 50% symptomatic stenosis, and those with more than 80% asymptomatic stenosis. The use of nickel-titanium (nitinol) crush-resistant self-expanding stents (Precise) and emblic-protection devices (Angioguard XP) has been approved. Intracranial atherosclerotic disease have frequently posed a risk for recurrent stroke despite the intensive medical treatment. The design of the Wingspan stent system is different from that of balloon-expandable stents. Target lesions are predilated with an undersized angioplasty balloon, followed by stent deployment. Another important indication is for intracranial aneurysms. Since the discovery Guglielmi dechatable coils (GDC) in the early 1990s, endovascular treatment has been drastically improved all over the world. However, a high recurrence rate is observed when large and wide-necked aneurysms are treated with detachble coils. The application of self-expanding stents such as Neuroform, Enterprize, or LEO, is effective for packing coils into the aneurysm, and flow modification effect can be achieved for the curative reconstruction of the parent arteries. Further reserch will confirm the application of stents for the treatment of cerebrovascular disease.

  10. 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.

  11. Cellular mechanisms of neurovascular damage and repair after stroke.

    PubMed

    Arai, Ken; Lok, Josephine; Guo, Shuzhen; Hayakawa, Kazuhide; Xing, Changhong; Lo, Eng H

    2011-09-01

    The biological processes underlying stroke are complex, and patients have a narrow repertoire of therapeutic opportunities. After the National Institutes of Health (NIH) convened the Stroke Progress Review Group in 2001, stroke research shifted from having a purely neurocentric focus to adopting a more integrated view wherein dynamic interactions between all cell types contribute to function and dysfunction in the brain. This so-called "neurovascular unit" provides a conceptual framework that emphasizes cell-cell interactions between neuronal, glial, and vascular elements. Under normal conditions, signaling within the neurovascular unit helps maintain homeostasis. After stroke, cell-cell signaling is disturbed, leading to pathophysiology. More recently, emerging data now suggest that these cell-cell signaling mechanisms may also mediate parallel processes of neurovascular remodeling during stroke recovery. Because plasticity is a signature feature of the young and developing brain, these concepts may have special relevance to how the pediatric brain responds after stroke.

  12. Cortical specificity in neurovascular coupling.

    PubMed

    Scott, Nadia Aleyna

    2015-12-01

    Despite mounting contrary evidence, the metabolic hypothesis is viewed as the predominant theory underlying neurovascular coupling, or the link between neural activity and cerebral blood flow. In a recent study, Huo et al. (Huo BX, Smith JB, Drew PJ. J Neurosci 34: 10975-10981, 2014) combined multimodal imaging and electrophysiology in experiments using awake, voluntarily moving mice to explore whether neurovascular coupling is uniform throughout the cortex. Whereas their results can be viewed as demonstrating that neural activity and blood flow are uncoupled in the frontal cortex during movement, the importance of this study is the elucidation that the metabolic hypothesis may not be the principle facilitator of neurovascular coupling in some regions of the cortex. Copyright © 2015 the American Physiological Society.

  13. The Neurovascular Unit Coming of Age: A Journey through Neurovascular Coupling in Health and Disease.

    PubMed

    Iadecola, Costantino

    2017-09-27

    The concept of the neurovascular unit (NVU), formalized at the 2001 Stroke Progress Review Group meeting of the National Institute of Neurological Disorders and Stroke, emphasizes the intimate relationship between the brain and its vessels. Since then, the NVU has attracted the interest of the neuroscience community, resulting in considerable advances in the field. Here the current state of knowledge of the NVU will be assessed, focusing on one of its most vital roles: the coupling between neural activity and blood flow. The evidence supports a conceptual shift in the mechanisms of neurovascular coupling, from a unidimensional process involving neuronal-astrocytic signaling to local blood vessels to a multidimensional one in which mediators released from multiple cells engage distinct signaling pathways and effector systems across the entire cerebrovascular network in a highly orchestrated manner. The recently appreciated NVU dysfunction in neurodegenerative diseases, although still poorly understood, supports emerging concepts that maintaining neurovascular health promotes brain health. Copyright © 2017 Elsevier Inc. All rights reserved.

  14. Pro-inflammatory prostaglandins and progression of colorectal cancer

    PubMed Central

    Wang, Dingzhi; DuBois, Raymond N.

    2008-01-01

    Chronic inflammation is a risk factor for several gastrointestinal malignancies, including esophageal, gastric, hepatic, pancreatic and colorectal cancer. It has long been known that long-term use of nonsteroidal anti-inflammatory drugs (NSAIDs) reduces the relative risk of developing colorectal cancer. NSAIDs exert their anti-inflammatory and anti-tumor effects primarily by inhibiting activity of cyclooxygenase (COX) enzymes. Cyclooxygenase enzymes catalyze the conversion of arachidonic acid into prostanoids, including prostaglandins (PGs) and thromboxanes (TXs). Emerging evidence demonstrates that prostaglandins play an important role in inflammation and cancer. In this review, we highlight recent breakthroughs in our understanding of the roles of the different prostaglandins in colorectal cancer (CRC) and inflammatory bowel disease (IBD). These findings may provide a rationale for the development of new anti-inflammatory therapeutic approaches to cancer prevention and/or treatment. PMID:18406516

  15. 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

  16. 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

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

    PubMed

    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

    2015-10-01

    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.

  18. Neurovascular impairment and compartment syndrome.

    PubMed

    Wright, Elizabeth

    2009-04-01

    Compartment syndrome is a potential complication of musculoskeletal trauma and surgery. Early identification of compartment syndrome is critical because, if left untreated, it may result in limb loss or death. Nurses routinely perform neurovascular observations as a part of the patient's essential care in hospital. However, there is limited literature on the assessment and early identification of compartment syndrome in children, although most authors agree on assessment criteria such as pain, warmth, colour, movement, sensation and pulses. Improved approaches to assessment and early recognition may be required so that effective action can be taken to reduce the severity of the outcome.

  19. The saphenous neurovascular free flap.

    PubMed

    Acland, R D; Schusterman, M; Godina, M; Eder, E; Taylor, G I; Carlisle, I

    1981-06-01

    A new neurovascular free-flap donor area on the medial side of the knee is described. The flap is supplied by the saphenous artery, a branch of the descending genicular artery. It is drained both by the long saphenous vein and by the saphenous venae comitantes. Its nerve supply is from the medial femoral cutaneous nerve above the knee and the saphenous nerve below the knee. The flap is thin, has a long vascular pedicle (up to 15 cm) and a dependable nerve supply, and can be made quite large. The principal disadvantage is the donor wound, which requires grafting in most cases. We describe the anatomy of the saphenous flap, the method of raising it, and our early clinical experience with it both as a free flap and as a pedicled flap. Potential uses of the saphenous flap and its broader significance in relation to flaps on the lower extremity are briefly discussed.

  20. Neurovascular anatomy: a practical guide.

    PubMed

    Bell, Randy; Severson, Meryl A; Armonda, Rocco A

    2009-07-01

    Students of cerebrovascular anatomy and physiology tend to model their learning based on normal patterns of blood flow. As such, the focus tends toward arterial physiology and pathology with less than adequate understanding of the significance of the venous system. This article presents a different approach to neurovascular anatomy, starting with the venous system and demonstrating both normal and pathologic states. It reviews the cerebral circulation with attention to the microsurgical relationships, angiographic patterns, and fusion of dual-volume imaging. The importance of bony, sulcal, and ventricular anatomy is presented as it relates to the angiographic representation of pathologic lesions. Examples are given of anatomic variants seen with the operating microscope, biplanar angiography, and three-dimensional rotational angiography." Note that in the synopsis and throughout the article, first person usage has been changed to third person per journal style.

  1. Inflammatory profile in X-linked adrenoleukodystrophy patients: Understanding disease progression.

    PubMed

    Marchetti, Desirèe Padilha; Donida, Bruna; Jacques, Carlos Eduardo; Deon, Marion; Hauschild, Tatiane Cristina; Koehler-Santos, Patricia; de Moura Coelho, Daniella; Coitinho, Adriana Simon; Jardim, Laura Bannach; Vargas, Carmen Regla

    2017-07-19

    X-linked adrenoleukodystrophy (X-ALD) is an inherited disease characterized by progressive inflammatory demyelization in the brain, adrenal insufficiency, and an abnormal accumulation of very long chain fatty acids (VLCFA) in tissue and body fluids. Considering that inflammation might be involved in pathophysiology of X-ALD, we aimed to investigate pro- and anti-inflammatory cytokines in plasma from three different male phenotypes (CCER, AMN, and asymptomatic individuals). Our results showed that asymptomatic patients presented increased levels of pro-inflammatory cytokines IL-1β, IL-2, IL-8, and TNF-α and the last one was also higher in AMN phenotype. Besides, asymptomatic patients presented higher levels of anti-inflammatory cytokines IL-4 and IL-10. AMN patients presented higher levels of IL-2, IL-5, and IL-4. We might hypothesize that inflammation in X-ALD is related to plasmatic VLCFA concentration, since there were positive correlations between C26:0 plasmatic levels and pro-inflammatory cytokines in asymptomatic and AMN patients and negative correlation between anti-inflammatory cytokine and C24:0/C22:0 ratio in AMN patients. The present work yields experimental evidence that there is an inflammatory imbalance associated Th1, (IL-2, IL-6, and IFN-γ), Th2 (IL-4 and IL-10), and macrophages response (TNF-α and IL-1β) in the periphery of asymptomatic and AMN patients, and there is correlation between VLCFA plasmatic levels and inflammatory mediators in X-ALD. Furthermore, we might also speculate that the increase of plasmatic cytokines in asymptomatic patients could be considered an early biomarker of brain damage and maybe also a predictor of disease progression. © 2017 Wiley Periodicals, Inc.

  2. 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

  3. Brain imaging of neurovascular dysfunction in Alzheimer’s disease

    PubMed Central

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

    2017-01-01

    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

  4. 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.

  5. Balance of inflammatory response in stable gingivitis and progressive periodontitis lesions

    PubMed Central

    Honda, T; Domon, H; Okui, T; Kajita, K; Amanuma, R; Yamazaki, K

    2006-01-01

    The balance between inflammatory mediators and their counter-regulatory molecules may be crucial for determining the outcome of immune pathology of periodontal diseases. Based on clinical and immunological findings, the immune response in stable gingivitis lesion is supposed to be in balance, whereas the response is skewed towards the predominance of proinflammatory reactivity in progressive periodontitis lesion. However, this hypothesis has not been verified. Therefore, the aim of this study was to compare the gene expression profile of inflammatory mediators including proinflammatory cytokines and other inflammatory molecules, and anti-inflammatory cytokines by using quantitative real-time polymerase chain reaction in gingivitis and periodontitis lesions showing distinct clinical entities. For inflammatory mediators, interleukin (IL)-1β, interferon (IFN)-γ and receptor activator of nuclear factor (NF)-κB ligand tended to be higher in periodontitis, whereas tumour necrosis factor (TNF)-α and IL-12 p40 showed no difference. Heat-shock protein 60 (HSP60) expression was up-regulated significantly in periodontitis. For anti-inflammatory cytokines, transforming growth factor (TGF)-β1 expression tended to be higher in periodontitis compared with gingivitis, whereas no difference was observed for IL-10 and IL-4. These findings support further our previous finding that autoimmune response to HSP60 may exert in periodontitis lesion, and suggest that perhaps subtle differences in the balance of cytokines may result in different disease expression. PMID:16542362

  6. Characterizing and Targeting Bone Marrow-Derived Inflammatory Cells in Driving the Malignancy and Progression of Childhood Astrocytic Brain Tumors

    DTIC Science & Technology

    2016-11-01

    AWARD NUMBER: W81XWH-13-1-0303 TITLE: Characterizing and Targeting Bone Marrow-Derived Inflammatory Cells in Driving the Malignancy and...W81XWH-13-1-0303 Characterizing and Targeting Bone Marrow-Derived Inflammatory Cells in Driving the Malignancy and Progression of Childhood Astrocytic...lineages during the progression of gliomas, and We observed bone marrow derived mesenchymal stem cells have only minimal effort on tumor progression. We

  7. Two mouse mutations mapped to chromosome 11 with differing morphologies but similar progressive inflammatory alopecia.

    PubMed

    Wood, Geoffrey A; Flenniken, Ann; Osborne, Lucy; Fleming, Craig; Vukobradovic, Igor; Morikawa, Lily; Xu, Qiang; Porter, Rebecca; Adamson, S Lee; Rossant, Janet; McKerlie, Colin

    2005-05-01

    Alopecia is a common dermatological condition in humans and other mammals. Here, we present two similar but histologically distinct mouse models of scarring alopecia. Both mutant lines were generated using random genome-wide N-ethyl-N-nitrosourea mutagenesis, and both harbor dominant mutations on chromosome 11. In both mutants, there is an early onset of alopecia that progresses to nearly complete pelage hair loss in both males and females by 20 weeks of age. Histologically, there is an increased dermal cellularity due to inflammatory cell infiltration at 7-10 days of age. By 3 weeks of age, the epidermis is acanthotic and the dermis is approximately twice as thick as in control mice due to a substantial, mostly mononuclear, inflammatory cell infiltrate. This infiltrate becomes more perifollicular by 4-5 weeks of age but is localized differently in the two mutants. In alopecia 1 (Alo-1), the perifollicular infiltrate is confined to the portion of the follicle within the dermis, whereas in Alo-2, the infiltrate extends the full length of the follicle. Expression of major histocompatibility complex (MHC) class I on the follicular epithelium in the two mutants is much greater than that in non-mutants. Furthermore, MHC class I expression is localized differently in the two mutant lines and mirrors the pattern of the inflammatory infiltrate. Despite these differences, the clinical progression of alopecia is identical in both mutants. The early onset of the disease, predictable progression, and differences in inflammatory cell localization between the two mutants make these mice particularly useful models for inflammatory hair loss and autoimmune diseases in general.

  8. Subgingival Microbial and Inflammatory Cell Morphotypes Associated with Chronic Periodontitis Progression in Treated Adults.

    PubMed

    Keyes, Paul H; Rams, Thomas E

    2015-04-01

    In a secondary data analysis, this pilot study evaluated the relationship between subgingival biofilm morphotypes and chronic periodontitis progression in treated adults. Periodontal parameters in 47 adults with chronic periodontitis were assessed by a calibrated examiner at baseline and a mean 4.5 years after a non-surgical periodontal therapy regimen. Microbial and inflammatory cell morphotypes in subgingival biofilm specimens from each patient were evaluated with phase-contrast microscopy at baseline, and at post-treatment intervals. Chronic periodontitis progression in patients was defined as ≥ 2 teeth exhibiting ≥ 3 mm interproximal clinical periodontal attachment loss from baseline evaluations. Bivariate and odds ratio analysis assessed baseline and post-treatment variables relative to chronic periodontitis progression. Eight (17%) patients had chronic periodontitis progression. No baseline clinical, radiographic or microbiological variables, and no post-treatment clinical variables demonstrated statistically significant relationships with chronic periodontitis progression. Elevated post-treatment counts of subgingival spirochetes, medium to large-sized motile rods, and crevicular leukocytes, both alone and concurrently, appeared more frequently in patients experiencing chronic periodontitis progression. A post-treatment occurrence of high concurrent counts of subgingival spirochetes and crevicular leukocytes exhibited the strongest association with chronic periodontitis progression (odds ratio = 10.1; 95% Cl = 2.2, 45.4; p = 0.004), which was greater than with either morphotype alone. Joint morphotype analysis of subgingival spirochetes and crevicular leukocytes, as simplified biomarkers of pathogenic biofilm infection and host inflammatory responses in periodontal pockets, may be diagnostically useful in assessing risk of progressive disease in treated chronic periodontitis patients.

  9. 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. Copyright © 2015 Elsevier Inc. All rights reserved.

  10. 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

  11. 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.

  12. Eosinophil-derived IL-4 drives progression of myocarditis to inflammatory dilated cardiomyopathy.

    PubMed

    Diny, Nicola L; Baldeviano, G Christian; Talor, Monica V; Barin, Jobert G; Ong, SuFey; Bedja, Djahida; Hays, Allison G; Gilotra, Nisha A; Coppens, Isabelle; Rose, Noel R; Čiháková, Daniela

    2017-04-03

    Inflammatory dilated cardiomyopathy (DCMi) is a major cause of heart failure in children and young adults. DCMi develops in up to 30% of myocarditis patients, but the mechanisms involved in disease progression are poorly understood. Patients with eosinophilia frequently develop cardiomyopathies. In this study, we used the experimental autoimmune myocarditis (EAM) model to determine the role of eosinophils in myocarditis and DCMi. Eosinophils were dispensable for myocarditis induction but were required for progression to DCMi. Eosinophil-deficient ΔdblGATA1 mice, in contrast to WT mice, showed no signs of heart failure by echocardiography. Induction of EAM in hypereosinophilic IL-5Tg mice resulted in eosinophilic myocarditis with severe ventricular and atrial inflammation, which progressed to severe DCMi. This was not a direct effect of IL-5, as IL-5TgΔdblGATA1 mice were protected from DCMi, whereas IL-5(-/-) mice exhibited DCMi comparable with WT mice. Eosinophils drove progression to DCMi through their production of IL-4. Our experiments showed eosinophils were the major IL-4-expressing cell type in the heart during EAM, IL-4(-/-) mice were protected from DCMi like ΔdblGATA1 mice, and eosinophil-specific IL-4 deletion resulted in improved heart function. In conclusion, eosinophils drive progression of myocarditis to DCMi, cause severe DCMi when present in large numbers, and mediate this process through IL-4. © 2017 Diny et al.

  13. Malignant transformation of oral lichen planus by a chronic inflammatory process. Use of topical corticosteroids to prevent this progression?

    PubMed

    Otero-Rey, Eva Maria; Suarez-Alen, Fatima; Peñamaria-Mallon, Manuel; Lopez-Lopez, Jose; Blanco-Carrion, Andres

    2014-11-01

    Oral lichen planus is a potentially malignant disorder with a capacity, although low, for malignant transformation. Of all the factors related to the process of malignant transformation, it is believed that the chronic inflammatory process plays a key role in the development of oral cancer. This inflammatory process is capable of providing a microenvironment based on different inflammatory cells and molecules that affect cellular growth, proliferation and differentiation. The objectives of our study are: to review the available evidence about the possible relationship between the chronic inflammatory process present in oral lichen planus and its malignant transformation, to discuss the potential therapeutic implications derived from this relationship and to study the role that topical corticosteroids play in the control of oral lichen planus inflammation and its possible progression to malignant transformation. The maintenance of a minimum dose of topical corticosteroids could prevent the inflammatory progression of oral lichen planus to oral cancer.

  14. Drug abuse and the neurovascular unit.

    PubMed

    Egleton, Richard D; Abbruscato, Thomas

    2014-01-01

    Drug abuse continues to create a major international epidemic affecting society. A great majority of past drug abuse research has focused mostly on the mechanisms of addiction and the specific effects of substance use disorders on brain circuits and pathways that modulate reward, motivation, craving, and decision making. Few studies have focused on the neurobiology of acute and chronic substance abuse as it relates to the neurovascular unit (brain endothelial cell, neuron, astrocyte, microglia, and pericyte). Increasing research indicates that all cellular components of the neurovascular unit play a pivotal role in both the process of addiction and how drug abuse affects the brain response to diseases. This review will focus on the specific effects of opioids, amphetamines, alcohol, and nicotine on the neurovascular unit and its role in addiction and adaption to brain diseases. Elucidation of the role of the neurovascular unit on the neurobiology associated with drug addiction will help to facilitate the development of better therapeutic approaches for drug-dependent individuals.

  15. Overlap between linear scleroderma, progressive facial hemiatrophy and immune-inflammatory encephalitis in a paediatric cohort.

    PubMed

    De Somer, Lien; Morren, Marie-Anne; Muller, P C E Hissink; Despontin, Karine; Jansen, Katrien; Lagae, Lieven; Wouters, Carine

    2015-09-01

    Linear scleroderma en coup the sabre (LSCS), progressive facial hemiatrophy (PFH) and autoimmune encephalitis are distinct clinical entities, although patients with overlapping features have been reported. We performed a multicenter retrospective review of a series of children with LSCS and/or PFH to explore the relation between these entities. The files of 16 children were reviewed, 11 presented with LSCS, 5 with PFH, with time overlapping cutaneous features were seen. Extracutaneous signs were found in both groups. ANA were present in more than 50 % of patients. Almost half of our patients presented with CNS manifestations comprising unilateral headache, migraine and epilepsy with or without abnormalities on MRI. Brain biopsy in one patient was consistent with Rasmussen encephalitis. In two other children, associated autoimmune manifestations were present. Our patient cohort brings more arguments to consider LSCS and PFH as a single disease entity with LSCS and superficial skin involvement at one end of the spectrum and PFH with involvement of subcutaneous deep tissue at the other end. In both entities, encephalitis can be observed. Our findings of circulating ANA, intradermal lymphocytes and IgG, intrathecal IgG production and clinical improvement with immunosuppressive therapy endorse the concept of a possible common immune-inflammatory pathogenesis. • LSCS, PFH and immune-inflammatory encephalitis are distinct clinical entities, but patients with overlapping features have been reported. • We present a unique paediatric cohort with LSCS, PFH and/or encephalitis. • We endorse the concept of a common immune-inflammatory disease process.

  16. Netrin-1 up-regulation in inflammatory bowel diseases is required for colorectal cancer progression

    PubMed Central

    Paradisi, Andrea; Maisse, Carine; Coissieux, Marie-May; Gadot, Nicolas; Lépinasse, Florian; Delloye-Bourgeois, Céline; Delcros, Jean-Guy; Svrcek, Magali; Neufert, Clemens; Fléjou, Jean-François; Scoazec, Jean-Yves; Mehlen, Patrick

    2009-01-01

    Chronic inflammation and cancer are intimately associated. This is particularly true for inflammatory bowel diseases (IBD), such as ulcerative colitis and Crohn's disease, which show a major increased risk for colorectal cancer. While the understanding of the molecular pathogenesis of IBD has recently improved, the mechanisms that link these chronic inflammatory states to colorectal cancer development are in large part unknown. One of these mechanisms is NF-κB pathway activation which in turn may contribute to tumor formation by providing anti-apoptotic survival signals to the epithelial cells. Based on the observation that netrin-1, the anti-apoptotic ligand for the dependence receptors DCC and UNC5H is up-regulated in colonic crypts in response to NF-κB, we show here that colorectal cancers from inflammatory bowel diseases patients have selected up-regulation of netrin-1. Moreover, we demonstrate that this inflammation-driven netrin-1 up-regulation is causal for colorectal cancer development as interference with netrin-1 autocrine loop in a mouse model for ulcerative colitis-associated colorectal cancer, while showing no effect on inflammation, inhibits colorectal cancer progression. PMID:19721007

  17. Netrin-1 up-regulation in inflammatory bowel diseases is required for colorectal cancer progression.

    PubMed

    Paradisi, Andrea; Maisse, Carine; Coissieux, Marie-May; Gadot, Nicolas; Lépinasse, Florian; Delloye-Bourgeois, Céline; Delcros, Jean-Guy; Svrcek, Magali; Neufert, Clemens; Fléjou, Jean-François; Scoazec, Jean-Yves; Mehlen, Patrick

    2009-10-06

    Chronic inflammation and cancer are intimately associated. This is particularly true for inflammatory bowel diseases (IBD), such as ulcerative colitis and Crohn's disease, which show a major increased risk for colorectal cancer. While the understanding of the molecular pathogenesis of IBD has recently improved, the mechanisms that link these chronic inflammatory states to colorectal cancer development are in large part unknown. One of these mechanisms is NF-kappaB pathway activation which in turn may contribute to tumor formation by providing anti-apoptotic survival signals to the epithelial cells. Based on the observation that netrin-1, the anti-apoptotic ligand for the dependence receptors DCC and UNC5H is up-regulated in colonic crypts in response to NF-kappaB, we show here that colorectal cancers from inflammatory bowel diseases patients have selected up-regulation of netrin-1. Moreover, we demonstrate that this inflammation-driven netrin-1 up-regulation is causal for colorectal cancer development as interference with netrin-1 autocrine loop in a mouse model for ulcerative colitis-associated colorectal cancer, while showing no effect on inflammation, inhibits colorectal cancer progression.

  18. 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

  19. Cerebral blood flow regulation and neurovascular dysfunction in Alzheimer disease.

    PubMed

    Kisler, Kassandra; Nelson, Amy R; Montagne, Axel; Zlokovic, Berislav V

    2017-07-01

    Cerebral blood flow (CBF) regulation is essential for normal brain function. The mammalian brain has evolved a unique mechanism for CBF control known as neurovascular coupling. This mechanism ensures a rapid increase in the rate of CBF and oxygen delivery to activated brain structures. The neurovascular unit is composed of astrocytes, mural vascular smooth muscle cells and pericytes, and endothelia, and regulates neurovascular coupling. This Review article examines the cellular and molecular mechanisms within the neurovascular unit that contribute to CBF control, and neurovascular dysfunction in neurodegenerative disorders such as Alzheimer disease.

  20. Neurovascular development and links to disease.

    PubMed

    Ruhrberg, Christiana; Bautch, Victoria L

    2013-05-01

    The developing central nervous system (CNS) is vascularized via ingression of blood vessels from the outside as the neural tissue expands. This angiogenic process occurs without perturbing CNS architecture due to exquisite cross-talk between the neural compartment and invading blood vessels. Subsequently, this intimate relationship also promotes the formation of the neurovascular unit that underlies the blood-brain barrier and regulates blood flow to match brain activity. This review provides a historical perspective on research into CNS blood vessel growth and patterning, discusses current models used to study CNS angiogenesis, and provides an overview of the cellular and molecular mechanisms that promote blood vessel growth and maturation. Finally, we highlight the significance of these mechanisms for two different types of neurovascular CNS disease.

  1. Neurovascular Compression After the Latarjet Procedure.

    PubMed

    Galvin, Joseph W; Romanowski, James R; Boykin, Robert E; Eichinger, Josef K; Lafosse, Laurent

    2015-12-01

    The Latarjet procedure is an established and effective option for the treatment of recurrent anterior shoulder instability. Symptomatic compression of the vasculature around the shoulder and adjacent brachial plexus is uncommon and may be difficult to diagnose and treat. The purpose of this report is to describe a patient with neurovascular compression of the axillary artery and brachial plexus after an open Latarjet procedure. This is the first known report of documented combined vascular and neurologic thoracic outlet syndrome after a Latarjet procedure. Evaluation of this suspected problem requires a detailed clinical examination and a dynamic angiogram to verify which neurovascular structures are compressed. Treatment includes decompression of the brachial plexus and axillary vasculature by releasing tethering scar tissue or the remaining pectoralis minor that is creating a constricting sling effect. An arthroscopic approach provides for a careful and specific decompression. Additionally, the authors provide a review of the literature for neurologic complications and management for these complications.

  2. Neurovascular complications following carotid body paraganglioma resection.

    PubMed

    Lamblin, E; Atallah, I; Reyt, E; Schmerber, S; Magne, J-L; Righini, C A

    2016-11-01

    The present consecutive case series reports our experience in the management of carotid body paraganglioma and aims to assess whether the Shamblin classification or tumor size are predictive of early and late postoperative neurovascular complications. A retrospective study included 54 carotid body tumor resections in 49 patients, between 1980 and 2011. Data comprised early (<1month) and late (18 months) postoperative neurovascular complications. Early postoperative complications occurred in 31 cases, including 30 cases of cranial nerve deficit (56%). Cranial nerve deficit occurred in 83% of Shamblin III carotid body paragangliomas and was associated with significantly larger mean tumor size (4±1.4cm versus 2.9±1.3cm; P<0.01). Shamblin III tumor and tumor size>3.2cm emerged as predictive factors for early postoperative peripheral neurological complications. Eight patients (17%) showed no cranial nerve deficit recovery, even after 18 months' follow-up; no predictive factors could be identified for this. Surgical resection remains the only curative treatment in carotid body paraganglioma, with low vascular morbidity. However, early postoperative nerve deficit remains frequent (56%), although mostly temporary, with 17% definitive sequelae at 18 months. Tumor size and Shamblin classification are predictive of early neurovascular complications. Copyright © 2016 Elsevier Masson SAS. All rights reserved.

  3. Inflammatory peroxidases promote breast cancer progression in mice via regulation of the tumour microenvironment.

    PubMed

    Panagopoulos, Vasilios; Leach, Damien A; Zinonos, Irene; Ponomarev, Vladimir; Licari, Giovanni; Liapis, Vasilios; Ingman, Wendy V; Anderson, Peter; DeNichilo, Mark O; Evdokiou, Andreas

    2017-04-01

    Myeloperoxidase (MPO) and eosinophil peroxidase (EPO) are heme-containing enzymes, well known for their antimicrobial activity, are released in high quantities by infiltrating immune cells in breast cancer. However, the functional importance of their presence within the tumour microenvironment is unclear. We have recently described a new role for peroxidases as key regulators of fibroblast and endothelial cell functionality. In the present study, we investigate for the first time, the ability of peroxidases to promote breast cancer development and progression. Using the 4T1 syngeneic murine orthotopic breast cancer model, we examined whether increased levels of peroxidases in developing mammary tumours influences primary tumour growth and metastasis. We showed that MPO and EPO stimulation increased mammary tumour growth and enhanced lung metastases, effects that were associated with reduced tumour necrosis, increased collagen deposition and neo-vascularisation within the primary tumour. In vitro, peroxidase treatment, robustly stimulated human mammary fibroblast migration and collagen type I and type VI secretion. Mechanistically, peroxidases induced the transcription of pro-tumorigenic and metastatic MMP1, MMP3 and COX-2 genes. Taken together, these findings identify peroxidases as key contributors to cancer progression by augmenting pro-tumorigenic collagen production and angiogenesis. Importantly, this identifies inflammatory peroxidases as therapeutic targets in breast cancer therapy.

  4. Hemifacial spasm and neurovascular compression.

    PubMed

    Lu, Alex Y; Yeung, Jacky T; Gerrard, Jason L; Michaelides, Elias M; Sekula, Raymond F; Bulsara, Ketan R

    2014-01-01

    Hemifacial spasm (HFS) is characterized by involuntary unilateral contractions of the muscles innervated by the ipsilateral facial nerve, usually starting around the eyes before progressing inferiorly to the cheek, mouth, and neck. Its prevalence is 9.8 per 100,000 persons with an average age of onset of 44 years. The accepted pathophysiology of HFS suggests that it is a disease process of the nerve root entry zone of the facial nerve. HFS can be divided into two types: primary and secondary. Primary HFS is triggered by vascular compression whereas secondary HFS comprises all other causes of facial nerve damage. Clinical examination and imaging modalities such as electromyography (EMG) and magnetic resonance imaging (MRI) are useful to differentiate HFS from other facial movement disorders and for intraoperative planning. The standard medical management for HFS is botulinum neurotoxin (BoNT) injections, which provides low-risk but limited symptomatic relief. The only curative treatment for HFS is microvascular decompression (MVD), a surgical intervention that provides lasting symptomatic relief by reducing compression of the facial nerve root. With a low rate of complications such as hearing loss, MVD remains the treatment of choice for HFS patients as intraoperative technique and monitoring continue to improve.

  5. Subarachnoid Hemorrhage, Spreading Depolarizations and Impaired Neurovascular Coupling

    PubMed Central

    Koide, Masayo; Sukhotinsky, Inna; Ayata, Cenk; Wellman, George C.

    2013-01-01

    Aneurysmal subarachnoid hemorrhage (SAH) has devastating consequences on brain function including profound effects on communication between neurons and the vasculature leading to cerebral ischemia. Physiologically, neurovascular coupling represents a focal increase in cerebral blood flow to meet increased metabolic demand of neurons within active regions of the brain. Neurovascular coupling is an ongoing process involving coordinated activity of the neurovascular unit—neurons, astrocytes, and parenchymal arterioles. Neuronal activity can also influence cerebral blood flow on a larger scale. Spreading depolarizations (SD) are self-propagating waves of neuronal depolarization and are observed during migraine, traumatic brain injury, and stroke. Typically, SD is associated with increased cerebral blood flow. Emerging evidence indicates that SAH causes inversion of neurovascular communication on both the local and global level. In contrast to other events causing SD, SAH-induced SD decreases rather than increases cerebral blood flow. Further, at the level of the neurovascular unit, SAH causes an inversion of neurovascular coupling from vasodilation to vasoconstriction. Global ischemia can also adversely affect the neurovascular response. Here, we summarize current knowledge regarding the impact of SAH and global ischemia on neurovascular communication. A mechanistic understanding of these events should provide novel strategies to treat these neurovascular disorders. PMID:23577279

  6. 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.

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

    PubMed Central

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

    2006-01-01

    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 was observed in Matrigel plugs implanted in C57BL/6 mice following 5 week exposures to 5-500 ppb arsenic (Soucy et al., 2005). 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. PMID:17123562

  8. Lactobacillus acidophilus ATCC 4356 attenuates the atherosclerotic progression through modulation of oxidative stress and inflammatory process.

    PubMed

    Chen, Lihua; Liu, Wenen; Li, Yanming; Luo, San; Liu, Qingxia; Zhong, Yiming; Jian, Zijuan; Bao, Meihua

    2013-09-01

    The aim of this study was to investigate the effect of Lactobacillus (L.) acidophilus ATCC 4356 on the progression of atherosclerosis in Apoliprotein-E knockout (ApoE(-/-)) mice and the underlying mechanisms. Eight week-old ApoE(-/-) mice were treated with L. acidophilus ATCC 4356 daily for 12 weeks. The wild type (WT) mice or ApoE(-/-) mice in the vehicle group were treated with saline only. Body weights, serum lipid levels, aortic atherosclerotic lesions, and tissue oxidative and inflammatory statuses were examined among the groups. As compared to ApoE(-/-) mice in the vehicle group, ApoE(-/-) mice treated with L. acidophilus ATCC 4356 had no changes in body weights and serum lipid profiles, but showed decreased atherosclerotic lesion size in en face aorta. In comparison with WT mice, ApoE(-/-) mice in the vehicle group showed higher levels of serum malondialdehyde (MDA), oxidized low density lipoprotein (oxLDL) and tumor necrosis factor-alpha (TNF-α), but lower levels of interleukin-10 (IL-10) and superoxide dismutase (SOD) activities in serum. Administration of L. acidophilus ATCC 4356 could reverse these trends in a dose-dependent manner in ApoE(-/-) mice. Furthermore, ApoE(-/-) mice treated with L. acidophilus ATCC 4356 showed an inhibition of translocation of NF-κB p65 from cytoplasm to nucleus, suppression of degradation of aortic IκB-α, and improvements of gut microbiota distribution, as compared to ApoE(-/-) mice in the vehicle group. Our findings suggest that administration of L. acidophilus ATCC 4356 can attenuate the development of atherosclerotic lesions in ApoE(-/-) mice through reducing oxidative stress and inflammatory response. Copyright © 2013 Elsevier B.V. All rights reserved.

  9. HMGA1 drives stem cell, inflammatory pathway, and cell cycle progression genes during lymphoid tumorigenesis

    PubMed Central

    2011-01-01

    Background Although the high mobility group A1 (HMGA1) gene is widely overexpressed in diverse cancers and portends a poor prognosis in some tumors, the molecular mechanisms that mediate its role in transformation have remained elusive. HMGA1 functions as a potent oncogene in cultured cells and induces aggressive lymphoid tumors in transgenic mice. Because HMGA1 chromatin remodeling proteins regulate transcription, HMGA1 is thought to drive malignant transformation by modulating expression of specific genes. Genome-wide studies to define HMGA1 transcriptional networks during tumorigenesis, however, are lacking. To define the HMGA1 transcriptome, we analyzed gene expression profiles in lymphoid cells from HMGA1a transgenic mice at different stages in tumorigenesis. Results RNA from lymphoid samples at 2 months (before tumors develop) and 12 months (after tumors are well-established) was screened for differential expression of > 20,000 unique genes by microarray analysis (Affymetrix) using a parametric and nonparametric approach. Differential expression was confirmed by quantitative RT-PCR in a subset of genes. Differentially expressed genes were analyzed for cellular pathways and functions using Ingenuity Pathway Analysis. Early in tumorigenesis, HMGA1 induced inflammatory pathways with NFkappaB identified as a major node. In established tumors, HMGA1 induced pathways involved in cell cycle progression, cell-mediated immune response, and cancer. At both stages in tumorigenesis, HMGA1 induced pathways involved in cellular development, hematopoiesis, and hematologic development. Gene set enrichment analysis showed that stem cell and immature T cell genes are enriched in the established tumors. To determine if these results are relevant to human tumors, we knocked-down HMGA1 in human T-cell leukemia cells and identified a subset of genes dysregulated in both the transgenic and human lymphoid tumors. Conclusions We found that HMGA1 induces inflammatory pathways early in

  10. [Myocarditis in a cachectic female, nonsteroidal anti-inflammatory drugs abuser, in a course of progressive systemic sclerosis].

    PubMed

    Wozakowska-Kapłon, Beata; Gorczyca, Iwona; Maciejowska-Roge, Maria

    2009-11-01

    A case of 70-year-old cachectic female, nonsteroid anti-inflammatory drugs abuser, with progressive systemic sclerosis, who was admitted to our hospital due to joint pain and fatigue is presented. During hospitalisation the patient developed symptoms of acute myocarditis. Angiography of coronary arteries did not reveal narrowing of the vessels. Alimentary supplementation and therapy for heart failure (diuretics, vasodilators, angiotensin-converting enzyme inhibitor and beta-blocker) were used. In repeated echocardiography examinations ejection fraction systematically improved and hemodynamic stabilisation was obtained. Scleroderma, malnutrition, toxicity of nonsteroid anti-inflammatory drugs and infectious agents were considered as a cause of myocarditis.

  11. 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

  12. Early neurovascular dysfunction in a transgenic rat model of Alzheimer’s disease

    PubMed Central

    Joo, Illsung L.; Lai, Aaron Y.; Bazzigaluppi, Paolo; Koletar, Margaret M.; Dorr, Adrienne; Brown, Mary E.; Thomason, Lynsie A. M.; Sled, John G.; McLaurin, JoAnne; Stefanovic, Bojana

    2017-01-01

    Alzheimer’s disease (AD), pathologically characterized by amyloid-β peptide (Aβ) accumulation, neurofibrillary tangle formation, and neurodegeneration, is thought to involve early-onset neurovascular abnormalities. Hitherto studies on AD-associated neurovascular injury have used animal models that exhibit only a subset of AD-like pathologies and demonstrated some Aβ-dependent vascular dysfunction and destabilization of neuronal network. The present work focuses on the early stage of disease progression and uses TgF344-AD rats that recapitulate a broader repertoire of AD-like pathologies to investigate the cerebrovascular and neuronal network functioning using in situ two-photon fluorescence microscopy and laminar array recordings of local field potentials, followed by pathological analyses of vascular wall morphology, tau hyperphosphorylation, and amyloid plaques. Concomitant to widespread amyloid deposition and tau hyperphosphorylation, cerebrovascular reactivity was strongly attenuated in cortical penetrating arterioles and venules of TgF344-AD rats in comparison to those in non-transgenic littermates. Blood flow elevation to hypercapnia was abolished in TgF344-AD rats. Concomitantly, the phase-amplitude coupling of the neuronal network was impaired, evidenced by decreased modulation of theta band phase on gamma band amplitude. These results demonstrate significant neurovascular network dysfunction at an early stage of AD-like pathology. Our study identifies early markers of pathology progression and call for development of combinatorial treatment plans. PMID:28401931

  13. Early neurovascular dysfunction in a transgenic rat model of Alzheimer's disease.

    PubMed

    Joo, Illsung L; Lai, Aaron Y; Bazzigaluppi, Paolo; Koletar, Margaret M; Dorr, Adrienne; Brown, Mary E; Thomason, Lynsie A M; Sled, John G; McLaurin, JoAnne; Stefanovic, Bojana

    2017-04-12

    Alzheimer's disease (AD), pathologically characterized by amyloid-β peptide (Aβ) accumulation, neurofibrillary tangle formation, and neurodegeneration, is thought to involve early-onset neurovascular abnormalities. Hitherto studies on AD-associated neurovascular injury have used animal models that exhibit only a subset of AD-like pathologies and demonstrated some Aβ-dependent vascular dysfunction and destabilization of neuronal network. The present work focuses on the early stage of disease progression and uses TgF344-AD rats that recapitulate a broader repertoire of AD-like pathologies to investigate the cerebrovascular and neuronal network functioning using in situ two-photon fluorescence microscopy and laminar array recordings of local field potentials, followed by pathological analyses of vascular wall morphology, tau hyperphosphorylation, and amyloid plaques. Concomitant to widespread amyloid deposition and tau hyperphosphorylation, cerebrovascular reactivity was strongly attenuated in cortical penetrating arterioles and venules of TgF344-AD rats in comparison to those in non-transgenic littermates. Blood flow elevation to hypercapnia was abolished in TgF344-AD rats. Concomitantly, the phase-amplitude coupling of the neuronal network was impaired, evidenced by decreased modulation of theta band phase on gamma band amplitude. These results demonstrate significant neurovascular network dysfunction at an early stage of AD-like pathology. Our study identifies early markers of pathology progression and call for development of combinatorial treatment plans.

  14. Conservative management of progressive external inflammatory root resorption after traumatic tooth intrusion.

    PubMed

    Ghafoor, Robia

    2013-05-01

    Intrusive luxation is one of the most severe types of dental trauma. The risk of development of inflammatory or replacement root resorption is high if not timely managed. Endodontic intervention is required soon after the occurrence of trauma, in an attempt to prevent or delay inflammatory root resorption. This case report emphasized timely referral for endodontic management of intruded tooth to prevent inflammatory root resorption.

  15. B cells moderate inflammatory progression and enhance bacterial containment upon pulmonary challenge with Mycobacterium tuberculosis.

    PubMed

    Maglione, Paul J; Xu, Jiayong; Chan, John

    2007-06-01

    Though much is known about the function of T lymphocytes in the adaptive immune response against Mycobacterium tuberculosis, comparably little is understood regarding the corresponding role of B lymphocytes. Indicating B cells as components of lymphoid neogenesis during pulmonary tuberculosis, we have identified ectopic germinal centers (GCs) in the lungs of infected mice. B cells in these pulmonary lymphoid aggregates express peanut agglutinin and GL7, two markers of GC B cells, as well as CXCR5, and migrate in response to the lymphoid-associated chemokine CXCL13 ex vivo. CXCL13 is negatively regulated by the presence of B cells, as its production is elevated in lungs of B cell-deficient (B cell(-/-)) mice. Upon aerosol with 100 CFU of M. tuberculosis Erdman, B cell(-/-) mice have exacerbated immunopathology corresponding with elevated pulmonary recruitment of neutrophils. Infected B cell(-/-) mice show increased production of IL-10 in the lungs, whereas IFN-gamma, TNF-alpha, and IL-10R remain unchanged from wild type. B cell(-/-) mice have enhanced susceptibility to infection when aerogenically challenged with 300 CFU of M. tuberculosis corresponding with elevated bacterial burden in the lungs but not in the spleen or liver. Adoptive transfer of B cells complements the phenotypes of B cell(-/-) mice, confirming a role for B cells in both modulation of the host response and optimal containment of the tubercle bacillus. As components of ectopic GCs, moderators of inflammatory progression, and enhancers of local immunity against bacterial challenge, B cells may have a greater role in the host defense against M. tuberculosis than previously thought.

  16. Differential microRNA expression tracks neoplastic progression in inflammatory bowel disease-associated colorectal cancer

    PubMed Central

    Kanaan, Ziad; Rai, Shesh N.; Eichenberger, M. Robert; Barnes, Christopher; Dworkin, Amy M.; Weller, Clayton; Cohen, Eric; Roberts, Henry; Keskey, Bobby; Petras, Robert E.; Crawford, Nigel P.S.; Galandiuk, Susan

    2012-01-01

    One of the most serious complications faced by inflammatory bowel disease (IBD) is the potential development of colorectal cancer (CRC). There is a compelling need to enhance the accuracy of cancer screening of IBD patients. MicroRNAs (miRNAs) are small non-protein-coding RNAs that play important roles in CRC oncogenesis. In this study, we report differential miRNA expression in IBD patients with associated CRC, from non-neoplastic tissue to dysplasia and eventually cancer. In addition, we identify and examine the role of dysregulated miRNAs in the TP53 pathway. In our CD patients, six miRNAs were up-regulated from non-neoplastic tissue to dysplasia, but down-regulated from dysplasia to cancer (miR-122, miR-181a, miR-146b-5p, let-7e, miR-17, miR-143) (p<0.001). Six differentially expressed miRNAs affected the TP53 pathway (miR-122, miR-214, miR-372, miR-15b, let-7e, miR-17) (p<0.001). Using two human colon cancer cell lines (HT-29 and HCT-116), E2F1, an upstream regulator of TP53, was down-regulated in both cell lines transfected with let-7e (p<0.05) as well as in HCT-116 cells transfected with miR-17 (p<0.05). Additionally, cyclin G, a cell-cycle regulator miR-122 target was down-regulated in both cell lines (p<0.05). Unique differentially expressed miRNAs were observed in CD-associated CRC progression. Six of these miRNAs had a tumorigenic effect on the TP53 pathway; the effect of three of which was studied using cell lines. PMID:22241525

  17. Serum bacterial toxins are related to the progression of inflammatory bowel disease.

    PubMed

    Qiu, Huajing; Sun, Xiaomin; Sun, Mingming; He, Chong; Li, Zhong; Liu, Zhanju

    2014-07-01

    Inflammatory bowel disease (IBD), including Crohn's disease (CD) and ulcerative colitis (UC), is an autoimmune disease. Disorder of intestinal microbes is thought to play a critical role in the pathogenesis of IBD. Detection of bacterial toxins could become a new approach to judge the situation of this disease. Serum samples were collected from 142 IBD patients and 40 healthy donors as well as 15 CD patients with anti-tumor necrosis factor (TNF) monoclonal antibody (infliximab [IFX]). Enzyme-linked immunosorbent assay kits for Clostridium difficile, Escherichia coli O157, salmonella, and Staphylococcus aureus were used to analyze these bacterial toxins in sera. The positive rates of bacterial toxins from C. difficile, E. coli O157, salmonella, and S. aureus in the IBD patients were found in low incidences and associated with disease duration, colonic involvement, and treatment with prednisone and immunomodulators. The active CD and UC patients had significant higher positive rates of these bacterial toxins than those in remission or healthy controls. Blockage of TNF with IFX in CD patients resulted in significant decreases of the levels of toxins of C. difficile, E. coli O157, salmonella, and S. aureus in sera. Some bacterial toxins are present in the sera of active IBD patients, and patients with long disease duration, colonic involvement, or treatment with prednisone and immunomodulators are more susceptible to bacterial infection. Inhibition of inflammation with IFX would reduce the bacterial toxins via improvement of intestinal inflammation. Detecting bacteria-derived toxins in sera can be used to predict the progression of IBD.

  18. Cutaneous neurovascular interaction involved in tactile sensation.

    PubMed

    Fromy, B; Sigaudo-Roussel, D; Saumet, J L

    2008-10-01

    The sense of touch is one of the most vital; still, it is incompletely understood. We review the afferent function that allows for the relay of sensory information from the periphery (the skin) to the central nervous system. Within this afferent function, we examine the different integrating levels including several candidates for cutaneous transducers, the conduction of the information via the afferent nervous fibres and the transmission of the sensory stimuli to higher brain structures, resulting in the perception of the different senses. We then examine the efferent system that stimulates the skin by secreting neurotransmitters. Finally, we discuss the tools available to study the cutaneous neurovascular interaction and conclude on a novel test that assesses this interaction triggered by the application of a local non noxious pressure (tactile stimulation).

  19. 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

  20. Stage Progression and Neurological Symptoms in Trypanosoma brucei rhodesiense Sleeping Sickness: Role of the CNS Inflammatory Response

    PubMed Central

    MacLean, Lorna; Reiber, Hansotto; Kennedy, Peter G. E.; Sternberg, Jeremy M.

    2012-01-01

    Background Human African trypanosomiasis progresses from an early (hemolymphatic) stage, through CNS invasion to the late (meningoencephalitic) stage. In experimental infections disease progression is associated with neuroinflammatory responses and neurological symptoms, but this concept requires evaluation in African trypanosomiasis patients, where correct diagnosis of the disease stage is of critical therapeutic importance. Methodology/Principal Findings This was a retrospective study on a cohort of 115 T.b.rhodesiense HAT patients recruited in Eastern Uganda. Paired plasma and CSF samples allowed the measurement of peripheral and CNS immunoglobulin and of CSF cytokine synthesis. Cytokine and immunoglobulin expression were evaluated in relation to disease duration, stage progression and neurological symptoms. Neurological symptoms were not related to stage progression (with the exception of moderate coma). Increases in CNS immunoglobulin, IL-10 and TNF-α synthesis were associated with stage progression and were mirrored by a reduction in TGF-β levels in the CSF. There were no significant associations between CNS immunoglobulin and cytokine production and neurological signs of disease with the exception of moderate coma cases. Within the study group we identified diagnostically early stage cases with no CSF pleocytosis but intrathecal immunoglobulin synthesis and diagnostically late stage cases with marginal CSF pleocytosis and no detectable trypanosomes in the CSF. Conclusions Our results demonstrate that there is not a direct linkage between stage progression, neurological signs of infection and neuroinflammatory responses in rhodesiense HAT. Neurological signs are observed in both early and late stages, and while intrathecal immunoglobulin synthesis is associated with neurological signs, these are also observed in cases lacking a CNS inflammatory response. While there is an increase in inflammatory cytokine production with stage progression, this is

  1. In vivo imaging of the neurovascular unit in CNS disease

    PubMed Central

    Merlini, Mario; Davalos, Dimitrios; Akassoglou, Katerina

    2014-01-01

    The neurovascular unit—comprised of glia, pericytes, neurons and cerebrovasculature—is a dynamic interface that ensures physiological central nervous system (CNS) functioning. In disease dynamic remodeling of the neurovascular interface triggers a cascade of responses that determine the extent of CNS degeneration and repair. The dynamics of these processes can be adequately captured by imaging in vivo, which allows the study of cellular responses to environmental stimuli and cell-cell interactions in the living brain in real time. This perspective focuses on intravital imaging studies of the neurovascular unit in stroke, multiple sclerosis (MS) and Alzheimer disease (AD) models and discusses their potential for identifying novel therapeutic targets. PMID:25197615

  2. New and safe experimental model of radiation-induced neurovascular histological changes for microsurgical research.

    PubMed

    Barrera-Ochoa, Sergi; Gallardo-Calero, Irene; Sallent, Andrea; López-Fernández, Alba; Vergés, Ramona; Giralt, Jordi; Aguirre-Canyadell, Marius; Velez, Roberto

    2017-04-01

    The aim is to create a new and safe experimental model of radiation-induced neurovascular histological changes with reduced morbidity and mortality for use with experimental microsurgical techniques. Seventy-two Sprague-Dawley rats (250-300 g) were divided as follows: Group I: control group, 24 rats clinically evaluated during six weeks; Group II: evaluation of acute side-effects (two-week follow-up period), 24 irradiated (20 Gy) rats; and Group III: evaluation of subacute side-effects (six-week follow-up period), 24 irradiated (20 Gy) rats. Variables included clinical assessments, weight, vascular permeability (arterial and venous), mortality and histological studies. No significant differences were observed between groups with respect to the variables studied. Significant differences were observed between groups I vs II-III regarding survival rates and histological changes to arteries, veins and nerves. Rat body weights showed progressive increases in all groups, and the mortality rate of the present model is 10.4% compared with 30-40% in the previous models. In conclusion, the designed model induces selective changes by radiotherapy in the neurovascular bundle without histological changes affecting the surrounding tissues. This model allows therapeutic experimental studies to be conducted, including the viability of microvascular and microneural sutures post radiotherapy in the cervical neurovascular bundle.

  3. Immune Reconstitution Inflammatory Syndrome Unmasking or Worsening AIDS-Related Progressive Multifocal Leukoencephalopathy: A Literature Review

    PubMed Central

    Fournier, Anna; Martin-Blondel, Guillaume; Lechapt-Zalcman, Emmanuèle; Dina, Julia; Kazemi, Apolline; Verdon, Renaud; Mortier, Emmanuel; de La Blanchardière, Arnaud

    2017-01-01

    Incidence of progressive multifocal leukoencephalopathy (PML) in HIV-infected patients has declined in the combined antiretroviral therapy (cART) era although a growing number of acquired immunodeficiency syndrome (AIDS)-related PML-immune reconstitution inflammatory syndromes (PML-IRIS) have been published during the same period. Therapeutic management of PML-IRIS is not consensual and mainly relies on corticosteroids. Our main aim was, in addition to provide a thoughtful analysis of published PML-IRIS cases, to assess the benefit of corticosteroids in the management of PML-IRIS, focusing on confirmed cases. We performed a literature review of the 46 confirmed cases of PML-IRIS cases occurring in HIV-infected patients from 1998 to September 2016 (21 unmasking and 25 paradoxical PML-IRIS). AIDS-related PML-IRIS patients were mostly men (sex ratio 4/1) with a median age of 40.5 years (range 12–66). Median CD4 T cell count before cART and at PML-IRIS onset was 45/μl (0–301) and 101/μl (20–610), respectively. After cART initiation, PML-IRIS occurred within a median timescale of 38 days (18–120). Clinical signs were motor deficits (69%), speech disorders (36%), cognitive disorders (33%), cerebellar ataxia (28%), and visual disturbances (23%). Brain MRI revealed hyperintense areas on T2-weighted sequences and FLAIR images (76%) and suggestive contrast enhancement (87%). PCR for John Cunningham virus (JCV) in cerebrospinal fluid (CSF) was positive in only 84% of cases; however, when performed, brain biopsy confirmed diagnosis of PML in 90% of cases and demonstrated histological signs of IRIS in 95% of cases. Clinical worsening related to PML-IRIS and leading to death was observed in 28% of cases. Corticosteroids were prescribed in 63% of cases and maraviroc in one case. Statistical analysis failed to demonstrate significant benefit from steroid treatment, despite spectacular improvement in certain cases. Diagnosis of PML-IRIS should be considered in HIV

  4. Immune Reconstitution Inflammatory Syndrome Unmasking or Worsening AIDS-Related Progressive Multifocal Leukoencephalopathy: A Literature Review.

    PubMed

    Fournier, Anna; Martin-Blondel, Guillaume; Lechapt-Zalcman, Emmanuèle; Dina, Julia; Kazemi, Apolline; Verdon, Renaud; Mortier, Emmanuel; de La Blanchardière, Arnaud

    2017-01-01

    Incidence of progressive multifocal leukoencephalopathy (PML) in HIV-infected patients has declined in the combined antiretroviral therapy (cART) era although a growing number of acquired immunodeficiency syndrome (AIDS)-related PML-immune reconstitution inflammatory syndromes (PML-IRIS) have been published during the same period. Therapeutic management of PML-IRIS is not consensual and mainly relies on corticosteroids. Our main aim was, in addition to provide a thoughtful analysis of published PML-IRIS cases, to assess the benefit of corticosteroids in the management of PML-IRIS, focusing on confirmed cases. We performed a literature review of the 46 confirmed cases of PML-IRIS cases occurring in HIV-infected patients from 1998 to September 2016 (21 unmasking and 25 paradoxical PML-IRIS). AIDS-related PML-IRIS patients were mostly men (sex ratio 4/1) with a median age of 40.5 years (range 12-66). Median CD4 T cell count before cART and at PML-IRIS onset was 45/μl (0-301) and 101/μl (20-610), respectively. After cART initiation, PML-IRIS occurred within a median timescale of 38 days (18-120). Clinical signs were motor deficits (69%), speech disorders (36%), cognitive disorders (33%), cerebellar ataxia (28%), and visual disturbances (23%). Brain MRI revealed hyperintense areas on T2-weighted sequences and FLAIR images (76%) and suggestive contrast enhancement (87%). PCR for John Cunningham virus (JCV) in cerebrospinal fluid (CSF) was positive in only 84% of cases; however, when performed, brain biopsy confirmed diagnosis of PML in 90% of cases and demonstrated histological signs of IRIS in 95% of cases. Clinical worsening related to PML-IRIS and leading to death was observed in 28% of cases. Corticosteroids were prescribed in 63% of cases and maraviroc in one case. Statistical analysis failed to demonstrate significant benefit from steroid treatment, despite spectacular improvement in certain cases. Diagnosis of PML-IRIS should be considered in HIV

  5. Altered neurovascular coupling during information-processing states.

    PubMed

    Jones, Myles; Devonshire, Ian M; Berwick, Jason; Martin, Chris; Redgrave, Peter; Mayhew, John

    2008-05-01

    Brain imaging techniques rely on changes in blood flow, volume and oxygenation to infer the loci and magnitude of changes in activity. Although progress has been made in understanding the link between stimulus-evoked neural activity and haemodynamics, the extent to which neurovascular-coupling relationships remain constant during different states of baseline cortical activity is poorly understood. Optical imaging spectroscopy, laser Doppler flowmetry and electrophysiology were used to measure haemodynamics and neural activity in the barrel cortex of anaesthetized rats. The responses to stimulation of the whisker pad were recorded during quiescence and cortical desynchronization produced by stimulation of the brainstem. Cortical desynchronization was accompanied by increases in baseline blood flow, volume and oxygenation. Haemodynamic responses to low-frequency whisker stimuli (1 Hz) were attenuated during arousal compared with that observed during quiescence. During arousal it was possible to increase stimulus-evoked haemodynamics by increasing the frequency of the stimulus. Neural responses to low-frequency stimuli were also attenuated but to a far lesser extent than the reduction in the accompanying haemodynamics. In contrast, neuronal activity evoked by high-frequency stimuli (40 Hz) was enhanced during arousal, but induced haemodynamic responses of a similar magnitude compared with that observed for the same high-frequency stimulus presented during quiescence. These data suggest that there may be differences in stimulus-evoked neural activity and accompanying haemodynamics during different information-processing states.

  6. Cerebral Vascular Disease and Neurovascular Injury in Ischemic Stroke.

    PubMed

    Hu, Xiaoming; De Silva, T Michael; Chen, Jun; Faraci, Frank M

    2017-02-03

    The consequences of cerebrovascular disease are among the leading health issues worldwide. Large and small cerebral vessel disease can trigger stroke and contribute to the vascular component of other forms of neurological dysfunction and degeneration. Both forms of vascular disease are driven by diverse risk factors, with hypertension as the leading contributor. Despite the importance of neurovascular disease and subsequent injury after ischemic events, fundamental knowledge in these areas lag behind our current understanding of neuroprotection and vascular biology in general. The goal of this review is to address select key structural and functional changes in the vasculature that promote hypoperfusion and ischemia, while also affecting the extent of injury and effectiveness of therapy. In addition, as damage to the blood-brain barrier is one of the major consequences of ischemia, we discuss cellular and molecular mechanisms underlying ischemia-induced changes in blood-brain barrier integrity and function, including alterations in endothelial cells and the contribution of pericytes, immune cells, and matrix metalloproteinases. Identification of cell types, pathways, and molecules that control vascular changes before and after ischemia may result in novel approaches to slow the progression of cerebrovascular disease and lessen both the frequency and impact of ischemic events.

  7. Significance of neurovascular contact in classical trigeminal neuralgia.

    PubMed

    Maarbjerg, Stine; Wolfram, Frauke; Gozalov, Aydin; Olesen, Jes; Bendtsen, Lars

    2015-02-01

    Neurovascular contact is considered a frequent cause of classical trigeminal neuralgia and microvascular decompression with transposition of a blood vessel is preferred over other surgical options in medically refractory patients with classical trigeminal neuralgia. However, the prevalence of neurovascular contact has not been investigated in a representative cohort of patients with classical trigeminal neuralgia based in a neurological setting and using high-quality neuroimaging and blinded evaluation. We aimed to investigate whether presence and degree of neurovascular contact are correlated to pain side in classical trigeminal neuralgia. Consecutive classical trigeminal neuralgia patients with unilateral symptoms were referred to 3.0 T magnetic resonance imaging and included in a cross-sectional study. Magnetic resonance imaging scans were evaluated blindly and graded according to presence and degree of neurovascular contact. Severe neurovascular contact was defined as displacement or atrophy of the trigeminal nerve. A total of 135 patients with classical trigeminal neuralgia were included. Average age of disease onset was 53.0 years (95% confidence interval mean 40.5-55.5) and current age was 60.1 years (95% % confidence interval mean 57.5-62.7). Eighty-two (61%, 95% confidence interval 52-69%) patients were female. Neurovascular contact was prevalent both on the symptomatic and asymptomatic side [89% versus 78%, P = 0.014, odds ratio = 2.4 (1.2-4.8), P = 0.017], while severe neurovascular contact was highly prevalent on the symptomatic compared to the asymptomatic side [53% versus 13%, P < 0.001, odds ratio = 11.6 (4.7-28.9), P < 0.001]. Severe neurovascular contact was caused by arteries in 98%. We conclude that neurovascular contact causing displacement or atrophy of the trigeminal nerve is highly associated with the symptomatic side in classical trigeminal neuralgia as opposed to neurovascular contact in general. Our findings demonstrate that severe

  8. Surgical Management of Neurovascular Bundle in Uterine Fibroid Pseudocapsule

    PubMed Central

    Malvasi, Antonio; Hurst, Brad S.; Tsin, Daniel A.; Davila, Fausto; Dominguez, Guillermo; Dell'edera, Domenico; Cavallotti, Carlo; Negro, Roberto; Gustapane, Sarah; Teigland, Chris M.; Mettler, Liselotte

    2012-01-01

    The uterine fibroid pseudocapsule is a fibro-neurovascular structure surrounding a leiomyoma, separating it from normal peripheral myometrium. The fibroid pseudocapsule is composed of a neurovascular network rich in neurofibers similar to the neurovascular bundle surrounding a prostate. The nerve-sparing radical prostatectomy has several intriguing parallels to myomectomy. It may serve either as a useful model in modern fibroid surgical removal, or it may accelerate our understanding of the role of the fibrovascular bundle and neurotransmitters in the healing and restoration of reproductive potential after intracapsular myomectomy. Surgical innovations, such as laparoscopic or robotic myomectomy applied to the intracapsular technique with magnification of the fibroid pseudocapsule surrounding a leiomyoma, originated from the radical prostatectomy method that highlighted a careful dissection of the neurovascular bundle to preserve sexual functioning after prostatectomy. Gentle uterine leiomyoma detachment from the pseudocapsule neurovascular bundle has allowed a reduction in uterine bleeding and uterine musculature trauma with sparing of the pseudocapsule neuropeptide fibers. This technique has had a favorable impact on functionality in reproduction and has improved fertility outcomes. Further research should determine the role of the myoma pseudocapsule neurovascular bundle in the formation, growth, and pathophysiological consequences of fibroids, including pain, infertility, and reproductive outcomes. PMID:22906340

  9. New-onset vitiligo and progression of pre-existing vitiligo during treatment with biological agents in chronic inflammatory diseases.

    PubMed

    Méry-Bossard, L; Bagny, K; Chaby, G; Khemis, A; Maccari, F; Marotte, H; Perrot, J L; Reguiai, Z; Sigal, M L; Avenel-Audran, M; Boyé, T; Grasland, A; Gillard, J; Jullien, D; Toussirot, E

    2017-01-01

    The development of vitiligo during treatment with biological agents is an unusual event and only a few isolated cases have been reported. To describe the clinical characteristics and evolution of patients developing new-onset vitiligo following initiation of a biological agent for chronic inflammatory disease; and also to report the clinical course of pre-existing vitiligo under biological therapy. This nationwide multicentre, retrospective study, carried out between July 2013 and January 2015, describes the characteristics of a large series of 18 patients (psoriasis N = 8, inflammatory rheumatic diseases N = 8, ulcerative colitis N = 1, uveitis N = 1) who developed new-onset vitiligo while receiving a biological agent. TNFα inhibitors were the most common biological agent involved (13/18) while anti-IL-12/23 and anti-IL-17 agents or abatacept were less common (4/18 and 1/18 respectively). Mean duration of biological agent exposure before vitiligo onset was 13.9 ± 16.5 months. Outcome was favourable for most patients (15/17) while maintaining the biological agent. Data were also collected for 18 patients (psoriasis N = 5, inflammatory rheumatic diseases N = 10, inflammatory bowel diseases N = 2, SAPHO N = 1) who had pre-existing vitiligo when treatment with a biological agent started (TNFα inhibitors N = 15, ustekinumab N = 1, rituximab N = 1, tocilizumab N = 1). Vitiligo progressed in seven patients and was stable or improved in eight cases. Vitiligo may thus emerge and/or progress during treatment with various biological agents, mainly TNFα inhibitors and could be a new paradoxical skin reaction. De novo vitiligo displays a favourable outcome when maintaining the biological agent, whereas the prognosis seems worse in cases of pre-existing vitiligo. © 2016 European Academy of Dermatology and Venereology.

  10. The oxygen paradox of neurovascular coupling

    PubMed Central

    Leithner, Christoph; Royl, Georg

    2014-01-01

    The coupling of cerebral blood flow (CBF) to neuronal activity is well preserved during evolution. Upon changes in the neuronal activity, an incompletely understood coupling mechanism regulates diameter changes of supplying blood vessels, which adjust CBF within seconds. The physiologic brain tissue oxygen content would sustain unimpeded brain function for only 1 second if continuous oxygen supply would suddenly stop. This suggests that the CBF response has evolved to balance oxygen supply and demand. Surprisingly, CBF increases surpass the accompanying increases of cerebral metabolic rate of oxygen (CMRO2). However, a disproportionate CBF increase may be required to increase the concentration gradient from capillary to tissue that drives oxygen delivery. However, the brain tissue oxygen content is not zero, and tissue pO2 decreases could serve to increase oxygen delivery without a CBF increase. Experimental evidence suggests that CMRO2 can increase with constant CBF within limits and decreases of baseline CBF were observed with constant CMRO2. This conflicting evidence may be viewed as an oxygen paradox of neurovascular coupling. As a possible solution for this paradox, we hypothesize that the CBF response has evolved to safeguard brain function in situations of moderate pathophysiological interference with oxygen supply. PMID:24149931

  11. The neurovascular retina in retinopathy of prematurity.

    PubMed

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

    2009-11-01

    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.

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

    PubMed

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

    2016-09-06

    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. Crown Copyright © 2016. Published by Elsevier Ireland Ltd. All rights reserved.

  13. 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. Copyright © 2015 by The American Society for Pharmacology and Experimental Therapeutics.

  14. Radiation induced pulmonary fibrosis as a model of progressive fibrosis: Contributions of DNA damage, inflammatory response and cellular senescence genes.

    PubMed

    Beach, Tyler A; Johnston, Carl J; Groves, Angela M; Williams, Jacqueline P; Finkelstein, Jacob N

    2017-04-01

    Purpose/Aim of Study: Studies of pulmonary fibrosis (PF) have resulted in DNA damage, inflammatory response, and cellular senescence being widely hypothesized to play a role in the progression of the disease. Utilizing these aforementioned terms, genomics databases were interrogated along with the term, "pulmonary fibrosis," to identify genes common among all 4 search terms. Findings were compared to data derived from a model of radiation-induced progressive pulmonary fibrosis (RIPF) to verify that these genes are similarly expressed, supporting the use of radiation as a model for diseases involving PF, such as human idiopathic pulmonary fibrosis (IPF). In an established model of RIPF, C57BL/6J mice were exposed to 12.5 Gy thorax irradiation and sacrificed at 24 hours, 1, 4, 12, and 32 weeks following exposure, and lung tissue was compared to age-matched controls by RNA sequencing. Of 176 PF associated gene transcripts identified by database interrogation, 146 (>82%) were present in our experimental model, throughout the progression of RIPF. Analysis revealed that nearly 85% of PF gene transcripts were associated with at least 1 other search term. Furthermore, of 22 genes common to all four terms, 16 were present experimentally in RIPF. This illustrates the validity of RIPF as a model of progressive PF/IPF based on the numbers of transcripts reported in both literature and observed experimentally. Well characterized genes and proteins are implicated in this model, supporting the hypotheses that DNA damage, inflammatory response and cellular senescence are associated with the pathogenesis of PF.

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

    PubMed Central

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

    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

  16. 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

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

    PubMed

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

    2014-11-01

    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 (Ly6C(high)) MO recruitment and accumulation of CD11b(high) MO-derived MPs. Loss-of-function of CCR2 preferentially reduced this CD11b(high) MP population by impeding the release of Ly6C(high) 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.

  18. Acute neurovascular events in cancer patients receiving anti-vascular endothelial growth factor agents: Clinical experience in Paris University Hospitals.

    PubMed

    Tlemsani, Camille; Mir, Olivier; Psimaras, Dimitri; Vano, Yann-Alexandre; Ducreux, Michel; Escudier, Bernard; Rousseau, Benoit; Loirat, Delphine; Ceccaldi, Bernard; André, Thierry; Goldwasser, François; Ricard, Damien

    2016-10-01

    Despite the increasing and broadening use of agents targeting the vascular endothelial growth factor (VEGF) pathway, little is known on their acute neurovascular toxicities. This retrospective, multi-centre study examined the characteristics of patients with solid tumours who experienced an ischaemic or haemorrhagic stroke, a transient ischaemic accident (TIA) or a posterior reversible encephalopathy syndrome (PRES) while under anti-VEGF and until 8 weeks after termination of treatment and evaluated their management in our institutions from 2004 to 2014. Patients with newly diagnosed or progressive cerebral metastases at the time of the acute neurovascular event were excluded. Thirty-four patients (55.9% men) were identified, and experienced either ischaemic stroke (n = 18), PRES (n = 9), TIA (n = 6) or haemorrhagic stroke (n = 1). At initiation of anti-VEGF agents, 64.7% of patients had previous cardiovascular risk factors, and 52.9% had hypertension. Eight patients (23.5%) had received cerebral radiotherapy, five of which concomitantly to anti-VEGF treatment. Six (17%) patients died in the 8 weeks following the acute neurovascular event, and only 55.9% recovered their initial neurological status. Overall, 1-year and 2-year survival rates after the acute neurovascular event were 67.9% and 50%, respectively. When anti-VEGF agents were reintroduced (n = 6), severe vascular toxicity recurred in two patients. Neurovascular events under VEGF treatments are potentially severe, and the management of comorbid conditions has to be improved. A prospective collection of data and standardised management of such events is therefore being structured in our institutions. Copyright © 2016 Elsevier Ltd. All rights reserved.

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

    PubMed Central

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

    2016-01-01

    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

  20. 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. © 2016 by the Society for Experimental Biology and Medicine.

  1. 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

  2. A murine toolbox for imaging the neurovascular unit

    PubMed Central

    Hartmann, David A.; Underly, Robert G.; Watson, Ashley N.; Shih, Andy Y.

    2014-01-01

    The neurovascular unit coordinates many essential functions in the brain including blood flow control, nutrient delivery, and maintenance of blood-brain barrier integrity. These functions are the result of a cellular and molecular interplay that we are just beginning to understand. Cells of the neurovascular unit can now be investigated in the intact brain through the combined use of high-resolution in vivo imaging and non-invasive molecular tools to observe and manipulate cell function. Mouse lines that target transgene expression to cells of the neurovascular unit will be of great value in future work. However, a detailed evaluation of target cell specificity and expression pattern within the brain is required for many existing lines. The purpose of this review is to catalog mouse lines available to cerebrovascular biologists and to discuss their utility and limitations in future imaging studies. PMID:25352367

  3. Bidirectional relationship of mast cells-neurovascular unit communication in neuroinflammation and its involvement in POCD.

    PubMed

    Li, Nana; Zhang, Xiang; Dong, Hongquan; Hu, Youli; Qian, Yanning

    2017-03-30

    Postoperative cognitive dysfunction (POCD) has been hypothesized to be mediated by surgery-induced neuroinflammation, which is also a key element in the pathobiology of neurodegenerative diseases, stroke, and neuropsychiatric disorders. There is extensive communication between the immune system and the central nervous system (CNS). Inflammation resulting from activation of the innate immune system cells in the periphery can impact central nervous system behaviors, such as cognitive performance. Mast cells (MCs), as the"first responders" in the CNS, can initiate, amplify, and prolong other immune and nervous responses upon activation. In addition, MCs and their secreted mediators modulate inflammatory processes in multiple CNS pathologies and can thereby either contribute to neurological damage or confer neuroprotection. Neuroinflammation has been considered to be linked to neurovascular dysfunction in several neurological disorders. This review will provide a brief overview of the bidirectional relationship of MCs-neurovascular unit communication in neuroinflammation and its involvement in POCD, providing a new and unique therapeutic target for the adjuvant treatment of POCD.

  4. Have genomic discoveries in inflammatory bowel disease translated into clinical progress?

    PubMed

    Weizman, Adam V; Silverberg, Mark S

    2012-04-01

    Inflammatory bowel disease (IBD) is a heterogeneous disease that can be challenging to diagnose and manage. As a result, significant efforts have been made in attempting to identify clinical, genomic, and serologic markers of disease that can aid in patient assessment and treatment. Recent genomic discoveries have the potential to change clinical practice by identifying those susceptible to IBD, predict natural history and guide choice of therapy. Panels of genetic and genomic markers are more likely to emerge as clinical tools, as opposed to individual allelic variants. Serology and biomarkers are already being used and guiding management but await integration with genomic panels before achieving their maximal potential. This article reviews the current state of IBD genetics and evolving molecular approaches that may have potential clinical impact.

  5. 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

  6. Inflammatory risk factors and pathologies promoting Alzheimer's disease progression: is RAGE the key?

    PubMed

    Matrone, Carmela; Djelloul, Mehdi; Taglialatela, Giulio; Perrone, Lorena

    2015-02-01

    Epidemiological studies reveal growing evidence that most cases of Alzheimer`s Disease (AD) likely involve a combination of genetic and environmental risk factors. Identifying and validating these risk factors remains one of the most critical scientific challenges. Several diseases appear to have strong implications for neurodegeneration leading to dementia. This risk encompasses different forms of cardiovascular disease, carotid atherosclerosis, history of hypertension or high cholesterol, Type II diabetes, stroke or transient ischemic attack and brain trauma. However, the molecular pathways that are common and central in the progression of these diseases and AD are not yet elucidated. Unveiling these critical mechanisms at the molecular level is necessary for the development of therapeutic strategies aimed at preventing AD progression. The Receptor for Advanced Glycation Endproducts (RAGE) plays a key role in all the diseases that represent a risk for AD. RAGE-mediated signaling also contributes to neurodegeneration in AD, suggesting that it may mediate the effect of risk factors in promoting AD. We will summarize the current knowledge on the role of RAGE in pathologies promoting AD and in AD progression. We will also provide evidence showing the relevance of RAGE-induced inflammation as a risk pathway that is implicated in AD pathophysiology.

  7. Circulating ribonucleic acids and metabolic stress parameters may reflect progression of autoimmune or inflammatory conditions in juvenile type 1 diabetes.

    PubMed

    Kocic, Gordana; Pavlovic, Radmila; Najman, Stevo; Nikolic, Goran; Sokolovic, Dusan; Jevtovic-Stoimenov, Tatjana; Musovic, Dijana; Veljkovic, Andrej; Kocic, Radivoj; Djindjic, Natasa

    2011-07-28

    The sensing of ribonucleic acids (RNAs) by the monocyte/macrophage system occurs through the TLR7/8 Toll-like receptor family, the retinoic acid-inducible protein I (RIG-I), and the melanoma differentiation-associated protein-5 (MDA-5). The aim of the present study was to evaluate the effect of circulating RNAs, isolated from juvenile type 1 diabetic patients and healthy control children, on the inflammatory, apoptotic, and antiviral response in human peripheral blood mononuclear cells (PBMCs) isolated from a healthy donor. Obtained effects were compared to the effects of metabolic stress parameters (hyperglycemia, oxidative and nitrosative stress). Forty-eight patients with juvenile type 1 diabetes and control children were included in the study. By performing the chromatographic analysis of circulating RNAs, the peak at the retention time 0.645 min for diabetic and control RNA samples was identified. To determine whether circulating RNAs have an agonistic or antagonistic effect on the signaling pathways involved in inflammatory, apoptotic, and antiviral cascade, their effect on TLR8, RIG-I, MDA-5, MyD88, NF-KB, IRF-3, phosphoIRF-3, IRF-7, RIP, and p38 was evaluated. A significantly lower level was achieved by cultivating PBMCs with circulating RNAs isolated from type 1 diabetic children, compared to the intact PBMCs, in relation to TLR-8, MDA-5, NF-KB, phospho IRF-3, and RIP, while it was higher for Bax. All the metabolic stress conditions up-regulated NF-KB, Bcl-2, and Bax. The NF-êB determination seems to be the most sensitive parameter that may reflect disease processes associated with the progression of autoimmune or inflammatory conditions, while the IRF3/phosphoIRF3 ratio may suggest an insufficient antiviral response.

  8. Soluble common gamma chain exacerbates COPD progress through the regulation of inflammatory T cell response in mice

    PubMed Central

    Lee, Byunghyuk; Ko, Eunhee; Lee, Jiyeon; Jo, Yuna; Hwang, Hyunju; Goh, Tae Sik; Joo, Myungsoo; Hong, Changwan

    2017-01-01

    Cigarette smoking (CS) is a major cause of considerable morbidity and mortality by inducing lung cancer and COPD. COPD, a smoking-related disorder, is closely related to the alteration of immune system and inflammatory processes that are specifically mediated by T cells. Soluble common gamma chain (sγc) has recently been identified as a critical regulator of the development and differentiation of T cells. We examined the effects of sγc in a cigarette smoke extract (CSE) mouse model. The sγc level in CSE mice serum is significantly downregulated, and the cellularity of lymph node (LN) is systemically reduced in the CSE group. Overexpression of sγc enhances the cellularity and IFNγ production of CD8 T cells in LN and also enhances Th1 and Th17 differentiation of CD4 T cells in the respiratory tract. Mechanistically, the downregulation of sγc expression mediated by CSE is required to prevent excessive inflammatory T cell responses. Therefore, our data suggest that sγc may be one of the target molecules for the control of immunopathogenic progresses in COPD. PMID:28331303

  9. Regulating Inflammatory Immune Response to Atherogenic Antigens Prevents Development and Progression of Atherosclerosis in New Zealand White Rabbits.

    PubMed

    Philip, Sheena; Ponnusamy, Thiruvelselvan; Rao, Lakshmi Narasimha; Biradar, Suryakant; Kumar, Ramesh; Deshpande, Vrushali; Lu, Xinjie; Kakkar, Vijay V; Mundkur, Lakshmi A

    2016-08-01

    Inflammatory immune response to atherogenic self-antigens plays an important role in the development of atherosclerosis. We evaluated the role of oral tolerance to three peptides in controlling atherosclerosis in New Zealand white rabbits. Peptides derived from apolipoprotein B (ApoB), heat shock protein 60, and outer membrane protein from Chlamydia pneumoniae were expressed as part of the dendroaspin protein scaffold (AHC). Groups of 3-month-old rabbits were dosed orally with purified AHC protein either before the onset of disease or 2 months after inducing atherosclerosis; they were euthanized at the age of 7 months to study disease development and progression. Oral treatment with AHC resulted in a marked increase in regulatory T cells in the lymphoid organs and reduced the development and progression of atherosclerosis by 48.6% and 28.4%, respectively (P < 0.05). Oral tolerance decreased plaque inflammation, enhanced expression of anti-inflammatory and regulatory markers in the aorta, and attenuated the adaptive immune response to self-antigens. AHC treatment in rabbits with established disease significantly decreased vascular cell adhesion molecule 1 (VCAM-1) (6.2 fold) and monocyte chemoattractant protein-1(MCP-1) (3 fold) expression and reduced the infiltration of macrophages into the aorta. Collagen content and the smooth muscle cell-to-macrophage ratio were higher in treated animals, whereas markers of plaque vulnerability, including matrix metalloproteinase expression, were reduced. Our results suggest that oral tolerance to multiantigenic AHC molecule restores the immune balance and induces markers of plaque stability in rabbits. Copyright © 2016 Canadian Cardiovascular Society. Published by Elsevier Inc. All rights reserved.

  10. Inflammatory Myofibroblastic Tumor of the Lung: Two Progressing Pulmonary Nodules in a 25-Year-Old Adult With a Moraxella catharalis Infection.

    PubMed

    Schweckendiek, Daniel; Inci, Ilhan; Schneiter, Didier; Weder, Walter

    2015-12-01

    Inflammatory myofibroblastic tumor of the lung is a rare pulmonary lesion of intermediate biologic potential. Approximately half of all inflammatory myofibroblastic tumors show a rearrangement of the anaplastic lymphoma kinase (ALK) gene locus with potentially aberrant kinase expression. We present a 25-year-old man with recurrent exertional hemoptysis and two progressing pulmonary nodules in the right lung shown by computed tomography. After an anterolateral thoracotomy, pathologic studies revealed an inflammatory myofibroblastic tumor with rearrangement in the ALK gene, although aberrant expression of the anaplastic lymphoma kinase was not detected. In preoperative bronchial washings Moraxella catharalis was found.

  11. Probiotics in Curing Allergic and Inflammatory Conditions - Research Progress and Futuristic Vision.

    PubMed

    Dhama, Kuldeep; Latheef, Shyma K; Munjal, Ashok K; Khandia, Rekha; Samad, Hari A; Iqbal, Hafiz M N; Joshi, Sunil K

    2017-01-01

    Probiotics constitute the viable and beneficial microbes, which offer a dietary means to sustain the balance of gastro-intestinal (GI) microflora. Owing to their multiple health benefits, these have recently gained wide attention among researchers for exploring their potential in safeguarding the health of humans and animals. Probiotics could also modulate host-immune responses, thereby help in counteracting the immunological dysfunctions. Probiotics can inhibit the systemic invasion of pathogens entering through the GI mucosa/ oral cavity and have been found to possess effective prophylactic and therapeutic utilities against various infectious pathogens as well as non-infectious diseases and disorders. The present review expedites the role of probiotics in curing the ailments related to allergic and inflammatory disease conditions. A thorough reviewing of the literature and patents available on probiotics and their role in countering inflammation and allergy was conducted using authentic published resources available on Medline, PubMed, PubMed Central, Science Direct and other scientific databases. The information retrieved has been compiled and analysed pertaining to the theme of the study. Various micro-organisms have been evaluated for their probiotic efficacy, among these, the lactic acid bacteria viz. Lactobacillus sp. and Bifidobacterium sp. have extensively been studied and widely exploited. In the current post-globalized era of self and complementary medicines, the concept of probiotics and their therapeutic as well as prophylactic usage is gaining wide acceptance. As more and more bacterial strains are being proven for their pronounced influence on down regulation of immune regulation, atopic, inflammatory conditions, the use of probiotics is getting increased especially in the developed countries where such indications are high in prevalence. Apart from usage in immune related disorders, probiotics have been found to be effective in treating pouchitis

  12. Neurovascular coupling and energy metabolism in the developing brain

    PubMed Central

    Kozberg, M.; Hillman, E.

    2016-01-01

    In the adult brain, increases in local neural activity are almost always accompanied by increases in local blood flow. However, many functional imaging studies of the newborn and developing human brain have observed patterns of hemodynamic responses that differ from adult responses. Among the proposed mechanisms for the observed variations is that neurovascular coupling itself is still developing in the perinatal brain. Many of the components thought to be involved in actuating and propagating this hemodynamic response are known to still be developing postnatally, including perivascular cells such as astrocytes and pericytes. Both neural and vascular networks expand and are then selectively pruned over the first year of human life. Additionally, the metabolic demands of the newborn brain are still evolving. These changes are highly likely to affect early postnatal neurovascular coupling, and thus may affect functional imaging signals in this age group. This chapter will discuss the literature relating to neurovascular development. Potential effects of normal and aberrant development of neurovascular coupling on the newborn brain will also be explored, as well as ways to effectively utilize imaging techniques that rely on hemodynamic modulation such as fMRI and NIRS in younger populations. PMID:27130418

  13. Neurovascular coupling and energy metabolism in the developing brain.

    PubMed

    Kozberg, M; Hillman, E

    2016-01-01

    In the adult brain, increases in local neural activity are almost always accompanied by increases in local blood flow. However, many functional imaging studies of the newborn and developing human brain have observed patterns of hemodynamic responses that differ from adult responses. Among the proposed mechanisms for the observed variations is that neurovascular coupling itself is still developing in the perinatal brain. Many of the components thought to be involved in actuating and propagating this hemodynamic response are known to still be developing postnatally, including perivascular cells such as astrocytes and pericytes. Both neural and vascular networks expand and are then selectively pruned over the first year of human life. Additionally, the metabolic demands of the newborn brain are still evolving. These changes are highly likely to affect early postnatal neurovascular coupling, and thus may affect functional imaging signals in this age group. This chapter will discuss the literature relating to neurovascular development. Potential effects of normal and aberrant development of neurovascular coupling on the newborn brain will also be explored, as well as ways to effectively utilize imaging techniques that rely on hemodynamic modulation such as fMRI and NIRS in younger populations. © 2016 Elsevier B.V. All rights reserved.

  14. Pro-inflammatory-Related Loss of CXCL12 Niche Promotes Acute Lymphoblastic Leukemic Progression at the Expense of Normal Lymphopoiesis

    PubMed Central

    Balandrán, Juan Carlos; Purizaca, Jessica; Enciso, Jennifer; Dozal, David; Sandoval, Antonio; Jiménez-Hernández, Elva; Alemán-Lazarini, Leticia; Perez-Koldenkova, Vadim; Quintela-Núñez del Prado, Henry; Rios de los Ríos, Jussara; Mayani, Héctor; Ortiz-Navarrete, Vianney; Guzman, Monica L.; Pelayo, Rosana

    2017-01-01

    Pediatric oncology, notably childhood acute lymphoblastic leukemia (ALL), is currently one of the health-leading concerns worldwide and a biomedical priority. Decreasing overall leukemia mortality in children requires a comprehensive understanding of its pathobiology. It is becoming clear that malignant cell-to-niche intercommunication and microenvironmental signals that control early cell fate decisions are critical for tumor progression. We show here that the mesenchymal stromal cell component of ALL bone marrow (BM) differ from its normal counterpart in a number of functional properties and may have a key role during leukemic development. A decreased proliferation potential, contrasting with the strong ability of producing pro-inflammatory cytokines and an aberrantly loss of CXCL12 and SCF, suggest that leukemic lymphoid niches in ALL BM are unique and may exclude normal hematopoiesis. Cell competence ex vivo assays within tridimensional coculture structures indicated a growth advantage of leukemic precursor cells and their niche remodeling ability by CXCL12 reduction, resulting in leukemic cell progression at the expense of normal niche-associated lymphopoiesis. PMID:28111575

  15. Pro-inflammatory-Related Loss of CXCL12 Niche Promotes Acute Lymphoblastic Leukemic Progression at the Expense of Normal Lymphopoiesis.

    PubMed

    Balandrán, Juan Carlos; Purizaca, Jessica; Enciso, Jennifer; Dozal, David; Sandoval, Antonio; Jiménez-Hernández, Elva; Alemán-Lazarini, Leticia; Perez-Koldenkova, Vadim; Quintela-Núñez Del Prado, Henry; Rios de Los Ríos, Jussara; Mayani, Héctor; Ortiz-Navarrete, Vianney; Guzman, Monica L; Pelayo, Rosana

    2016-01-01

    Pediatric oncology, notably childhood acute lymphoblastic leukemia (ALL), is currently one of the health-leading concerns worldwide and a biomedical priority. Decreasing overall leukemia mortality in children requires a comprehensive understanding of its pathobiology. It is becoming clear that malignant cell-to-niche intercommunication and microenvironmental signals that control early cell fate decisions are critical for tumor progression. We show here that the mesenchymal stromal cell component of ALL bone marrow (BM) differ from its normal counterpart in a number of functional properties and may have a key role during leukemic development. A decreased proliferation potential, contrasting with the strong ability of producing pro-inflammatory cytokines and an aberrantly loss of CXCL12 and SCF, suggest that leukemic lymphoid niches in ALL BM are unique and may exclude normal hematopoiesis. Cell competence ex vivo assays within tridimensional coculture structures indicated a growth advantage of leukemic precursor cells and their niche remodeling ability by CXCL12 reduction, resulting in leukemic cell progression at the expense of normal niche-associated lymphopoiesis.

  16. Postacute stromal cell-derived factor-1α expression promotes neurovascular recovery in ischemic mice.

    PubMed

    Li, Yaning; Huang, Jun; He, Xiaosong; Tang, Guanghui; Tang, Yao-Hui; Liu, Yanqun; Lin, Xiaojie; Lu, Yifan; Yang, Guo-Yuan; Wang, Yongting

    2014-06-01

    Acute interventions of stroke are often challenged by a narrow treatment window. In this study, we explore treatments in the postacute phase of stroke with wider windows of opportunity. We investigated the effects of stromal cell-derived factor (SDF-1α) in neurovascular recovery during the postacute phase and downstream signaling pathways, underlying SDF-1α-mediated neurovascular recovery. Adult male Institute of Cancer Research (ICR) mice underwent middle cerebral artery occlusion. One week after middle cerebral artery occlusion, the animals received stereotactic injection of adenoassociated virus (AAV) carrying SDF-1α gene as treatment or AAV-green fluorescent protein as control and were monitored for 5 weeks. Neurobehavioral outcomes were evaluated, and brain atrophy was measured. Neurogenesis and angiogenesis were examined. The proliferation and migration of neural progenitor cells were evaluated. Downstream pathways of SDF-1α were investigated. Inflammatory response was monitored. Neurobehavioral outcomes were improved, and brain atrophy was greatly reduced for ≤5 weeks in AAV-SDF-1α groups when compared with the control. SDF-1 receptor CXCR4 was upregulated and colocalized with neural and endothelial progenitor cells. The number of nestin(+) and doublecortin(+)/bromodeoxyuridine(+) cells in the subventricular zone, doublecortin(+) and neuron(+)/bromodeoxyuridine(+) cells in the perifocal region, and cluster of differentiation (CD)31(+) and bromodeoxyuridine(+)/CD31(+) microvessels are also significantly increased in AAV-SDF-1α groups. Administration of CXCR4 antagonist AMD3100 eliminated the beneficial effects of SDF-1α. SDF-1α/CXCR4 interaction activated AKT, extracellular signal-regulated kinases (ERK), and P38 mitogen-activated protein kinase (MAPK) signaling pathways but not the c-Jun N-terminal kinase (JNK) pathway. SDF-1α promoted neurogenesis and angiogenesis during the postacute phase of ischemia without eliciting an inflammatory response

  17. Headache as a risk factor for neurovascular events in pediatric brain tumor patients.

    PubMed

    Kranick, Sarah M; Campen, Cynthia J; Kasner, Scott E; Kessler, Sudha K; Zimmerman, Robert A; Lustig, Robert A; Phillips, Peter C; Beslow, Lauren A; Ichord, Rebecca; Fisher, Michael J

    2013-04-16

    To determine whether severe recurrent headache is a risk factor for neurovascular events in children who received radiation for brain tumors. This is a retrospective cohort study of children with brain tumors who received cranial irradiation at a large tertiary care center, aged 0-21 years at diagnosis, with initial treatment between January 1, 1993 and December 31, 2002, and 2 or more follow-up visits. Patients were considered to have severe recurrent headache if this appeared as a complaint on 2 or more visits. Headaches attributed to tumor progression, shunt malfunction, or infection, or appearing at the end of life, were excluded. Medical records were reviewed for events of stroke or TIA. Of 265 subjects followed for a median of 6.0 years (interquartile range 1.7-9.2 years), stroke or TIA occurred in 7/37 (19%) with severe headaches compared to 6/228 (3%) without these symptoms (hazard ratio 5.3, 95% confidence interval 1.8-15.9, p = 0.003). Adjusting for multiple variables did not remove the significance of this risk. Median time to first neurovascular event for the entire cohort was 4.9 years (interquartile range 1.7-5.5 years). Severe recurrent headache appears to be a risk factor or predictor for subsequent cerebral ischemia in pediatric brain tumor survivors treated with radiation. This finding has clinical implications for both monitoring survivors and targeting a specific population for primary stroke prevention.

  18. Pericytes control key neurovascular functions and neuronal phenotype in the adult brain and during brain aging

    PubMed Central

    Bell, Robert D.; Winkler, Ethan A.; Sagare, Abhay P.; Singh, Itender; LaRue, Barb; Deane, Rashid; Zlokovic, Berislav V.

    2010-01-01

    SUMMARY Pericytes play a key role in the development of cerebral microcirculation. The exact role of pericytes in the neurovascular unit in the adult brain and during brain aging remains, however, elusive. Using adult viable pericyte-deficient mice, we show that pericyte loss leads to brain vascular damage by two parallel pathways: (1) reduction in brain microcirculation causing diminished brain capillary perfusion, cerebral blood flow and cerebral blood flow responses to brain activation which ultimately mediates chronic perfusion stress and hypoxia, and (2) blood-brain barrier breakdown associated with brain accumulation of serum proteins and several vasculotoxic and/or neurotoxic macromolecules ultimately leading to secondary neuronal degenerative changes. We show that age-dependent vascular damage in pericyte-deficient mice precedes neuronal degenerative changes, learning and memory impairment and the neuroinflammatory response. Thus, pericytes control key neurovascular functions that are necessary for proper neuronal structure and function, and pericytes loss results in a progressive age-dependent vascular-mediated neurodegeneration. PMID:21040844

  19. 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

  20. Selective inhibitors of nuclear export avert progression in preclinical models of inflammatory demyelination

    PubMed Central

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

    2015-01-01

    Axonal damage has been associated with aberrant protein trafficking. This study characterizes a novel class of compounds targeting nucleo-cytoplasmic shuttling, by binding to the catalytic groove of the nuclear export protein XPO1/CRM1 (chromosome region maintenance protein1). Oral administration of novel 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 observed also in other mouse models of axonal damage (i.e. kainic acid injection) and detected in cultured neurons after knockdown of Xpo1, the gene encoding for 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

  1. Inflammatory neuropathies.

    PubMed

    Whitesell, Jackie

    2010-09-01

    Inflammatory neuropathies are acquired disorders of peripheral nerves and occasionally of the central nervous system that can affect individuals at any age. The course can be monophasic, relapsing, or progressive. Inflammatory neuropathies are classified as acute or chronic. The acute form reaches a nadir by 4 weeks and the chronic form over 8 weeks or greater. The most common example of an acute inflammatory neuropathy is acute inflammatory demyelinating polyradiculoneuropathy (AIDP), which is part of the Guillain-Barré syndrome (GBS). The most common chronic inflammatory neuropathy is chronic inflammatory demyelinating polyradiculopathy (CIDP). Other chronic inflammatory neuropathies are multifocal motor neuropathy (MMN) and the Lewis-Sumner syndrome. The Fisher syndrome and Bickerstaff brainstem encephalitis occur acutely and have clinical overlap with AIDP.

  2. 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

  3. Growth Differentiation Factor‐15 Deficiency Inhibits Atherosclerosis Progression by Regulating Interleukin‐6–Dependent Inflammatory Response to Vascular Injury

    PubMed Central

    Bonaterra, Gabriel A.; Zügel, Stefanie; Thogersen, Joel; Walter, Sabrina A.; Haberkorn, Uwe; Strelau, Jens; Kinscherf, Ralf

    2012-01-01

    Background Growth differentiation factor (GDF)‐15 is a distant and divergent member of the transforming growth factor‐β superfamily (TGF‐β) . There is growing evidence indicating the involvement of GDF‐15 in various pathologies. Expression of GDF‐15 is induced under conditions of inflammation and increased GDF‐15 serum levels are suggested as a risk factor for cardiovascular diseases. Methods and Results We show here that GDF‐15 and proinflammatory cytokine interleukin (IL)‐6 levels are highly increased (5‐fold) in cultured oxidized low‐density lipoproteins–stimulated peritoneal macrophages derived from GDF‐15+/+/apolipoprotein (apo) E−/−, mice. Notably, IL‐6 induction on oxidized low‐density lipoproteins stimulation is completely abolished in the absence of GDF‐15. Consistent with our in vitro data GDF‐15 mRNA expression and protein levels are upregulated (2.5‐ to 6‐fold) in the atherosclerotic vessel wall of GDF‐15+/+/apoE−/− mice after a cholesterol‐enriched diet. GDF‐15 deficiency inhibits lumen stenosis (52%) and 18FDG uptake (34%) in the aortic arch despite increased serum triglyceride/cholesterol levels and elevated body weight. Immunohistomorphometric investigations of atherosclerotic lesions reveal a decreased percentage of inflammatory CD11b+ (57%) or IL‐6+, leukocytes, and apoptotic cells (74%) after 20 weeks. However, the total number of macrophages and cell density in atherosclerotic lesions of the innominate artery are increased in GDF‐15−/−/apoE−/− mice. Conclusions Our data suggest that GDF‐15 is involved in orchestrating atherosclerotic lesion progression by regulating apoptotic cell death and IL‐6–dependent inflammatory responses to vascular injury. PMID:23316317

  4. Neurovascular unit remodelling in the subacute stage of stroke recovery.

    PubMed

    Lake, Evelyn M R; Bazzigaluppi, Paolo; Mester, James; Thomason, Lynsie A M; Janik, Rafal; Brown, Mary; McLaurin, JoAnne; Carlen, Peter L; Corbett, Dale; Stanisz, Greg J; Stefanovic, Bojana

    2017-02-01

    Brain plasticity following focal cerebral ischaemia has been observed in both stroke survivors and in preclinical models of stroke. Endogenous neurovascular adaptation is at present incompletely understood yet its potentiation may improve long-term functional outcome. We employed longitudinal MRI, intracranial array electrophysiology, Montoya Staircase testing, and immunofluorescence to examine function of brain vessels, neurons, and glia in addition to forelimb skilled reaching during the subacute stage of ischemic injury progression. Focal ischemic stroke (~100mm(3) or ~20% of the total brain volume) was induced in adult Sprague-Dawley rats via direct injection of endothelin-1 (ET-1) into the right sensori-motor cortex, producing sustained impairment in left forelimb reaching ability. Resting perfusion and vascular reactivity to hypercapnia in the peri-lesional cortex were elevated by approximately 60% and 80% respectively seven days following stroke. At the same time, the normal topological pattern of local field potential (LFP) responses to peripheral somatosensory stimulation was abolished and the average power of spontaneous LFP activity attenuated by approximately 50% relative to the contra-lesional cortex, suggesting initial response attenuation within the peri-infarct zone. By 21 days after stroke, perilesional blood flow resolved, but peri-lesional vascular reactivity remained elevated. Concomitantly, the LFP response amplitudes increased with distance from the site of ET-1 injection, suggesting functional remodelling from the core of the lesion to its periphery. This notion was further buttressed by the lateralization of spontaneous neuronal activity: by day 21, the average ipsi-lesional power of spontaneous LFP activity was almost twice that of the contra-lesional cortex. Over the observation period, the peri-lesional cortex exhibited increased vascular density, along with neuronal loss, astrocytic activation, and recruitment and activation of microglia

  5. Genetic, Immune-Inflammatory, and Oxidative Stress Biomarkers as Predictors for Disability and Disease Progression in Multiple Sclerosis.

    PubMed

    Kallaur, Ana Paula; Reiche, Edna Maria Vissoci; Oliveira, Sayonara Rangel; Simão, Andrea Name Colado; Pereira, Wildea Lice de Carvalho Jennings; Alfieri, Daniela Frizon; Flauzino, Tamires; Proença, Caio de Meleck; Lozovoy, Marcell Alysson Batisti; Kaimen-Maciel, Damacio Ramón; Maes, Michael

    2017-01-01

    The aim of this study was to evaluate the TNFβ NcoI polymorphism (rs909253) and immune-inflammatory, oxidative, and nitrosative stress (IO&NS) biomarkers as predictors of disease progression in multiple sclerosis (MS). We included 212 MS patients (150 female, 62 male, mean (±standard deviation (SD)) age = 42.7 ± 13.8 years) and 249 healthy controls (177 female, 72 male, 36.8 ± 11 years). The disability was measured the Expanded Disability Status Scale (EDSS) in 2006 and 2011. We determined the TNFβ NcoI polymorphism and serum levels of interleukin (IL)-6, tumor necrosis factor (TNF)-α, interferon (IFN)-γ, IL-4, IL-10, and IL-17, albumin, ferritin, and plasma levels of lipid hydroperoxides (CL-LOOH), carbonyl protein, advanced oxidation protein products (AOPPs), nitric oxide metabolites (NOx), and total radical-trapping antioxidant parameter (TRAP). The mean EDSS (±SD) in 2006 was 1.62 ± 2.01 and in 2011 3.16 ± 2.29, and disease duration was 7.34 ± 7.0 years. IL-10, TNF-α, IFN-γ, AOPP, and NOx levels were significantly higher and IL-4 lower in MS patients with a higher 2011 EDSS scores (≥3) as compared with those with EDSS < 3. The actual increases in EDSS from 2006 to 2011 were positively associated with TNF-α and IFN-γ. Increased IFN-γ values were associated with higher pyramidal symptoms and increased IL-6 with sensitive symptoms. Increased carbonyl protein and IL-10 but lowered albumin levels predicted cerebellar symptoms. The TNFB1/B2 genotype decreased risk towards progression of pyramidal symptoms. Treatments with IFN-β and glatiramer acetate significantly reduced TNF-α but did not affect the other IO&NS biomarkers or disease progression. Taken together, IO&NS biomarkers and NcoI TNFβ genotypes predict high disability in MS and are associated with different aspects of disease progression. New drugs to treat MS should also target oxidative stress pathways.

  6. Inflammatory markers and extent and progression of early atherosclerosis: Meta-analysis of individual-participant-data from 20 prospective studies of the PROG-IMT collaboration

    PubMed Central

    Willeit, Peter; Thompson, Simon G; Agewall, Stefan; Bergström, Göran; Bickel, Horst; Catapano, Alberico L; Chien, Kuo-Liong; de Groot, Eric; Empana, Jean-Philippe; Etgen, Thorleif; Franco, Oscar H; Iglseder, Bernhard; Johnsen, Stein H; Kavousi, Maryam; Lind, Lars; Liu, Jing; Mathiesen, Ellisiv B; Norata, Giuseppe D; Olsen, Michael H; Papagianni, Aikaterini; Poppert, Holger; Price, Jackie F; Sacco, Ralph L; Yanez, David N; Zhao, Dong; Schminke, Ulf; Bülbül, Alpaslan; Polak, Joseph F; Sitzer, Matthias; Hofman, Albert; Grigore, Liliana; Dörr, Marcus; Su, Ta-Chen; Ducimetière, Pierre; Xie, Wuxiang; Ronkainen, Kimmo; Kiechl, Stefan; Rundek, Tatjana; Robertson, Christine; Fagerberg, Björn; Bokemark, Lena; Steinmetz, Helmuth; Ikram, M Arfan; Völzke, Henry; Lin, Hung-Ju; Plichart, Matthieu; Tuomainen, Tomi-Pekka; Desvarieux, Moise; McLachlan, Stela; Schmidt, Caroline; Kauhanen, Jussi; Willeit, Johann; W Lorenz, Matthias; Sander, Dirk

    2015-01-01

    Background Large-scale epidemiological evidence on the role of inflammation in early atherosclerosis, assessed by carotid ultrasound, is lacking. We aimed to quantify cross-sectional and longitudinal associations of inflammatory markers with common-carotid-artery intima-media thickness (CCA-IMT) in the general population. Methods Information on high-sensitivity C-reactive protein, fibrinogen, leucocyte count and CCA-IMT was available in 20 prospective cohort studies of the PROG-IMT collaboration involving 49,097 participants free of pre-existing cardiovascular disease. Estimates of associations were calculated within each study and then combined using random-effects meta-analyses. Results Mean baseline CCA-IMT amounted to 0.74mm (SD = 0.18) and mean CCA-IMT progression over a mean of 3.9 years to 0.011 mm/year (SD = 0.039). Cross-sectional analyses showed positive linear associations between inflammatory markers and baseline CCA-IMT. After adjustment for traditional cardiovascular risk factors, mean differences in baseline CCA-IMT per one-SD higher inflammatory marker were: 0.0082mm for high-sensitivity C-reactive protein (p < 0.001); 0.0072mm for fibrinogen (p < 0.001); and 0.0025mm for leucocyte count (p = 0.033). ‘Inflammatory load’, defined as the number of elevated inflammatory markers (i.e. in upper two quintiles), showed a positive linear association with baseline CCA-IMT (p < 0.001). Longitudinal associations of baseline inflammatory markers and changes therein with CCA-IMT progression were null or at most weak. Participants with the highest ‘inflammatory load’ had a greater CCA-IMT progression (p = 0.015). Conclusion Inflammation was independently associated with CCA-IMT cross-sectionally. The lack of clear associations with CCA-IMT progression may be explained by imprecision in its assessment within a limited time period. Our findings for ‘inflammatory load’ suggest important combined effects of the three inflammatory markers on early

  7. Inflammatory markers and extent and progression of early atherosclerosis: Meta-analysis of individual-participant-data from 20 prospective studies of the PROG-IMT collaboration.

    PubMed

    Willeit, Peter; Thompson, Simon G; Agewall, Stefan; Bergström, Göran; Bickel, Horst; Catapano, Alberico L; Chien, Kuo-Liong; de Groot, Eric; Empana, Jean-Philippe; Etgen, Thorleif; Franco, Oscar H; Iglseder, Bernhard; Johnsen, Stein H; Kavousi, Maryam; Lind, Lars; Liu, Jing; Mathiesen, Ellisiv B; Norata, Giuseppe D; Olsen, Michael H; Papagianni, Aikaterini; Poppert, Holger; Price, Jackie F; Sacco, Ralph L; Yanez, David N; Zhao, Dong; Schminke, Ulf; Bülbül, Alpaslan; Polak, Joseph F; Sitzer, Matthias; Hofman, Albert; Grigore, Liliana; Dörr, Marcus; Su, Ta-Chen; Ducimetière, Pierre; Xie, Wuxiang; Ronkainen, Kimmo; Kiechl, Stefan; Rundek, Tatjana; Robertson, Christine; Fagerberg, Björn; Bokemark, Lena; Steinmetz, Helmuth; Ikram, M Arfan; Völzke, Henry; Lin, Hung-Ju; Plichart, Matthieu; Tuomainen, Tomi-Pekka; Desvarieux, Moise; McLachlan, Stela; Schmidt, Caroline; Kauhanen, Jussi; Willeit, Johann; Lorenz, Matthias W; Sander, Dirk

    2016-01-01

    Large-scale epidemiological evidence on the role of inflammation in early atherosclerosis, assessed by carotid ultrasound, is lacking. We aimed to quantify cross-sectional and longitudinal associations of inflammatory markers with common-carotid-artery intima-media thickness (CCA-IMT) in the general population. Information on high-sensitivity C-reactive protein, fibrinogen, leucocyte count and CCA-IMT was available in 20 prospective cohort studies of the PROG-IMT collaboration involving 49,097 participants free of pre-existing cardiovascular disease. Estimates of associations were calculated within each study and then combined using random-effects meta-analyses. Mean baseline CCA-IMT amounted to 0.74 mm (SD = 0.18) and mean CCA-IMT progression over a mean of 3.9 years to 0.011 mm/year (SD = 0.039). Cross-sectional analyses showed positive linear associations between inflammatory markers and baseline CCA-IMT. After adjustment for traditional cardiovascular risk factors, mean differences in baseline CCA-IMT per one-SD higher inflammatory marker were: 0.0082 mm for high-sensitivity C-reactive protein (p < 0.001); 0.0072 mm for fibrinogen (p < 0.001); and 0.0025 mm for leucocyte count (p = 0.033). 'Inflammatory load', defined as the number of elevated inflammatory markers (i.e. in upper two quintiles), showed a positive linear association with baseline CCA-IMT (p < 0.001). Longitudinal associations of baseline inflammatory markers and changes therein with CCA-IMT progression were null or at most weak. Participants with the highest 'inflammatory load' had a greater CCA-IMT progression (p = 0.015). Inflammation was independently associated with CCA-IMT cross-sectionally. The lack of clear associations with CCA-IMT progression may be explained by imprecision in its assessment within a limited time period. Our findings for 'inflammatory load' suggest important combined effects of the three inflammatory markers on early atherosclerosis

  8. Protective effect of telmisartan on neurovascular unit and inflammasome in stroke-resistant spontaneously hypertensive rats.

    PubMed

    Liu, Wentao; Yamashita, Toru; Kurata, Tomoko; Kono, Syoichiro; Hishikawa, Nozomi; Deguchi, Kentaro; Zhai, Yun; Abe, Koji

    2015-06-01

    Hypertension is a crucial risk factor for both stroke and dementia, including Alzheimer's disease (AD). We inspected the effect of telmisartan on the neurovascular unit (NVU) and related inflammatory responses in spontaneously hypertensive rat stroke resistant (SHR-SR) by observing the components of NVU such as N-acetyl glucosamine oligomer (NAGO), collagen IV, astrocytes, and matrix metalloproteinase-9 (MMP-9), as well as inflammasome NOD-like receptors family protein 3 (NLRP3). In the present study, we examined the effect of a highly selective angiotensin type 1 (AT-1) antagonist of angiotensin 2 receptor with high lipid solubility, telmisartan, on NVU and related inflammatory responses in SHR-SR with a low dose (0.3 mg/kg/day) only for improving metabolic syndrome, and a high dose (3 mg/kg/day) for improving both metabolic syndrome and SHR-SR hypertension. Compared to normotensive Wistar rats, long-lasting hypertension in SHR-SR disrupted NVU by changing immunohistological components such as NAGO, collagen IV, astrocytes, and MMP-9. SHR-SR also strongly induced AD-related inflammasome NLRP3 in neuronal cells with age. However, such NVU disruption and inflammasome activation were greatly improved with dose-dependent telmisartan treatments. These results suggest that telmisartan comprehensively protected the NVU components by reducing inflammatory reactions relative to AD in hypertensive rats, which could also preclude the risk of AD under hypertension.

  9. Neurovascular aspects of skin neurogenic inflammation.

    PubMed

    Aubdool, Aisah A; Brain, Susan D

    2011-12-01

    Neurogenic inflammation is involved in skin inflammation. It is hypothesized that it is involved in the pathogenesis of the common chronic cutaneous vascular disorder rosacea, but the exact mechanism of action is currently unknown. Transient receptor potential vanilloid 1 (TRPV1) and ankyrin 1 (TRPA1) are widely expressed on primary sensory neuron endings and non-neuronal cells such as keratinocytes. Here we describe the potential for TRPV1 and TRPA1 receptors to be involved in the pathophysiology of rosacea due to their polymodal activation, including cold and hot temperature, pungent products from vegetable and spices, reactive oxygen species, and mechanical stimuli. We discuss the role of both receptors and the sensory neuropeptides that they release in inflammation and pain sensation and evidence suggesting that both TRPV1 and TRPA1 receptors may be promising therapeutic targets for the treatment of the inflammatory symptoms of rosacea.

  10. 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

  11. Computed tomography angiography to evaluate thoracic outlet neurovascular compression.

    PubMed

    Hasanadka, Ravishankar; Towne, Jonathan B; Seabrook, Gary R; Brown, Kellie R; Lewis, Brian D; Foley, W Dennis

    2007-01-01

    The objective was to evaluate the efficacy of computed tomography angiography with upper extremity hyperabduction to diagnose thoracic outlet syndrome. Over 5 years, 21 patients were treated surgically for neurogenic symptoms of thoracic outlet syndrome. For patients whose diagnosis was unclear after history and physical examination, adjunctive tests (duplex, magnetic resonance angiography, or computed tomography angiography) were performed to help establish the diagnosis. Five of the 6 computed tomography angiograms were positive. The sixth computed tomography was deemed to be an incomplete study. With mean follow-up of 9.4 months, 95% (n = 19) of patients with a positive hyperabduction test on physical examination were free of symptoms postoperatively. All patients with a positive computed tomography angiogram, with their neurovascular compression localized to the thoracic outlet, had successful operative decompression. Computed tomography angiogram with abduction of the arm can be used as an adjunct to confirm the diagnosis of neurovascular compression and then predict successful operative decompression.

  12. Inherited neurovascular diseases affecting cerebral blood vessels and smooth muscle.

    PubMed

    Sam, Christine; Li, Fei-Feng; Liu, Shu-Lin

    2015-10-01

    Neurovascular diseases are among the leading causes of mortality and permanent disability due to stroke, aneurysm, and other cardiovascular complications. Cerebral autosomal-dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) and Marfan syndrome are two neurovascular disorders that affect smooth muscle cells through accumulation of granule and osmiophilic materials and defective elastic fiber formations respectively. Moyamoya disease, hereditary hemorrhagic telangiectasia (HHT), microcephalic osteodysplastic primordial dwarfism type II (MOPD II), and Fabry's disease are disorders that affect the endothelium cells of blood vessels through occlusion or abnormal development. While much research has been done on mapping out mutations in these diseases, the exact mechanisms are still largely unknown. This paper briefly introduces the pathogenesis, genetics, clinical symptoms, and current methods of treatment of the diseases in the hope that it can help us better understand the mechanism of these diseases and work on ways to develop better diagnosis and treatment.

  13. Clavicular caution: an anatomic study of neurovascular structures.

    PubMed

    Robinson, Luke; Persico, Federico; Lorenz, Eric; Seligson, David

    2014-12-01

    Open reduction and internal fixation of the clavicle is used to treat displaced fractures of the midshaft of the clavicle. Complications of operative intervention include injuries to major neurovascular structures including the subclavian artery and vein. Unlike other surgical approaches, palpation or visualization of the deep neurovascular structures at risk is rarely performed and is not part of the routine approach. This study aims to further elucidate the relationship of major neurovascular structures in the shoulder to the clavicle using sectioned fresh frozen cadaveric specimens. Using five cadaveric specimens, sagittal sections were performed using a band saw. Sections were taken every 15mm. Using these sections, structures were identified and photos were taken using a standardized approach to allow for precise and accurate measurements. Measurements taken included the distance from the nearest clavicular cortex to the centre of the subclavian artery, vein, and brachial plexus. These measurements were taken from five limbs on five different cadavers. Our results were consistent with previous studies. Medially, the subclavian vein was intimately related medially (4.8mm) to the clavicle, whereas the artery and brachial plexus were both >2cm from the clavicle. At about the junction of the middle and second-thirds of the clavicle, all three structures were within 2cm of the clavicle. Moving laterally, these structures moved further away and at the acromioclavicular (AC) joint were at least 4.5cm away from the clavicle on average. This study reiterates that the medial third of the clavicle is closely associated with neurovascular structures and that care should be taken here when using drills, depth gauges, and clamps.

  14. Neurovascular ultrasound in emergency settings: diagnostic and therapeutic aspects.

    PubMed

    Santos, T; Veloso, M; Barros, P

    2017-04-16

    Introduccion. La ecografia neurovascular es una tecnica de diagnostico por imagenes rapida, portatil e incruenta que en manos de un ecografista experimentado aporta informacion reproducible y fiable acerca del estado hemodinamico y morfologico de los vasos craneales y cervicales. Objetivo. Revisar los datos disponibles sobre el uso de esta herramienta en el abordaje del ictus isquemico agudo. Desarrollo. La ecografia neurovascular se divide en dos modalidades de uso: diagnostica y terapeutica. A la luz de los bajos porcentajes de recanalizacion de las oclusiones de la arteria carotida interna y del segmento proximal de la arteria cerebral media logradas por el activador del plasminogeno tisular recombinante (r-tPA) por via intravenosa, el uso diligente de la ecografia neurovascular en el servicio de urgencias ayuda a dirimir que pacientes son susceptibles de beneficiarse del tratamiento endovascular. Asimismo, la vigilancia ecografica durante el curso del tratamiento con el r-tPA permite analizar la evolucion de la recanalizacion arterial. La ecografia cervical permite valorar el grado de estenosis y la composicion o la superficie de la placa arterial, extremos que, por ejemplo, pueden indicar la idoneidad de una intervencion carotidea. Por ultimo, tambien se esta investigando el potencial terapeutico de la ecografia. La sonotrombolisis y la sonolisis, la primera combinando el r-tPA con las ondas ultrasonicas y la segunda sirviendose unicamente de ellas como medio para lisar el trombo, han evidenciado hasta el momento resultados alentadores. Conclusion. La ecografia neurovascular ha progresado enormemente hasta adquirir un protagonismo destacado en el estudio de los trastornos cerebrovasculares.

  15. Is There a Persistent Dysfunction of Neurovascular Coupling in Migraine?

    PubMed Central

    Žvan, Bojana

    2015-01-01

    Changes in cerebral blood flow are one of the main features of migraine attack and have inspired the vascular theory of migraine. This traditional view has been reshaped with recent experimental data, which gave rise to the neural theory of migraine. In this review, we speculate that there might be an important link between the two theories, that is, the dysfunction of neurovascular coupling. PMID:25705673

  16. Arginase 2 promotes neurovascular degeneration during ischemia/reperfusion injury

    PubMed Central

    Shosha, Esraa; Xu, Zhimin; Yokota, Harumasa; Saul, Alan; Rojas, Modesto; Caldwell, R William; Caldwell, Ruth B; Narayanan, S Priya

    2016-01-01

    Retinal ischemia is a major cause of visual impairment and blindness and is involved in various disorders including diabetic retinopathy, glaucoma, optic neuropathies and retinopathy of prematurity. Neurovascular degeneration is a common feature of these pathologies. Our lab has previously reported that the ureahydrolase arginase 2 (A2) is involved in ischemic retinopathies. Here, we are introducing A2 as a therapeutic target to prevent neurovascular injury after retinal ischemia/reperfusion (I/R) insult. Studies were performed with mice lacking both copies of A2 (A2−/−) and wild-type (WT) controls (C57BL6J). I/R insult was conducted on the right eye and the left eye was used as control. Retinas were collected for analysis at different times (3 h–4 week after injury). Neuronal and microvascular degeneration were evaluated using NeuN staining and vascular digests, respectively. Glial activation was evaluated by glial fibrillary acidic protein expression. Necrotic cell death was studied by propidium iodide labeling and western blot for RIP-3. Arginase expression was determined by western blot and quantitative RT-PCR. Retinal function was determined by electroretinography (ERG). A2 mRNA and protein levels were increased in WT I/R. A2 deletion significantly reduced ganglion cell loss and microvascular degeneration and preserved retinal morphology after I/R. Glial activation, reactive oxygen species formation and cell death by necroptosis were significantly reduced by A2 deletion. ERG showed improved positive scotopic threshold response with A2 deletion. This study shows for the first time that neurovascular injury after retinal I/R is mediated through increased expression of A2. Deletion of A2 was found to be beneficial in reducing neurovascular degeneration after I/R. PMID:27882947

  17. 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.

  18. Analysis of Early Neurovascular Complications of Pediatric Supracondylar Humerus Fractures: A Long-Term Observation.

    PubMed

    Tomaszewski, Ryszard; Wozowicz, Artur; Wysocka-Wojakiewicz, Paulina

    2017-01-01

    Purpose. Analysis of early vascular and nerve complications of supracondylar humerus fractures in children. Material and Methods. 220 children hospitalized in the Pediatric Trauma-Orthopedic Department in the years 2004-2014. The group consisted of 143 males and 77 females. Results. Acute neurovascular complications occurred in 16.81% of patients with displaced supracondylar fracture (37 children). Nerve damage was found in 10% of patients with displaced fracture (22 children). The most injured nerve was median nerve; this complication occurred in 15 patients (68.18%). The total nerve function returned after average of 122 days (0-220 days after surgery). Symptoms of vascular injury occurred in 7.7% children with displaced fracture (17 children). Conclusions. (1) In children with supracondylar fracture the most often injured nerve is median nerve. (2) The incidence of vascular and nerve complications positively correlates with the progression of fracture according to Gartland classification.

  19. Analysis of Early Neurovascular Complications of Pediatric Supracondylar Humerus Fractures: A Long-Term Observation

    PubMed Central

    Wozowicz, Artur; Wysocka-Wojakiewicz, Paulina

    2017-01-01

    Purpose. Analysis of early vascular and nerve complications of supracondylar humerus fractures in children. Material and Methods. 220 children hospitalized in the Pediatric Trauma-Orthopedic Department in the years 2004–2014. The group consisted of 143 males and 77 females. Results. Acute neurovascular complications occurred in 16.81% of patients with displaced supracondylar fracture (37 children). Nerve damage was found in 10% of patients with displaced fracture (22 children). The most injured nerve was median nerve; this complication occurred in 15 patients (68.18%). The total nerve function returned after average of 122 days (0–220 days after surgery). Symptoms of vascular injury occurred in 7.7% children with displaced fracture (17 children). Conclusions. (1) In children with supracondylar fracture the most often injured nerve is median nerve. (2) The incidence of vascular and nerve complications positively correlates with the progression of fracture according to Gartland classification. PMID:28367440

  20. Supra and infralevator neurovascular pathways to the penile corpora cavernosa

    PubMed Central

    BENOIT, G.; DROUPY, S.; QUILLARD, J.; PARADIS, V.; GIULIANO, F.

    1999-01-01

    The aim of this study was to provide a comprehensive description of both penile innervation and vascularisation. Eighty-five male cadavers were examined through gross and microscopic anatomical analysis. The pelvic nerve plexus had both parasympathetic and sympathetic roots. It was distributed to the external urethral sphincter giving rise to cavernous nerves which anastomosed in 70% of the cases with the pudendal nerve in the penile root. Accessory pudendal arteries were present in the pelvis in 70% of the cases, anastomosing in 70% of the cases with the cavernous arteries that originated from the pudendal arteries. Transalbugineal anastomoses were always seen between the cavernous artery and the spongiosal arterial network. There were 2 venous pathways, 1 in the pelvis and 1 in the perineum with a common origin from the deep dorsal penile vein. It is concluded that there are 2 neurovascular pathways destined for the penis that are topographically distinct. One is located in the pelvis and the other in the perineum. We were unable to determine the functional balance between these 2 anastomosing pathways but experimental data have shown that they are both involved in penile erection. These 2 neurovascular pathways, above and below the levator ani, together with their anastomoses, form a neurovascular loop around the levator ani. PMID:10634698

  1. Neurovascular coupling: in vivo optical techniques for functional brain imaging.

    PubMed

    Liao, Lun-De; Tsytsarev, Vassiliy; Delgado-Martínez, Ignacio; Li, Meng-Lin; Erzurumlu, Reha; Vipin, Ashwati; Orellana, Josue; Lin, Yan-Ren; Lai, Hsin-Yi; Chen, You-Yin; Thakor, Nitish V

    2013-04-30

    Optical imaging techniques reflect different biochemical processes in the brain, which is closely related with neural activity. Scientists and clinicians employ a variety of optical imaging technologies to visualize and study the relationship between neurons, glial cells and blood vessels. In this paper, we present an overview of the current optical approaches used for the in vivo imaging of neurovascular coupling events in small animal models. These techniques include 2-photon microscopy, laser speckle contrast imaging (LSCI), voltage-sensitive dye imaging (VSDi), functional photoacoustic microscopy (fPAM), functional near-infrared spectroscopy imaging (fNIRS) and multimodal imaging techniques. The basic principles of each technique are described in detail, followed by examples of current applications from cutting-edge studies of cerebral neurovascular coupling functions and metabolic. Moreover, we provide a glimpse of the possible ways in which these techniques might be translated to human studies for clinical investigations of pathophysiology and disease. In vivo optical imaging techniques continue to expand and evolve, allowing us to discover fundamental basis of neurovascular coupling roles in cerebral physiology and pathophysiology.

  2. The BOLD signal and neurovascular coupling in autism.

    PubMed

    Reynell, Clare; Harris, Julia J

    2013-10-01

    BOLD (blood oxygen level dependent) fMRI (functional magnetic resonance imaging) is commonly used to study differences in neuronal activity between human populations. As the BOLD response is an indirect measure of neuronal activity, meaningful interpretation of differences in BOLD responses between groups relies upon a stable relationship existing between neuronal activity and the BOLD response across these groups. However, this relationship can be altered by changes in neurovascular coupling or energy consumption, which would lead to problems in identifying differences in neuronal activity. In this review, we focus on fMRI studies of people with autism, and comparisons that are made of their BOLD responses with those of control groups. We examine neurophysiological differences in autism that may alter neurovascular coupling or energy use, discuss recent studies that have used fMRI to identify differences between participants with autism and control participants, and explore experimental approaches that could help attribute between-group differences in BOLD signals to either neuronal or neurovascular factors. Copyright © 2013 Elsevier Ltd. All rights reserved.

  3. Neurovascular coupling develops alongside neural circuits in the postnatal brain.

    PubMed

    Kozberg, Mariel G; Hillman, Elizabeth M C

    2016-01-01

    In the adult brain, increases in local neural activity are accompanied by increases in regional blood flow. This relationship between neural activity and hemodynamics is termed neurovascular coupling and provides the blood flow-dependent contrast detected in functional magnetic resonance imaging (fMRI). Neurovascular coupling is commonly assumed to be consistent and reliable from birth; however, numerous studies have demonstrated markedly different hemodynamics in the early postnatal brain. Our recent study in J. Neuroscience examined whether different hemodynamics in the immature brain are driven by differences in the underlying spatiotemporal properties of neural activity during this period of robust neural circuit expansion. Using a novel wide-field optical imaging technique to visualize both neural activity and hemodynamics in the mouse brain, we observed longer duration and increasingly complex patterns of neural responses to stimulus as cortical connectivity developed over time. However, imaging of brain blood flow, oxygenation, and metabolism in the same mice demonstrated an absence of coupled blood flow responses in the newborn brain. This lack of blood flow coupling was shown to lead to oxygen depletions following neural activations - depletions that may affect the duration of sustained neural responses and could be important to the vascular patterning of the rapidly developing brain. These results are a step toward understanding the unique neurovascular and neurometabolic environment of the newborn brain, and provide new insights for interpretation of fMRI BOLD studies of early brain development.

  4. 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.

  5. The BOLD signal and neurovascular coupling in autism

    PubMed Central

    Reynell, Clare; Harris, Julia J.

    2013-01-01

    BOLD (blood oxygen level dependent) fMRI (functional magnetic resonance imaging) is commonly used to study differences in neuronal activity between human populations. As the BOLD response is an indirect measure of neuronal activity, meaningful interpretation of differences in BOLD responses between groups relies upon a stable relationship existing between neuronal activity and the BOLD response across these groups. However, this relationship can be altered by changes in neurovascular coupling or energy consumption, which would lead to problems in identifying differences in neuronal activity. In this review, we focus on fMRI studies of people with autism, and comparisons that are made of their BOLD responses with those of control groups. We examine neurophysiological differences in autism that may alter neurovascular coupling or energy use, discuss recent studies that have used fMRI to identify differences between participants with autism and control participants, and explore experimental approaches that could help attribute between-group differences in BOLD signals to either neuronal or neurovascular factors. PMID:23917518

  6. Neurovascular coupling: in vivo optical techniques for functional brain imaging

    PubMed Central

    2013-01-01

    Optical imaging techniques reflect different biochemical processes in the brain, which is closely related with neural activity. Scientists and clinicians employ a variety of optical imaging technologies to visualize and study the relationship between neurons, glial cells and blood vessels. In this paper, we present an overview of the current optical approaches used for the in vivo imaging of neurovascular coupling events in small animal models. These techniques include 2-photon microscopy, laser speckle contrast imaging (LSCI), voltage-sensitive dye imaging (VSDi), functional photoacoustic microscopy (fPAM), functional near-infrared spectroscopy imaging (fNIRS) and multimodal imaging techniques. The basic principles of each technique are described in detail, followed by examples of current applications from cutting-edge studies of cerebral neurovascular coupling functions and metabolic. Moreover, we provide a glimpse of the possible ways in which these techniques might be translated to human studies for clinical investigations of pathophysiology and disease. In vivo optical imaging techniques continue to expand and evolve, allowing us to discover fundamental basis of neurovascular coupling roles in cerebral physiology and pathophysiology. PMID:23631798

  7. Trigeminal neuralgia without neurovascular compression presents earlier than trigeminal neuralgia with neurovascular compression.

    PubMed

    Ko, Andrew L; Lee, Albert; Raslan, Ahmed M; Ozpinar, Alp; McCartney, Shirley; Burchiel, Kim J

    2015-12-01

    Trigeminal neuralgia (TN) occurs and recurs in the absence of neurovascular compression (NVC). To characterize what may be distinct patient populations, the authors examined age at onset in patients with TN with and without NVC. A retrospective review of patients undergoing posterior fossa surgery for Type I TN at Oregon Health & Science University from 2009 to 2013 was undertaken. Charts were reviewed, and imaging and operative data were collected for patients with and without NVC. Mean, median, and the empirical cumulative distribution of onset age were determined. Statistical analysis was performed using Student t-test, Wilcoxon and Kolmogorov-Smirnoff tests, and Kaplan-Meier analysis. Multivariate analysis was performed using a Cox proportional hazards model. The charts of 219 patients with TN were reviewed. There were 156 patients who underwent posterior fossa exploration and microvascular decompression or internal neurolysis: 129 patients with NVC and 27 without NVC. Mean age at symptoms onset for patients with and without NVC was 51.1 and 42.6 years, respectively. This difference (8.4 years) was significant (t-test: p = 0.007), with sufficient power to detect an effect size of 8.2 years. Median age between groups with and without NVC was 53.25 and 41.2 years, respectively (p = 0.003). Histogram analysis revealed a bimodal age at onset in patients without NVC, and cumulative distribution of age at onset revealed an earlier presentation of symptoms (p = 0.003) in patients without NVC. Chi-square analysis revealed a trend toward female predominance in patients without NVC, which was not significant (p = 0.08). Multivariate analysis revealed that age at onset was related to NVC but not sex, symptom side or distribution, or patient response to medical treatment. NVC is neither sufficient nor necessary for the development of TN. Patients with TN without NVC may represent a distinct population of younger, predominantly female patients. Further research into the

  8. Progression of perianeurysmal inflammation after endovascular aneurysm repair for inflammatory abdominal aortic and bilateral common iliac artery aneurysms.

    PubMed

    Igari, Kimihiro; Kudo, Toshifumi; Uchiyama, Hidetoshi; Toyofuku, Takahiro; Inoue, Yoshinori

    2015-02-01

    The use of endovascular aneurysm repair (EVAR) to treat inflammatory abdominal aortic aneurysms (IAAAs) has been reported, and this procedure appears to be preferable to open surgical repair because of intraoperative difficulties related to inflammation. We herein report a case of IAAA and bilateral inflammatory common iliac artery aneurysms that was successfully treated with bifurcated stent grafting. The perianeurysmal inflammation worsened postoperatively, requiring the placement of a ureteric stent. EVAR is feasible in cases of inflammatory aneurysms; however, the potential for an inflammatory response should be taken into account when considering the application of EVAR in patients with IAAA.

  9. In Mice, Tuberculosis Progression Is Associated with Intensive Inflammatory Response and the Accumulation of Gr-1dim Cells in the Lungs

    PubMed Central

    Lyadova, Irina V.; Tsiganov, Evgeny N.; Kapina, Marina A.; Shepelkova, Galena S.; Sosunov, Vasily V.; Radaeva, Tatiana V.; Majorov, Konstantin B.; Shmitova, Natalya S.; van den Ham, Henk-Jan; Ganusov, Vitaly V.; De Boer, Rob J.; Racine, Rachael; Winslow, Gary M.

    2010-01-01

    Background Infection with Mycobacterium tuberculosis (Mtb) results in different clinical outcomes ranging from asymptomatic containment to rapidly progressing tuberculosis (TB). The mechanisms controlling TB progression in immunologically-competent hosts remain unclear. Methodology/Principal Findings To address these mechanisms, we analyzed TB progression in a panel of genetically heterogeneous (A/SnxI/St) F2 mice, originating from TB-highly-susceptible I/St and more resistant A/Sn mice. In F2 mice the rates of TB progression differed. In mice that did not reach terminal stage of infection, TB progression did not correlate with lung Mtb loads. Nor was TB progression correlated with lung expression of factors involved in antibacterial immunity, such as iNOS, IFN-γ, or IL-12p40. The major characteristics of progressing TB was high lung expression of the inflammation-related factors IL-1β, IL-6, IL-11 (p<0.0003); CCL3, CCL4, CXCL2 (p<0.002); MMP-8 (p<0.0001). The major predictors of TB progression were high expressions of IL-1β and IL-11. TNF-α had both protective and harmful effects. Factors associated with TB progression were expressed mainly by macrophages (F4-80+ cells) and granulocytes (Gr-1hi/Ly-6Ghi cells). Macrophages and granulocytes from I/St and A/Sn parental strains exhibited intrinsic differences in the expression of inflammatory factors, suggesting that genetically determined peculiarities of phagocytes transcriptional response could account for the peculiarities of gene expression in the infected lungs. Another characteristic feature of progressing TB was the accumulation in the infected lungs of Gr-1dim cells that could contribute to TB progression. Conclusions/Significance In a population of immunocompetent hosts, the outcome of TB depends on quantitatively- and genetically-controlled differences in the intensity of inflammatory responses, rather than being a direct consequence of mycobacterial colonization. Local accumulation of Gr-1dim cells is

  10. Neurovascular protection by telmisartan via reducing neuroinflammation in stroke-resistant spontaneously hypertensive rat brain after ischemic stroke.

    PubMed

    Kono, Syoichiro; Kurata, Tomoko; Sato, Kota; Omote, Yoshio; Hishikawa, Nozomi; Yamashita, Toru; Deguchi, Kentaro; Abe, Koji

    2015-03-01

    Telmisartan is a highly lipid-soluble angiotensin receptor blocker (ARB), which improves insulin sensitivity and reduces triglyceride levels and, thus, is called metabo-sartan. We examined the effects of telmisartan on neurovascular unit (N-acetylglucosamine oligomer [NAGO], collagen IV, and glial fibrillary acidic protein [GFAP]) and neuroinflammation (matrix metalloproteinase-9 [MMP-9] and inflammasome) in brain of stroke-resistant spontaneously hypertensive rat (SHR-SR). At 12 weeks of age, SHR-SR received transient middle cerebral artery occlusion (tMCAO) for 90 minutes and were divided into the following 3 groups, that is, vehicle group, low-dose telmisartan group (.3 mg/kg/d), and high-dose telmisartan group (3 mg/kg/d, postoral). Immunohistologic analysis at ages 6, 12, and 18 months showed progressive decreases of NAGO-positive endothelium and collagen IV-positive basement membrane and progressive increases of MMP-9-positive neurons, GFAP-positive astrocytes, and NLRP3-positive inflammasome in the cerebral cortex of vehicle group. Low-dose telmisartan reduced such changes without lowering blood pressure (BP), and high-dose telmisartan further improved such changes with lowering BP. The present findings suggest that a persistent hypertension caused a long-lasting inflammation after tMCAO in SHR-SR, which accelerated neurovascular disruption and emergent inflammasome, and that telmisartan greatly reduced such inflammation and protected the neurovascular unit via its pleiotropic effects in living hypertensive rat brain after ischemic stroke. Copyright © 2015 National Stroke Association. Published by Elsevier Inc. All rights reserved.

  11. Headache as a risk factor for neurovascular events in pediatric brain tumor patients

    PubMed Central

    Campen, Cynthia J.; Kasner, Scott E.; Kessler, Sudha K.; Zimmerman, Robert A.; Lustig, Robert A.; Phillips, Peter C.; Beslow, Lauren A.; Ichord, Rebecca; Fisher, Michael J.

    2013-01-01

    Objective: To determine whether severe recurrent headache is a risk factor for neurovascular events in children who received radiation for brain tumors. Methods: This is a retrospective cohort study of children with brain tumors who received cranial irradiation at a large tertiary care center, aged 0–21 years at diagnosis, with initial treatment between January 1, 1993 and December 31, 2002, and 2 or more follow-up visits. Patients were considered to have severe recurrent headache if this appeared as a complaint on 2 or more visits. Headaches attributed to tumor progression, shunt malfunction, or infection, or appearing at the end of life, were excluded. Medical records were reviewed for events of stroke or TIA. Results: Of 265 subjects followed for a median of 6.0 years (interquartile range 1.7–9.2 years), stroke or TIA occurred in 7/37 (19%) with severe headaches compared to 6/228 (3%) without these symptoms (hazard ratio 5.3, 95% confidence interval 1.8–15.9, p = 0.003). Adjusting for multiple variables did not remove the significance of this risk. Median time to first neurovascular event for the entire cohort was 4.9 years (interquartile range 1.7–5.5 years). Conclusions: Severe recurrent headache appears to be a risk factor or predictor for subsequent cerebral ischemia in pediatric brain tumor survivors treated with radiation. This finding has clinical implications for both monitoring survivors and targeting a specific population for primary stroke prevention. PMID:23486881

  12. Neurovascular saturation thresholds under high intensity auditory stimulation during wake.

    PubMed

    Schei, J L; Van Nortwick, A S; Meighan, P C; Rector, D M

    2012-12-27

    Coupling between neural activity and hemodynamic responses is important in understanding brain function, interpreting brain-imaging signals, and assessing pathological conditions. Tissue state is a major factor in neurovascular coupling and may alter the relationship between neural and hemodynamic activity. However, most neurovascular-coupling studies are performed under anesthetized or sedated states which may have severe consequences on coupling mechanisms. Our previous studies showed that following prolonged periods of sleep deprivation, evoked hemodynamic responses were muted despite consistent electrical responses, suggesting that sustained neural activity may decrease vascular compliance and limit blood perfusion. To investigate potential perfusion limitations during natural waking conditions, we simultaneously measured evoked response potentials (ERPs) and evoked hemodynamic responses using optical-imaging techniques to increase intensity auditory stimulation. The relationship between evoked hemodynamic responses and integrated ERPs followed a sigmoid relationship where the hemodynamic response approached saturation at lower stimulus intensities than the ERP. If limits in blood perfusion are caused by stretching of the vessel wall, then these results suggest there may be decreased vascular compliance due to sustained neural activity during wake, which could limit vascular responsiveness and local blood perfusion. Conditions that stress cerebral vasculature, such as sleep deprivation and some pathologies (e.g., epilepsy), may further decrease vascular compliance, limit metabolic delivery, and cause tissue trauma. While ERPs and evoked hemodynamic responses provide an indication of the correlated neural activity and metabolic demand, the relationship between these two responses is complex and the different measurement techniques are not directly correlated. Future studies are required to verify these findings and further explore neurovascular coupling during

  13. 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

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

    PubMed

    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.

  15. Ultrasonographic evaluation of displaced neurovascular bundle in Dupuytren disease.

    PubMed

    Uehara, Kosuke; Miura, Toshiki; Morizaki, Yutaka; Miyamoto, Hideaki; Ohe, Takashi; Tanaka, Sakae

    2013-01-01

    Neurovascular injury is a serious complication after surgery for Dupuytren disease. The purpose of this study was to evaluate the relationship between the cord and the neurovascular bundle ultrasonographically. We included 22 healthy volunteers and 14 Dupuytren disease patients (25 fingers) in this study. We evaluated the cord and the digital artery with high-resolution ultrasound. We first investigated the effect of the angle of metacarpophalangeal joint on the position of the radial and ulnar digital arteries in volunteers without evidence of Dupuytren disease. We compared 3 parameters of the radial and ulnar digital arteries, including differences in depth, differences in lateral shift, and the shape of the cross-section of the artery, between volunteers and patients with Dupuytren disease. None of these parameters changed with flexion of the metacarpophalangeal joint of 0°, 30°, and 60°. Digital arteries and cords could be identified ultrasonographically in all patients, and we confirmed ultrasonographic findings by operative findings in 13 fingers. We classified the fingers into 3 subgroups based on the ultrasonographic findings: type A (n = 13), in which the cord was above the artery; type B (n = 5), in which the cord was below the artery; and type C (n = 7), in which the cord was located between the radial and ulnar digital arteries. Types A, B, and C corresponded to natatory cord/abductor digiti minimi cord, spiral cord, and central cord, respectively. Comparisons among volunteers and patient subgroups showed that the difference in depth in type B patients was significantly larger than that of the other groups. When we set the cutoff point of the difference in depth to 3 mm, sensitivity and specificity to detect the spiral cord were 80% and 76%, respectively. The relationship between the neurovascular bundle and the type of Dupuytren disease cord can be evaluated by high-resolution ultrasound. Diagnostic III. Copyright © 2013 American Society for

  16. [Study about target-network of anti-cerebral infarction neuropathy based on theory of neurovascular unit and network pharmacology].

    PubMed

    Liu, Qingshan; Fang, Liang; Wang, Weiqun; Zhang, Ziqian; Yang, Hongjun

    2012-01-01

    Potention drug-targets on anti-neuropathy of stroke were summarized, and it will provide materials for developing innovation components traditional Chinese medicine on anti-cerebral infarction neuropathy. This article had done a series of researching work about neurovascular unit which includes three kinds of cells: neuron, gliacyte,brain microvascular endothelial cell, then signal mechanism of cell death or apoptosis of each section of stroke neuropathy was analysised by the historical documents. There are five important pathways: inflammatory factor-MMPs pathway- Caspases, Ca2+ -mitochondrial pathway-Caspases, Ca2+ -Phospholipase-PI-3K/AK pathway, Ca2+ -radical-MAPK pathway, Ca2+ -NO-protease pathway, among all the nodes, Caspases, Ca2+, NO were the most important ones. Developing the multi-mechanism and multilevel of traditional chinese medicine under the guidance of the theories of network pharmacology and neurovascular unit will play an important role in studying the key links of signal-network of stroke neuropathy.

  17. 3-D imaging and illustration of mouse intestinal neurovascular complex.

    PubMed

    Fu, Ya-Yuan; Peng, Shih-Jung; Lin, Hsin-Yao; Pasricha, Pankaj J; Tang, Shiue-Cheng

    2013-01-01

    Because of the dispersed nature of nerves and blood vessels, standard histology cannot provide a global and associated observation of the enteric nervous system (ENS) and vascular network. We prepared transparent mouse intestine and combined vessel painting and three-dimensional (3-D) neurohistology for joint visualization of the ENS and vasculature. Cardiac perfusion of the fluorescent wheat germ agglutinin (vessel painting) was used to label the ileal blood vessels. The pan-neuronal marker PGP9.5, sympathetic neuronal marker tyrosine hydroxylase (TH), serotonin, and glial markers S100B and GFAP were used as the immunostaining targets of neural tissues. The fluorescently labeled specimens were immersed in the optical clearing solution to improve photon penetration for 3-D confocal microscopy. Notably, we simultaneously revealed the ileal microstructure, vasculature, and innervation with micrometer-level resolution. Four examples are given: 1) the morphology of the TH-labeled sympathetic nerves: sparse in epithelium, perivascular at the submucosa, and intraganglionic at myenteric plexus; 2) distinct patterns of the extrinsic perivascular and intrinsic pericryptic innervation at the submucosal-mucosal interface; 3) different associations of serotonin cells with the mucosal neurovascular elements in the villi and crypts; and 4) the periganglionic capillary network at the myenteric plexus and its contact with glial fibers. Our 3-D imaging approach provides a useful tool to simultaneously reveal the nerves and blood vessels in a space continuum for panoramic illustration and analysis of the neurovascular complex to better understand the intestinal physiology and diseases.

  18. The role of nitric oxide in neurovascular coupling.

    PubMed

    Dormanns, K; Brown, R G; David, T

    2016-04-07

    Nitric oxide (NO) is a neurotransmitter known to act as a potent cerebral vasodilator. Its role in neurovascular coupling (NVC) is discussed controversially and one of the main unanswered questions is which cell type provides the governing source of NO for the regulation of vasodynamics. Mathematical modelling can be an appropriate tool to investigate the contribution of NO towards the key components of NVC and analyse underlying mechanisms. The lumped parameter model of a neurovascular unit, including neurons (NE), astrocytes (AC), smooth muscle cells (SMC) and endothelial cells (EC), was extended to model the NO signalling pathway. Results show that NO leads to a general shift of the resting regional blood flow by dilating the arteriolar radius. Furthermore, dilation during neuronal activation is enhanced. Simulations show that potassium release is responsible for the fast onset of vascular response, whereas NO-modulated mechanisms maintain dilation. Wall shear stress-activated NO release from the EC leads to a delayed return to the basal state of the arteriolar radius. The governing source of vasodilating NO that diffuses into the SMC, which determine the arteriolar radius, depends on neuronal activation. In the resting state the EC provides the major contribution towards vasorelaxation, whereas during neuronal stimulation NO produced by the NE dominates.

  19. Reconstruction of the thumb tip using palmar neurovascular flaps.

    PubMed

    Harenberg, P S; Jakubietz, R G; Jakubietz, M G; Schmidt, K; Meffert, R H

    2012-04-01

    Reconstruction of the tip of the thumb using a neurovascular flap. Transverse defects of the thumb's tip or large defects of the palmar pulp (max. 2.0-2.5 cm) with exposure of bone and/or tendons. Extensive crush injury, heavy wound contamination, circulatory disorders, acute infection, very large defects (> 2.0-2.5 cm finger length), circumferential soft tissue defects, and previous defects/operations (relative). Supine position, hand supinated, tourniquet, loupe magnification. Mid-lateral incisions along both sides of the finger running from the defect to the interphalangeal joint (small defect) or proceeding further proximally. Careful elevation of the flap including both neurovascular bundles leaving dorsal branches of the bundles (long fingers only) and the flexor tendon sheath intact. Suture of the flap in either flexion position (i.e., advancement flap) (Moberg) or by creating an island-flap through an additional transverse skin incision along the flap's base (O'Brien). Finally, closure of the defect at the flap's base using a full thickness skin graft, Z plasty, or V-Y plasty. Plaster cast (finger slightly flexed) for 2 weeks. Reliable method. Good functional results with good sensibility and only minor reduction in range of motion.

  20. Neurovascular and Neuroimmune Aspects in the Pathophysiology of Rosacea

    PubMed Central

    Schwab, Verena D.; Sulk, Mathias; Seeliger, Stephan; Nowak, Pawel; Aubert, Jerome; Mess, Christian; Rivier, Michel; Carlavan, Isabelle; Rossio, Patricia; Metze, Dieter; Buddenkotte, Jörg; Cevikbas, Ferda; Voegel, Johannes J.; Steinhoff, Martin

    2013-01-01

    Rosacea is a common skin disease with a high impact on quality of life. Characterized by erythema, edema, burning pain, immune infiltration, and facial skin fibrosis, rosacea has all the characteristics of neurogenic inflammation, a condition induced by sensory nerves via antidromically released neuromediators. To investigate the hypothesis of a central role of neural interactions in the pathophysiology, we analyzed molecular and morphological characteristics in the different subtypes of rosacea by immunohistochemistry, double immunofluorescence, morphometry, real-time PCR, and gene array analysis, and compared the findings with those for lupus erythematosus or healthy skin. Our results showed significantly dilated blood and lymphatic vessels. Signs of angiogenesis were only evident in phymatous rosacea. The number of mast cells and fibroblasts was increased in rosacea, already in subtypes in which fibrosis is not clinically apparent, indicating early activation. Sensory nerves were closely associated with blood vessels and mast cells, and were increased in erythematous rosacea. Gene array studies and qRT-PCR confirmed upregulation of genes involved in vasoregulation and neurogenic inflammation. Thus, dysregulation of mediators and receptors implicated in neurovascular and neuroimmune communication may be crucial at early stages of rosacea. Drugs that function on neurovascular and/or neuroimmune communication may be beneficial for the treatment of rosacea. PMID:22076328

  1. 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

  2. Patterned optogenetic modulation of neurovascular and metabolic signals.

    PubMed

    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.

  3. Impact of the inflammatory microenvironment on T-cell phenotype in the progression from reflux oesophagitis to Barrett oesophagus and oesophageal adenocarcinoma.

    PubMed

    Kavanagh, Maria E; Conroy, Melissa J; Clarke, Niamh E; Gilmartin, Niamh T; O'Sullivan, Katie E; Feighery, Ronan; MacCarthy, Finbar; O'Toole, Dermot; Ravi, Narayanasamy; Reynolds, John V; O'Sullivan, Jacintha; Lysaght, Joanne

    2016-01-01

    The incidence of oesophageal adenocarcinoma (OAC), arising from reflux-induced Barrett oesophagus (BO), is increasing dramatically. T-cells have recently been implicated in the initiation of oesophagitis; however, their role in the progression from oesophagitis to BO and OAC has not been fully elucidated. Previous studies have examined the secreted cytokines from oesophageal tissue during disease progression but this study is the first to examine the activation phenotype and the inflammatory profile of CD4(+) and CD8(+) T-cells in human oesophagitis, BO and OAC tissue. Results demonstrated significantly higher levels of IL-4 producing CD4(+) T-cells and secreted levels of IL-6, confirming a Th2 phenotype in BO. In OAC tissue, both pro- and anti-inflammatory cytokines were secreted, with significantly higher levels of IL-6, IL-1β, TNF-α, IFN-γ, IL-2 and IL-10 compared with normal oesophageal tissue. In addition, CD4(+) T-cells infiltrating OAC tissue displayed a decreased activation profile, with significantly lower CD45RO and CD69 expression compared with normal tissue. Data from this study suggest that factors in the tissue microenvironment may alter T-cell phenotype and function early during oesophageal disease progression and may represent targets for immune intervention. Copyright © 2015 Elsevier Ireland Ltd. All rights reserved.

  4. Genetic and metabolic signals during acute enteric bacterial infection alter the microbiota and drive progression to chronic inflammatory disease

    SciTech Connect

    Kamdar, Karishma; Khakpour, Samira; Chen, Jingyu; Leone, Vanessa; Brulc, Jennifer; Mangatu, Thomas; Antonopoulos, Dionysios A.; Chang, Eugene B; Kahn, Stacy A.; Kirschner, Barbara S; Young, Glenn; DePaolo, R. William

    2016-01-13

    Chronic inflammatory disorders are thought to arise due to an interplay between predisposing host genetics and environmental factors. For example, the onset of inflammatory bowel disease is associated with enteric proteobacterial infection, yet the mechanistic basis for this association is unclear. We have shown previously that genetic defiency in TLR1 promotes acute enteric infection by the proteobacteria Yersinia enterocolitica. Examining that model further, we uncovered an altered cellular immune response that promotes the recruitment of neutrophils which in turn increases metabolism of the respiratory electron acceptor tetrathionate by Yersinia. These events drive permanent alterations in anti-commensal immunity, microbiota composition, and chronic inflammation, which persist long after Yersinia clearence. Deletion of the bacterial genes involved in tetrathionate respiration or treatment using targeted probiotics could prevent microbiota alterations and inflammation. Thus, acute infection can drive long term immune and microbiota alterations leading to chronic inflammatory disease in genetically predisposed individuals.

  5. 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

  6. Pro-inflammatory cytokines and structural biomarkers are effective to categorize osteoarthritis phenotype and progression in Standardbred racehorses over five years of racing career.

    PubMed

    Bertuglia, Andrea; Pagliara, Eleonora; Grego, Elena; Ricci, Alessandro; Brkljaca-Bottegaro, Nika

    2016-11-08

    Joint impact injuries initiate a progressive articular damage finally leading to post-traumatic osteoarthritis (PTOA). Racehorses represent an ideal, naturally available, animal model of the disease. Standardbred racehorses developing traumatic osteoarthritis of the fetlock joint during the first year of their career were enrolled in our study. Age-matched controls were contemporarily included. Biomarker levels of equine osteoarthritis were measured in serum and synovial fluid (SF) at baseline, and repeated yearly over the next 4 years of training (from T1 to T4). The effect of time and disease on the biomarker concentrations were analysed, and their relationship with clinical and radiographic parameters were assessed. We hypothesized that the kinetics of pro-inflammatory cytokines and structural biomarkers of joint disease would demonstrate progression of degenerative joint status during post-traumatic osteoarthritis and clarify the effect of early joint trauma. The concentrations of IL1-ß, IL-6, TNF-α in the SF of PTOA group peaked at T0, decreased at T1, and then progressively increased with time, reaching levels higher than those observed at baseline starting from T3. CTXII and COMP levels were similar in PTOA and control horses at baseline, and increased in serum and synovial fluid of PTOA horses starting from T2 (serum and synovial CTXII, and serum COMP) or T3 (synovial COMP). The percentual change of TNF-α in the SF of the affected joints independently contributed to explaining the radiological changes at T3 vs T2 and T4 vs T3. Temporal changes of selected biomarkers in STBRs with an acute episode of traumatic fetlock OA demonstrated that long-term increased concentrations of inflammatory cytokines, type II collagen fragments and COMP, in the SF and serum, are related to PTOA. Based on the observed decrease in inflammatory merkers at T1, we hypothesize that the progression of PTOA could be effectively modulated by proper treatment strategies. Annual

  7. 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.

  8. Assessment of endothelial and neurovascular function in human skin microcirculation.

    PubMed

    Roustit, Matthieu; Cracowski, Jean-Luc

    2013-07-01

    Peripheral microvascular dysfunction has been described in many physiological and pathological conditions. Owing to its accessibility, the cutaneous microcirculation provides a unique index of microvascular function. Skin microvascular function has therefore been proposed as a prognostic marker or for evaluating the effect of drugs on the microcirculation. Various reactivity tests, coupled with techniques measuring skin blood flux, are used to non-invasively explore both endothelial and neurovascular microvascular functioning in humans. We review the advantages and limitations of the main reactivity tests, including post-occlusive reactive hyperemia, local thermal hyperemia, pressure-induced vasodilation, and iontophoresis of vasodilators, combined with measurement techniques such as laser Doppler and laser speckle contrast imaging. Recent advances in our comprehension of the physiological pathways underlying these reactivity tests, as well as technological developments in microcirculation imaging, have provided reliable and reproducible tools for studying the microcirculation.

  9. Augmented reality visualization for guidance in neurovascular surgery.

    PubMed

    Kersten-Oertel, Marta; Chen, Sean S J; Drouin, Simon; Sinclair, David S; Collins, D Louis

    2012-01-01

    In neurovascular surgery, and in particular surgery for arteriovenous malformations (AVMs), the surgeon maps pre-operative images to the patient on the operating table to aid in vessel localization and resection. This type of spatial mapping is not trivial, is time consuming, and may be prone to error. Using augmented reality (AR) we can register the microscope/camera image of the patient to pre-operative data in order to help the surgeon better understand the topology and locations of vessels that lie below the visible surface of the cortex. In this work we describe a prototype system, developed using open source software and built with off-the-shelf hardware, for AR visualization for AVM neurosurgery. Furthermore, we consider two visualization techniques, colour-coding and chromadepth, to enhance the depth perception of vessels.

  10. Neurovascular Control and Cardiac Structure in Amateur Runners with Hypertension.

    PubMed

    De Sá Perlingeiro, Patricia; Azevedo, Luciene Ferreira; Gomes-Santos, Igor Lucas; Bortolotto, Luiz Aparecido; Rondon, Maria Urbana Pinto Brandão; Negrão, Carlos Eduardo; De Matos, Luciana Diniz Nagem Janot

    2016-01-01

    The neurovascular mechanisms underlying hypertension are minimized by exercise training. However, it is not known whether previously trained individuals with hypertension would have deleterious repercussion of this disease. Our aim was to investigate the neurovascular control and the cardiac structure of athletes with hypertension. Muscle sympathetic nerve activity (MSNA) (microneurography), baroreflex sensitivity (intravenous infusion of phenylephrine and nitroprusside), arterial stiffness (pulse wave velocity and echotracking), and cardiac structure (echocardiography) were evaluated in 17 runners with hypertension (42 ± 1 yr) and 20 normotensive (43 ± 1 yr) amateur runners. Runners with hypertension had higher MSNA (+24% burst frequency, P = 0.02; +24%, burst incidence, P < 0.01), left ventricular mass (+22%, P < 0.01), septum wall thickness (+9%, P = 0.04), posterior wall thickness (+11%, P = 0.04), and left atrium (+11%, P < 0.001) compared with normotensive runners. Baroreflex control of heart rate was lower in runners with hypertension during increase (P = 0.05) but not during decrease (P = 0.11) of systolic blood pressure when compared with normotensive runners. There was no difference between groups in baroreflex control of MSNA during increase (P = 0.38) and decrease (P = 0.36) of diastolic blood pressure. Pulse wave velocity (P = 0.71) and carotid variables: intima media thickness (P = 0.18), diameter (P = 0.09), and distension (P = 0.79) were similar between groups. Sympathetic overactivity seems to be involved in the underlying mechanisms of hypertension in amateur runners. Alterations in cardiac structure and decreased baroreflex control of heart rate suggest limited protection from exercise training. However, baroreflex control of MSNA and elastic properties of artery are preserved in this population.

  11. Neuropeptide Y and neurovascular control in skeletal muscle and skin.

    PubMed

    Hodges, Gary J; Jackson, Dwayne N; Mattar, Louis; Johnson, John M; Shoemaker, J Kevin

    2009-09-01

    Neuropeptide Y (NPY) is a ubiquitous peptide with multiple effects on energy metabolism, reproduction, neurogenesis, and emotion. In addition, NPY is an important sympathetic neurotransmitter involved in neurovascular regulation. Although early studies suggested that the vasoactive effects of NPY were limited to periods of high stress, there is growing evidence for the involvement of NPY on baseline vasomotor tone and sympathetically evoked vasoconstriction in vivo in both skeletal muscle and the cutaneous circulation. In Sprague-Dawley rat skeletal muscle, Y(1)-receptor activation appears to play an important role in the regulation of basal vascular conductance, and this effect is similar in magnitude to the alpha(1)-receptor contribution. Furthermore, under baseline conditions, agonist and receptor-based mechanisms for Y(1)-receptor-dependent control of vascular conductance in skeletal muscle are greater in male than female rats. In skin, there is Y(1)-receptor-mediated vasoconstriction during whole body, but not local, cooling. As with the NPY system in muscle, this neural effect in skin differs between males and females and in addition, declines with aging. Intriguingly, skin vasodilation to local heating also requires NPY and is currently thought to be acting via a nitric oxide pathway. These studies are establishing further interest in the role of NPY as an important vasoactive agent in muscle and skin, adding to the complexity of neurovascular regulation in these tissues. In this review, we focus on the role of NPY on baseline vasomotor tone in skeletal muscle and skin and how NPY modulates vasomotor tone in response to stress, with the aim of compiling what is currently known, while highlighting some of the more pertinent questions yet to be answered.

  12. 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.

  13. Progressive Obesity Alters Ovarian Folliculogenesis with Impacts on Pro-Inflammatory and Steroidogenic Signaling in Female Mice1

    PubMed Central

    Nteeba, Jackson; Ganesan, Shanthi; Keating, Aileen F.

    2014-01-01

    ABSTRACT Diet-induced obesity induces immune cell infiltration and inflammation in peri-ovarian adipose tissue and mRNA expression of inflammatory markers in ovarian tissue. Whether these changes are associated with obesity-related ovarian dysfunction remains unknown. In the present study, qRT-PCR and Western blotting techniques were used to compare mRNA and protein abundance of ovarian immune cell and inflammation markers, along with NF-kappaB and steroidogenic pathway members in normal wild-type non-agouti (a/a; lean) and lethal yellow mice (KK.CG-Ay/J; obese) at 6, 12, 18, or 24 wk of age. Our data revealed that, beginning at 12 wk of age, NF-kappaB inflammatory signaling members were elevated (P < 0.05) in obese females. Interestingly obesity had opposing and temporal effects on the steroidogenic enzyme pathway. Obesity decreased (P < 0.05) STAR protein at 12, 18, and 24 wk of age. CYP11A1 and CYP19A1 proteins were increased (P < 0.05) at 12 wk but were decreased (P < 0.05) at 18 and 24 wk. Interestingly, CYP19A1 was increased in lethal yellow mouse ovaries at 6 wk of age, potentially indicating early puberty onset. These data demonstrate that obesity alters expression of ovarian inflammatory and steroidogenic pathway genes in ways which could adversely affect ovarian function. PMID:25143355

  14. Dynamic Neurovascular Coupling and Uncoupling during Ictal Onset, Propagation, and Termination Revealed by Simultaneous In Vivo Optical Imaging of Neural Activity and Local Blood Volume

    PubMed Central

    Zhao, Mingrui; Schwartz, Theodore H.

    2013-01-01

    Traditional models of ictal propagation involve the concept of an initiation site and a progressive outward march of activation. The process of neurovascular coupling, whereby the brain supplies oxygenated blood to metabolically active neurons presumably results in a similar outward cascade of hyperemia. However, ictal neurovascular coupling has never been assessed in vivo using simultaneous measurements of membrane potential change and hyperemia with wide spatial sampling. In an acute rat ictal model, using simultaneous intrinsic optical signal (IOS) and voltage-sensitive dye (VSD) imaging of cerebral blood volume and membrane potential changes, we demonstrate that seizures consist of multiple dynamic multidirectional waves of membrane potential change with variable onset sites that spread through a widespread network. Local blood volume evolves on a much slower spatiotemporal scale. At seizure onset, the VSD waves extend beyond the IOS signal. During evolution, spatial correlation with hemodynamic signal only exists briefly at the maximal spread of the VSD signal. At termination, the IOS signal extends spatially and temporally beyond the VSD waves. Hence, vascular reactivity evolves in a separate but parallel fashion to membrane potential changes resulting in a mechanism of neurovascular coupling and uncoupling, which is as dynamic as the seizure itself. PMID:22499798

  15. Cerebrospinal fluid biomarkers of neurovascular dysfunction in mild dementia and Alzheimer's disease

    PubMed Central

    Sweeney, Melanie D; Sagare, Abhay P; Zlokovic, Berislav V

    2015-01-01

    Alzheimer's disease (AD) is the most common form of age-related dementias. In addition to genetics, environment, and lifestyle, growing evidence supports vascular contributions to dementias including dementia because of AD. Alzheimer's disease affects multiple cell types within the neurovascular unit (NVU), including brain vascular cells (endothelial cells, pericytes, and vascular smooth muscle cells), glial cells (astrocytes and microglia), and neurons. Thus, identifying and integrating biomarkers of the NVU cell-specific responses and injury with established AD biomarkers, amyloid-β (Aβ) and tau, has a potential to contribute to better understanding of the disease process in dementias including AD. Here, we discuss the existing literature on cerebrospinal fluid biomarkers of the NVU cell-specific responses during early stages of dementia and AD. We suggest that the clinical usefulness of established AD biomarkers, Aβ and tau, could be further improved by developing an algorithm that will incorporate biomarkers of the NVU cell-specific responses and injury. Such biomarker algorithm could aid in early detection and intervention as well as identify novel treatment targets to delay disease onset, slow progression, and/or prevent AD. PMID:25899298

  16. 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

  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

    McCarthy, Ryan C; Kosman, Daniel J

    2015-02-01

    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.

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

    PubMed

    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.

  20. Characterizing and Targeting Bone Marrow-Derived Inflammatory Cells in Driving the Malignancy and Progression of Childhood Astrocytic Brain Tumors

    DTIC Science & Technology

    2015-09-01

    figures below: 5 Figure 1. Characterizing myeloid lineage of BMDCs in patients (CD11b, CD33, CD14, and CD16 ) by flow cytometery in peripheral...progression of diseases. The MDSCs are heterogeneous regarding the 7 expression of CD14/ CD16 , representing monocytic or granulocytic sub-lineages (Figure

  1. Characterizing and Targeting Bone Marrow-Derived Inflammatory Cells in Driving the Malignancy and Progression of Childhood Astrocytic Brain Tumors

    DTIC Science & Technology

    2014-09-01

    CD16 ) by flow cytometery in peripheral of low-grade astrocytoma patients (LGA) vs glioblastoma patients (GBM). Figure 2. IHC of CD11b...myeloid lineage increased following the progression of diseases. The MDSCs are heterogeneous regarding the expression of CD14/ CD16 , representing

  2. Role of cytokines and reactive oxygen intermediates in the inflammatory response produced by sulfur mustard. A progress report

    SciTech Connect

    Dannenberg, A.M.; Tsuruta, J.

    1993-05-13

    Cytokines play a major role in both acute and chronic inflammatory processes, including those produced by sulfur mustard (SM). In situ hybridization of the mRNA of various cytokines with radiolabeled antisense RNA probes enables us to visualize under the microscope which cells in tissue sections of SM lesions are producing which type of cytokine. This technique, therefore, demonstrates cell function histologically, even though the cells are no longer alive at the time of analysis. Cytokines from infiltrating phagocytes. We have successfully demonstrated the mRNAs of four major cytokines in developing and healing rabbit SM lesions: Interleukin 1 beta (IL-1 beta), neutrophil attractant/activation protein 1 (NAP-1 or IL-8), monocyte chemoattractant (activating) protein 1 (MCP-1), and GRO, which is macrophage inflammatory protein 2. The macrophage/fibroblast group in the lesions contained the mRNA of all four cytokines, and granulocytes contained the mRNA of IL-1 beta and NAP-1. More cytokine producing cells were present in the peak lesions than in healing lesions.

  3. 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

  4. Incidence and pattern of direct blunt neurovascular injury associated with trauma to the skull base.

    PubMed

    Feiz-Erfan, Iman; Horn, Eric M; Theodore, Nicholas; Zabramski, Joseph M; Klopfenstein, Jeffrey D; Lekovic, Gregory P; Albuquerque, Felipe C; Partovi, Shahram; Goslar, Pamela W; Petersen, Scott R

    2007-08-01

    Skull base fractures are often associated with potentially devastating injuries to major neural arteries in the head and neck, but the incidence and pattern of this association are unknown. Between April and September 2002, 1738 Level 1 trauma patients were admitted to St. Joseph's Hospital and Medical Center in Phoenix, Arizona. Among them, a skull base fracture was diagnosed in 78 patients following computed tomography (CT) scans. Seven patients had no neurovascular imaging performed and were excluded. Altogether, 71 patients who received a diagnosis of skull base fractures after CT and who also underwent a neurovascular imaging study were included (54 men and 17 women, mean age 29 years, range 1-83 years). Patients underwent CT angiography, magnetic resonance angiography, or digital subtraction angiography of the head and craniovertebral junction, or combinations thereof. Nine neurovascular injuries were identified in six (8.5%) of the 71 patients. Fractures of the clivus were very likely to be associated with neurovascular injury (p < 0.001). A high risk of neurovascular injury showed a strong tendency to be associated with fractures of the sella turcica-sphenoid sinus complex (p = 0.07). The risk of associated blunt neurovascular injury appears to be significant in Level 1 trauma patients in whom a diagnosis of skull base fracture has been made using CT. The incidence of neurovascular trauma is particularly high in patients with clival fractures. The authors recommend neurovascular imaging for Level 1 trauma patients with a high-risk fracture pattern of the central skull base to rule out cerebrovascular injuries.

  5. Pro-inflammatory chemokine-chemokine receptor interactions within the Ewing sarcoma microenvironment determine CD8(+) T-lymphocyte infiltration and affect tumour progression.

    PubMed

    Berghuis, Dagmar; Santos, Susy J; Baelde, Hans J; Taminiau, Antonie Hm; Egeler, R Maarten; Schilham, Marco W; Hogendoorn, Pancras Cw; Lankester, Arjan C

    2011-02-01

    Ewing sarcoma is an aggressive round cell sarcoma with poor patient prognosis, particularly in cases of advanced-stage disease. Dynamic tumor-host immune interations within the tumor microenvironment may polarize in situ immune responses and shape tumor development and/or progression. To gain insight into the nature of tumour-host immune interactions within the Ewing sarcoma microenvironment, the presence and spatial distribution of infiltrating CD8(+) /CD4(+) T-lymphocytes were evaluated in therapy-naive Ewing sarcoma. Expression profiling of 40 different chemokines and several chemokine receptors was performed in therapy-naive tumours and cell lines by qPCR, immunohistochemistry, and flow cytometry. Considerable inter-tumour variation was observed regarding density, type, and distribution of infiltrating T-lymphocytes. Tumour-infiltrating T-cells contained significantly higher percentages of CD8(+) T-lymphocytes as compared to stroma-infiltrating cells, suggesting preferential migration of this T-cell type into tumour areas. Gene expression levels of several type 1-associated, pro-inflammatory chemokines (CXCR3- and CCR5-ligands CXCL9, CXCL10, and CCL5) correlated positively with infiltrating (CD8(+) ) T-lymphocyte numbers expressing corresponding chemokine receptors. Survival analyses demonstrated an impact of tumour-infiltrating, and not stroma-infiltrating, CD8(+) T-lymphocytes on tumour progression. At protein level, both tumour and stromal cells expressed the IFNγ-inducible chemokines CXCL9 and CXCL10. CCR5-ligand CCL5 was exclusively expressed by non-tumoural stromal/infiltrating cells. Together, our results indicate that an inflammatory immune microenvironment with high expression of type 1-associated chemokines may be critical for the recruitment of (CD8(+) ) T-lymphocytes expressing corresponding chemokine receptors. The observed impact of tumour-infiltrating (CD8(+) ) T-lymphocytes is consistent with a role for adaptive anti-tumour immunity in the

  6. 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

  7. 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

  8. 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

  9. Cannabinoids ameliorate disease progression in a model of multiple sclerosis in mice, acting preferentially through CB1 receptor-mediated anti-inflammatory effects.

    PubMed

    de Lago, Eva; Moreno-Martet, Miguel; Cabranes, Ana; Ramos, José A; Fernández-Ruiz, Javier

    2012-06-01

    Multiple sclerosis (MS) is an autoimmune disease that affects the CNS and it is characterized by inflammation, demyelination, remyelination, gliosis and axonal damage that occur mainly in the spinal cord. Cannabinoids have been proposed as promising therapeutic agents in MS given their capability to alleviate specific MS symptoms (e.g., spasticity, pain). Although MS has been considered mainly an inflammatory disorder, recent evidence, however, revealed the importance of neurodegenerative events, opening the possibility that cannabinoid agonists, given their cytoprotective properties, may also serve to reduce oligodendrocyte death and axonal damage in MS. Thus, the treatment with WIN55,512-2, a potent CB(1) and CB(2) agonist, was reported to be effective to ameliorate tremor and spasticity in mice with chronic relapsing experimental autoimmune encephalomyelitis, a murine model of MS, but also to delay disease progression in this and other murine models of MS. The purpose of this investigation was to further explore the mechanism(s) underlying the amelioration in disease progression caused by WIN55,212-2. We have particularly focused on anti-glutamatergic and anti-inflammatory effects of this cannabinoid agonist. In this study, we used mice treated with myelin oligodendrocyte glycoprotein (MOG) that induces a progressive pattern of EAE and conducted the pharmacological experiments in early stages of the disease. As expected, the administration of WIN55,512-2 (5 mg/kg, i.p) had a positive effect in reducing neurological disability and improving motor coordination of EAE mice. Levels of glutamate and GABA in the spinal cord and also in the brainstem of EAE mice were similar to control animals, and, accordingly, they were not altered by the treatment with WIN55,212-2. However, EAE mice showed some subtle alterations in mRNA levels for the glutamate transporter GLT1 and, to a lesser extent, GLAST too, changes that were altered by the treatment with WIN55,212-2 in the

  10. Early changes in serum type II collagen biomarkers predict radiographic progression at one year in inflammatory arthritis patients after biologic therapy.

    PubMed

    Mullan, Ronan H; Matthews, Clare; Bresnihan, Barry; FitzGerald, Oliver; King, Lindsay; Poole, A Robin; Fearon, Ursula; Veale, Douglas J

    2007-09-01

    To investigate whether short-term changes in serum biomarkers of type II collagen degradation (C2C) and types I and II collagen degradation (C1,2C), as well as the biomarker for the synthesis of type II procollagen (CPII) can predict radiographic progression at 1 year following initiation of biologic therapy in patients with inflammatory arthritis. Serum levels of biomarkers were measured at baseline and at 1, 3, 6, 9, and 12 months after initiation of biologic therapy. A composite score reflecting changes from baseline in all 3 biomarkers (DeltaCOL) was calculated. Associations with clinical responses according to the 28-joint count Disease Activity Score and with radiographic progression according to the modified Sharp/van der Heijde score (SHS) were assessed. The 1-year increase in the SHS correlated with the 1-month change in C2C results (r = 0.311, P = 0.028) and the DeltaCOL score (r = 0.342, P = 0.015). Radiographic progression was predicted by increases in serum C2C at 1 month (P = 0.031). The DeltaCOL score was significantly associated with 1-year radiographic progression after 1 (P = 0.022), 3 (P = 0.015), 6 (P = 0.048), and 9 (P = 0.019) months of therapy. Clinical remission was predicted by 1-month decreases in serum levels of C2C (P = 0.008) and C1,2C (P = 0.036). By regression analysis, 1-month changes in C2C, C1,2C, and CPII levels were independently associated with, and correctly predicted radiographic outcome in, 88% of the patients. Short-term changes in serum levels of collagen biomarkers following initiation of biologic therapy may better predict long-term clinical and radiographic outcomes. These collagen biomarkers may therefore be valuable new early indicators of short-term biologic treatment efficacy in clinical trials and in individual patients with inflammatory erosive arthritis.

  11. Knockdown of CXCL14 disrupts neurovascular patterning during ocular development.

    PubMed

    Ojeda, Ana F; Munjaal, Ravi P; Lwigale, Peter Y

    2017-03-01

    The C-X-C motif ligand 14 (CXCL14) is a recently discovered chemokine that is highly conserved in vertebrates and expressed in various embryonic and adult tissues. CXCL14 signaling has been implicated to function as an antiangiogenic and anticancer agent in adults. However, its function during development is unknown. We previously identified novel expression of CXCL14 mRNA in various ocular tissues during development. Here, we show that CXCL14 protein is expressed in the anterior eye at a critical time during neurovascular development and in the retina during neurogenesis. We report that RCAS-mediated knockdown of CXCL14 causes severe neural defects in the eye including precocious and excessive innervation of the cornea and iris. Absence of CXCL14 results in the malformation of the neural retina and misprojection of the retinal ganglion neurons. The ocular neural defects may be due to loss of CXCL12 modulation since recombinant CXCL14 diminishes CXCL12-induced axon growth in vitro. Furthermore, we show that knockdown of CXCL14 causes neovascularization of the cornea. Altogether, our results show for the first time that CXCL14 plays a critical role in modulating neurogenesis and inhibiting ectopic vascularization of the cornea during ocular development. Copyright © 2017 Elsevier Inc. All rights reserved.

  12. 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

  13. 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.

  14. Breaking boundaries—coagulation and fibrinolysis at the neurovascular interface

    PubMed Central

    Bardehle, Sophia; Rafalski, Victoria A.; Akassoglou, Katerina

    2015-01-01

    Blood proteins at the neurovascular unit (NVU) are emerging as important molecular determinants of communication between the brain and the immune system. Over the past two decades, roles for the plasminogen activation (PA)/plasmin system in fibrinolysis have been extended from peripheral dissolution of blood clots to the regulation of central nervous system (CNS) functions in physiology and disease. In this review, we discuss how fibrin and its proteolytic degradation affect neuroinflammatory, degenerative and repair processes. In particular, we focus on novel functions of fibrin—the final product of the coagulation cascade and the main substrate of plasmin—in the activation of immune responses and trafficking of immune cells into the brain. We also comment on the suitability of the coagulation and fibrinolytic systems as potential biomarkers and drug targets in diseases, such as multiple sclerosis (MS), Alzheimer’s disease (AD) and stroke. Studying coagulation and fibrinolysis as major molecular pathways that regulate cellular functions at the NVU has the potential to lead to the development of novel strategies for the detection and treatment of neurologic diseases. PMID:26441525

  15. 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

  16. Neurovascular Bundle Decompression without Excessive Dissection for Tarsal Tunnel Syndrome

    PubMed Central

    KIM, Kyongsong; ISU, Toyohiko; MORIMOTO, Daijiro; SASAMORI, Toru; SUGAWARA, Atsushi; CHIBA, Yasuhiro; ISOBE, Masahiro; KOBAYASHI, Shiro; MORITA, Akio

    2014-01-01

    Tarsal tunnel syndrome (TTS) is an entrapment neuropathy of the posterior tibial nerve and its branches in the tarsal tunnel. We present our less invasive surgical treatment of TTS in 69 patients (116 feet) and their clinical outcomes. The mean follow-up period was 64.6 months. With the patient under local anesthesia we use a microscope to perform sharp dissection of the flexor retinaculum and remove the connective tissues surrounding the posterior tibial nerve and vessels. To prevent postoperative adhesion and delayed neuropathy, decompression is performed to achieve symptom improvement without excessive dissection. Decompression is considered complete when the patient reports intraoperative symptom abatement and arterial pulsation is sufficient. The sensation of numbness and/or pain and of foreign substance adhesion was reduced in 92% and 95% of our patients, respectively. In self-assessments, 47 patients (68%) reported the treatment outcome as satisfactory, 15 (22%) as acceptable, and 7 (10%) were dissatisfied. Of 116 feet, 4 (3%) required re-operation, initial decompression was insufficient in 2 feet and further decompression was performed; in the other 2 feet improvement was achieved by decompression of the distal tarsal tunnel. Our surgical method involves neurovascular bundle decompression to obtain sufficient arterial pulsation. As we use local anesthesia, we can confirm symptom improvement intraoperatively, thereby avoiding unnecessary excessive dissection. Our method is simple, safe, and without detailed nerve dissection and it prevents postoperative adhesion. PMID:25367582

  17. Neurovascular bundle decompression without excessive dissection for tarsal tunnel syndrome.

    PubMed

    Kim, Kyongsong; Isu, Toyohiko; Morimoto, Daijiro; Sasamori, Toru; Sugawara, Atsushi; Chiba, Yasuhiro; Isobe, Masahiro; Kobayashi, Shiro; Morita, Akio

    2014-01-01

    Tarsal tunnel syndrome (TTS) is an entrapment neuropathy of the posterior tibial nerve and its branches in the tarsal tunnel. We present our less invasive surgical treatment of TTS in 69 patients (116 feet) and their clinical outcomes. The mean follow-up period was 64.6 months. With the patient under local anesthesia we use a microscope to perform sharp dissection of the flexor retinaculum and remove the connective tissues surrounding the posterior tibial nerve and vessels. To prevent postoperative adhesion and delayed neuropathy, decompression is performed to achieve symptom improvement without excessive dissection. Decompression is considered complete when the patient reports intraoperative symptom abatement and arterial pulsation is sufficient. The sensation of numbness and/or pain and of foreign substance adhesion was reduced in 92% and 95% of our patients, respectively. In self-assessments, 47 patients (68%) reported the treatment outcome as satisfactory, 15 (22%) as acceptable, and 7 (10%) were dissatisfied. Of 116 feet, 4 (3%) required re-operation, initial decompression was insufficient in 2 feet and further decompression was performed; in the other 2 feet improvement was achieved by decompression of the distal tarsal tunnel. Our surgical method involves neurovascular bundle decompression to obtain sufficient arterial pulsation. As we use local anesthesia, we can confirm symptom improvement intraoperatively, thereby avoiding unnecessary excessive dissection. Our method is simple, safe, and without detailed nerve dissection and it prevents postoperative adhesion.

  18. 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.

  19. 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.

  20. Evidence that remodeling of insular cortex neurovascular unit contributes to hypertension-related sympathoexcitation.

    PubMed

    Marins, Fernanda R; Iddings, Jennifer A; Fontes, Marco A P; Filosa, Jessica A

    2017-03-01

    The intermediate region of the posterior insular cortex (intermediate IC) mediates sympathoexcitatory responses to the heart and kidneys. Previous studies support hypertension-evoked changes to the structure and function of neurons, blood vessels, astrocytes and microglia, disrupting the organization of the neurovascular unit (NVU). In this study, we evaluated the functional and anatomical integrity of the NVU at the intermediate IC in the spontaneously hypertensive rat (SHR) and its control the Wistar-Kyoto (WKY). Under urethane anesthesia, NMDA microinjection (0.2 mmol/L/100 nL) was performed at the intermediate IC with simultaneous recording of renal sympathetic nerve activity (RSNA), heart rate (HR) and mean arterial pressure (MAP). Alterations in NVU structure were investigated by immunofluorescence for NMDA receptors (NR1), blood vessels (70 kDa FITC-dextran), astrocytes (GFAP), and microglia (Iba1). Injections of NMDA into intermediate IC of SHR evoked higher amplitude responses of RSNA, MAP, and HR On the other hand, NMDA receptor blockade decreased baseline RSNA, MAP and HR in SHR, with no changes in WKY Immunofluorescence data from SHR intermediate IC showed increased NMDA receptor density, contributing to the SHR enhanced sympathetic responses, and increased in vascular density (increased number of branches and endpoints, reduced average branch length), suggesting angiogenesis. Additionally, IC from SHR presented increased GFAP immunoreactivity and contact between astrocyte processes and blood vessels. In SHR, IC microglia skeleton analysis supports their activation (reduced number of branches, junctions, endpoints and process length), suggesting an inflammatory process in this region. These findings indicate that neurogenic hypertension in SHR is accompanied by marked alterations to the NVU within the IC and enhanced NMDA-mediated sympathoexcitatory responses likely contributors of the maintenance of hypertension.

  1. Organotypic brain slices: a model to study the neurovascular unit micro-environment in epilepsies.

    PubMed

    Morin-Brureau, Mélanie; De Bock, Frédéric; Lerner-Natoli, Mireille

    2013-02-07

    It is now recognized that the neuro-vascular unit (NVU) plays a key role in several neurological diseases including epilepsy, stroke, Alzheimer's disease, multiple sclerosis and the development of gliomas. Most of these disorders are associated with NVU dysfunction, due to overexpression of inflammatory factors such as vascular endothelial growth factor (VEGF). Various in vitro models have been developed previously to study the micro-environment of the blood-brain barrier (BBB). However none of these in vitro models contained a complete complement of NVU cells, nor maintained their interactions, thus minimizing the influence of the surrounding tissue on the BBB development and function. The organotypic hippocampal culture (OHC) is an integrative in vitro model that allows repeated manipulations over time to further understand the development of cell circuits or the mechanisms of brain diseases. OHCs were cultured from hippocampi of 6-7 day-old Sprague Dawley rats. After 2 weeks in culture, seizures were induced by application of kainate or bicuculline into culture medium. The regulation of BBB integrity under physiological and pathological conditions was evaluated by immunostaining of the main tight junction (TJ) proteins and of the basal membrane of microvessels. To mimic or prevent BBB disassembly, we used diverse pro- or anti-angiogenic treatments. This study demonstrates that NVU regulation can be investigated using OHCs. We observed in this model system an increase in vascularization and a down-regulation of TJ proteins, similar to the vascular changes described in a chronic focus of epileptic patients, and in rodent models of epilepsy or inflammation. We observed that Zonula occludens-1 (ZO-1) protein disappeared after seizures associated with neuronal damage. In these conditions, the angiopoeitin-1 system was down-regulated, and the application of r-angiopoeitin-1 allowed TJ re-assembly. This article demonstrates that organotypic culture is a useful model to

  2. Acute-phase serum amyloid A regulates tumor necrosis factor α and matrix turnover and predicts disease progression in patients with inflammatory arthritis before and after biologic therapy.

    PubMed

    Connolly, Mary; Mullan, Ronan H; McCormick, Jennifer; Matthews, Clare; Sullivan, Owen; Kennedy, Aisling; FitzGerald, Oliver; Poole, A Robin; Bresnihan, Barry; Veale, Douglas J; Fearon, Ursula

    2012-04-01

    To investigate the relationship between acute-phase serum amyloid A (A-SAA) and joint destruction in inflammatory arthritis. Serum A-SAA and C-reactive protein (CRP) levels, the erythrocyte sedimentation rate (ESR), and levels of matrix metalloproteinase 1 (MMP-1), MMP-2, MMP-3, MMP-9, MMP-13, tissue inhibitor of metalloproteinases 1 (TIMP-1), vascular endothelial growth factor (VEGF), and type I and type II collagen-generated biomarkers C2C and C1,2C were measured at 0-3 months in patients with inflammatory arthritis commencing anti-tumor necrosis factor α (anti-TNFα) therapy and were correlated with 1-year radiographic progression. The effects of A-SAA on MMP/TIMP expression on RA fibroblast-like synoviocytes (FLS), primary human chondrocytes, and RA/psoriatic arthritis synovial explant cultures were assessed using real-time polymerase chain reaction, enzyme-linked immunosorbent assay, antibody protein arrays, and gelatin zymography. Serum A-SAA levels were significantly (P < 0.05) correlated with MMP-3, the MMP-3:TIMP-1 ratio, C1,2C, C2C, and VEGF. The baseline A-SAA level but not the ESR or the CRP level correlated with the 28-joint swollen joint count and was independently associated with 1-year radiographic progression (P = 0.038). A-SAA increased MMP-1, MMP-3, MMP-13, and MMP/TIMP expression in RA FLS and synovial explants (P < 0.05). In chondrocytes, A-SAA induced MMP-1, MMP-3, and MMP-13 messenger RNA and protein expression (all P < 0.01), resulting in a significant shift in MMP:TIMP ratios (P < 0.05). Gelatin zymography revealed that A-SAA induced MMP-2 and MMP-9 activity. Blockade of the A-SAA receptor SR-B1 (A-SAA receptor scavenger receptor-class B type 1) inhibited MMP-3, MMP-2, and MMP-9 expression in synovial explant cultures ex vivo. Importantly, we demonstrated that A-SAA has the ability to induce TNFα expression in RA synovial explant cultures (P < 0.05). A-SAA may be involved in joint destruction though MMP induction and collagen cleavage in

  3. Chromoplectic TPM3–ALK rearrangement in a patient with inflammatory myofibroblastic tumor who responded to ceritinib after progression on crizotinib

    PubMed Central

    Mansfield, A. S.; Murphy, S. J.; Harris, F. R.; Robinson, S. I.; Marks, R. S.; Johnson, S. H.; Smadbeck, J. B.; Halling, G. C.; Yi, E. S.; Wigle, D.; Vasmatzis, G.; Jen, J.

    2016-01-01

    Background Inflammatory myofibroblastic tumors (IMTs) are rare sarcomas that can occur at any age. Surgical resection is the primary treatment for patients with localized disease; however, these tumors frequently recur. Less commonly, patients with IMTs develop or present with metastatic disease. There is no standard of care for these patients and traditional cytotoxic therapy is largely ineffective. Most IMTs are associated with oncogenic ALK, ROS1 or PDGFRβ fusions and may benefit from targeted therapy. Patient and methods We sought to understand the genomic abnormalities of a patient who presented for management of metastatic IMT after progression of disease on crizotinib and a significant and durable partial response to the more potent ALK inhibitor ceritinib. Results The residual IMT was resected based on the recommendations of a multidisciplinary tumor sarcoma tumor board and analyzed by whole-genome mate pair sequencing. Analysis of the residual, resected tumor identified a chromoplectic TPM3–ALK rearrangement that involved many other known oncogenes and was confirmed by rtPCR. Conclusions In our analysis of the treatment-resistant, residual IMT, we identified a complex pattern of genetic rearrangements consistent with chromoplexy. Although it is difficult to know for certain if these chromoplectic rearrangements preceded treatment, their presence suggests that chromoplexy has a role in the oncogenesis of IMTs. Furthermore, this patient's remarkable response suggests that ceritinib should be considered as an option after progression on crizotinib for patients with metastatic or unresectable IMT and ALK mutations. PMID:27742657

  4. 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

  5. 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.

  6. Serum Anti-Glycan Antibody Biomarkers for Inflammatory Bowel Disease Diagnosis and Progression: A Systematic Review and Meta-analysis

    PubMed Central

    Kaul, Amit; Hutfless, Susan; Liu, Ling; Bayless, Theodore M.; Marohn, Michael R.; Li, Xuhang

    2011-01-01

    BACKGROUND Anti-glycan antibody serologic markers may serve as useful adjunct in the diagnosis/prognosis of inflammatory bowel disease (IBD), including Crohn’s disease (CD) and ulcerative colitis (UC). This meta-analysis/systemic review was aimed to evaluate the diagnostic value, as well as the association of anti-glycan biomarkers with IBD susceptible gene variants, disease complications, and need for surgery in IBD. METHODS The diagnostic odds ratio (DOR), 95% confidence interval (CI), and sensitivity/specificity were used to compare the diagnostic value of individual and combinations of anti-glycan markers and their association with disease course (complication and/or need for surgery). RESULTS Fourteen studies were included in the systemic review and nine in the meta-analysis. Individually, ASCA had the highest DOR for differentiating IBD from healthy (DOR 21.1; 1.8-247.3; 2 studies), and CD from UC (DOR 10.2; CI 7.7-13.7; 7 studies). For combination of ≥2 markers, the DOR was 2.8 (CI 2.2-3.6; 2 studies) for CD-related surgery, higher than any individual marker, while the DOR for differentiating CD from UC was 10.2 (CI 5.6-18.5; 3 studies) and for complication was 2.8 (CI 2.2-3.7; 2 studies), similar to individual markers. CONCLUSIONS ASCA had the highest diagnostic value among individual anti-glycan markers. While ACCA had the highest association with complications, ASCA and ACCA associated equally with need for surgery. Although in most individual studies, combination of ≥2 markers had a better diagnostic value as well as higher association with complications and need for surgery, we found the combination performing slightly better than any individual marker in our meta-analysis. PMID:22294465

  7. Dexamethasone prevents motor deficits and neurovascular damage produced by shiga toxin 2 and lipopolysaccharide in the mouse striatum.

    PubMed

    Pinto, Alipio; Cangelosi, Adriana; Geoghegan, Patricia A; Goldstein, Jorge

    2017-03-06

    Shiga toxin 2 (Stx2) from enterohemorrhagic Escherichia coli (EHEC) causes bloody diarrhea and Hemolytic Uremic Syndrome (HUS) that may derive to fatal neurological outcomes. Neurological abnormalities in the striatum are frequently observed in affected patients and in studies with animal models while motor disorders are usually associated with pyramidal and extra pyramidal systems. A translational murine model of encephalopathy was employed to demonstrate that systemic administration of a sublethal dose of Stx2 damaged the striatal microvasculature and astrocytes, increase the blood brain barrier permeability and caused neuronal degeneration. All these events were aggravated by lipopolysaccharide (LPS). The injury observed in the striatum coincided with locomotor behavioral alterations. The anti-inflammatory Dexamethasone resulted to prevent the observed neurologic and clinical signs, proving to be an effective drug. Therefore, the present work demonstrates that: (i) systemic sub-lethal Stx2 damages the striatal neurovascular unit as it succeeds to pass through the blood brain barrier. (ii) This damage is aggravated by the contribution of LPS which is also produced and secreted by EHEC, and (iii) the observed neurological alterations may be prevented by an anti-inflammatory treatment.

  8. 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

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

    PubMed

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

    2015-11-24

    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.

  10. Caloric restriction preserves memory and reduces anxiety of aging mice with early enhancement of neurovascular functions

    PubMed Central

    Parikh, Ishita; Guo, Janet; Chuang, Kai-Hsiang; Zhong, Yu; Rempe, Ralf G.; Hoffman, Jared D.; Armstrong, Rachel; Bauer, Björn; Hartz, Anika M.S.; Lin, Ai-Ling

    2016-01-01

    Neurovascular integrity plays an important role in protecting cognitive and mental health in aging. Lifestyle interventions that sustain neurovascular integrity may thus be critical on preserving brain functions in aging and reducing the risk for age-related neurodegenerative disorders. Here we show that caloric restriction (CR) had an early effect on neurovascular enhancements, and played a critical role in preserving vascular, cognitive and mental health in aging. In particular, we found that CR significantly enhanced cerebral blood flow (CBF) and blood-brain barrier function in young mice at 5-6 months of age. The neurovascular enhancements were associated with reduced mammalian target of rapamycin expression, elevated endothelial nitric oxide synthase signaling, and increased ketone bodies utilization. With age, CR decelerated the rate of decline in CBF. The preserved CBF in hippocampus and frontal cortex were highly correlated with preserved memory and learning, and reduced anxiety, of the aging mice treated with CR (18-20 months of age). Our results suggest that dietary intervention started in the early stage (e.g., young adults) may benefit cognitive and mental reserve in aging. Understanding nutritional effects on neurovascular functions may have profound implications in human brain aging and age-related neurodegenerative disorders. PMID:27829242

  11. Revisional operations improve results of neurovascular free muscle transfer for treatment of facial paralysis.

    PubMed

    Takushima, Akihiko; Harii, Kiyonori; Asato, Hirotaka; Momosawa, Akira

    2005-08-01

    Neurovascular free muscle transfer is currently the mainstay for smile reconstruction. However, problems such as excessive muscle bulk and dislocation of the transferred muscle attachment have been described. Furthermore, dynamic movements of the transferred muscle are sometimes too strong or too weak, resulting in facial asymmetry. In these cases, secondary revisional operations for the transferred muscle are required after neurovascular free muscle transfer. This report describes revisional operative procedures in detail and examines the extent of improvement of the smile by comparing preoperative and postoperative results. Of 468 patients in whom neurovascular free muscle transfer was performed between 1977 and 2000, a total of 183 received revisional operations for the transferred muscle. Operations included revision of muscle attachment in 129 patients, debulking of the cheek in 114 patients, and fascia graft in 21 patients. Evaluation with the grading scale was performed in 117 of the 183 patients. Grading improved in 59 patients and worsened in seven patients. The remaining 51 patients displayed no change in grading. Differences between preoperative and post-operative grading were compared statistically, and revisional operations improved the grading score. Revisional operations are effective and important as secondary operations after neurovascular free muscle transfer. However, care must be taken not to damage the neurovascular pedicles.

  12. Preoperative demonstration of neurovascular relationship in trigeminal neuralgia by using 3D FIESTA sequence.

    PubMed

    Zhou, Qin; Liu, Zhi-Ling; Qu, Chun-Cheng; Ni, Shi-Lei; Xue, Feng; Zeng, Qing-Shi

    2012-06-01

    The purpose of the study was to evaluate the value of high-resolution three-dimensional fast imaging employing steady-state acquisition (3D FIESTA) imaging in the visualization of neurovascular relationship in patients with trigeminal neuralgia (TN). Thirty-seven patients with unilateral typical TN underwent 3D FIESTA imaging. Neurovascular relationship at the trigeminal root entry zone was reviewed by an experienced neuroradiologist, who was blinded to the clinical details. The imaging results were compared with the operative findings in all patients. In 37 patients with TN, 3D FIESTA imaging identified surgically verified neurovascular contact in 35 of 36 symptomatic nerves. Based on surgical findings, the sensitivity and specificity of magnetic resonance (MR) imaging were 97.2% and 100%, respectively. Agreement between the position (medial, lateral, superior and inferior) of the compressing vessel relative to the trigeminal nerve identified by MR imaging and surgery was excellent (K=0.81; 95% confidence interval, 0.56-1.00). A statistically significant difference was found between the site of neurovascular contact and the clinical symptom related to the trigeminal branch (Fisher's Exact Test, P<.001). Use of 3D FIESTA sequence enables accurate visualization of neurovascular contact in patients with TN. Anatomic relationships defined by this method can be useful in surgical planning and predicting surgical findings. Copyright © 2012 Elsevier Inc. All rights reserved.

  13. IGF-1 deficiency impairs neurovascular coupling in mice: implications for cerebromicrovascular aging.

    PubMed

    Toth, Peter; Tarantini, Stefano; Ashpole, Nicole M; Tucsek, Zsuzsanna; Milne, Ginger L; Valcarcel-Ares, Noa M; Menyhart, Akos; Farkas, Eszter; Sonntag, William E; Csiszar, Anna; Ungvari, Zoltan

    2015-12-01

    Aging is associated with marked deficiency in circulating IGF-1, which has been shown to contribute to age-related cognitive decline. Impairment of moment-to-moment adjustment of cerebral blood flow (CBF) via neurovascular coupling is thought to play a critical role in the genesis of age-related cognitive impairment. To establish the link between IGF-1 deficiency and cerebromicrovascular impairment, neurovascular coupling mechanisms were studied in a novel mouse model of IGF-1 deficiency (Igf1(f/f) -TBG-Cre-AAV8) and accelerated vascular aging. We found that IGF-1-deficient mice exhibit neurovascular uncoupling and show a deficit in hippocampal-dependent spatial memory test, mimicking the aging phenotype. IGF-1 deficiency significantly impaired cerebromicrovascular endothelial function decreasing NO mediation of neurovascular coupling. IGF-1 deficiency also impaired glutamate-mediated CBF responses, likely due to dysregulation of astrocytic expression of metabotropic glutamate receptors and impairing mediation of CBF responses by eicosanoid gliotransmitters. Collectively, we demonstrate that IGF-1 deficiency promotes cerebromicrovascular dysfunction and neurovascular uncoupling mimicking the aging phenotype, which are likely to contribute to cognitive impairment.

  14. Telmisartan reduces progressive accumulation of cellular amyloid beta and phosphorylated tau with inflammatory responses in aged spontaneously hypertensive stroke resistant rat.

    PubMed

    Kurata, Tomoko; Lukic, Violeta; Kozuki, Miki; Wada, Daisuke; Miyazaki, Kazunori; Morimoto, Nobutoshi; Ohta, Yasuyuki; Deguchi, Kentaro; Ikeda, Yoshio; Kamiya, Tatsushi; Abe, Koji

    2014-01-01

    In addition to reducing the level of blood pressure (BP), telmisartan was expected to show the long-term neuroprotective effects preventing accumulation of cellular amyloid beta peptide (Aβ) and phosphorylated tau (pτ) by ameliorating neuroinflammation. We examined effects of telmisartan on cellular Aβ and pτ with inflammatory responses in the brain of a spontaneously hypertensive stroke resistant (SHR-SR) rat by giving either telmisartan at 0 (vehicle), .3 mg/kg/day or 3 mg/kg/day, orally, from 3 months of age and performed immunohistologic analysis at 6, 12, and 18 months. Compared with normotensive Wistar rats, numbers of Aβ- and pτ-positive neurons in the cerebral cortex progressively increased with age until 18 months in the SHR-SR rats, as did the numbers of ionized calcium-binding adapter molecule 1 (Iba-1)-positive microglia, tumor necrosis factor alpha (TNF-α)-positive neurons, and monocyte chemotactic protein 1 (MCP-1)-positive neurons. Low-dose telmisartan significantly decreased the numbers of Aβ- and pτ-positive neuron as well as the numbers of TNF-α-positive neurons, Iba-1-positive microglia, and MCP-1-positive neurons at 6, 12, and 18 months. High-dose telmisartan reduced BP and showed a further reduction of cellular Aβ and pτ. The present study suggests that accumulation of cellular Aβ and pτ and the inflammatory responses were decreased via improving metabolic syndrome with low-dose telmisartan and improving both metabolic syndrome and hypertension with high-dose telmisartan. Copyright © 2014 National Stroke Association. Published by Elsevier Inc. All rights reserved.

  15. 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

  16. TNFR1-JNK signaling is the shared pathway of neuroinflammation and neurovascular damage after LPS-sensitized hypoxic-ischemic injury in the immature brain.

    PubMed

    Wang, Lan-Wan; Chang, Ying-Chao; Chen, Shyi-Jou; Tseng, Chien-Hang; Tu, Yi-Fang; Liao, Nan-Shih; Huang, Chao-Ching; Ho, Chien-Jung

    2014-12-24

    Hypoxic-ischemia (HI) and inflammation are the two major pathogenic mechanisms of brain injury in very preterm infants. The neurovascular unit is the major target of HI injury in the immature brain. Systemic inflammation may worsen HI by up-regulating neuroinflammation and disrupting the blood-brain barrier (BBB). Since neurons and oligodendrocytes, microvascular endothelial cells, and microglia may closely interact with each other, there may be a common signaling pathway leading to neuroinflammation and neurovascular damage after injury in the immature brain. TNF-α is a key pro-inflammatory cytokine that acts through the TNF receptor (TNFR), and c-Jun N-terminal kinases (JNK) are important stress-responsive kinases. To determine if TNFR1-JNK signaling is a shared pathway underlying neuroinflammation and neurovascular injury after lipopolysaccharide (LPS)-sensitized HI in the immature brain. Postpartum (P) day-5 mice received LPS or normal saline (NS) injection before HI. Immunohistochemistry, immunoblotting and TNFR1- and TNFR2-knockout mouse pups were used to determine neuroinflammation, BBB damage, TNF-α expression, JNK activation, and cell apoptosis. The cellular distribution of p-JNK, TNFR1/TNFR2 and cleaved caspase-3 were examined using immunofluorescent staining. The LPS + HI group had significantly greater up-regulation of activated microglia, TNF-α and TNFR1 expression, and increases of BBB disruption and cleaved caspase-3 levels at 24 hours post-insult, and showed more cortical and white matter injury on P17 than the control and NS + HI groups. Cleaved caspase-3 was highly expressed in microvascular endothelial cells, neurons, and oligodendroglial precursor cells. LPS-sensitized HI also induced JNK activation and up-regulation of TNFR1 but not TNFR2 expression in the microglia, endothelial cells, neurons, and oligodendrocyte progenitors, and most of the TNFR1-positive cells co-expressed p-JNK. Etanercept (a TNF-α inhibitor) and AS601245 (a

  17. A neurovascular transmission model for acupuncture-induced nitric oxide.

    PubMed

    Hsiao, Sheng-Hsiung; Tsai, Li-Jen

    2008-09-01

    Acupuncture is the practice of inserting needles into the body to reduce pain or induce anesthesia. More broadly, acupuncture is a family of procedures involving the stimulation of anatomical locations on or in the skin by a variety of techniques. Employing acupuncture to treat human disease or maintain bodily condition has been practiced for thousands of years. However, the mechanism(s) of action of acupuncture at the various meridians are poorly understood. Most studies have indicated that acupuncture is able to increase blood flow. The acupuncture points have high electrical conductance and a relationship of the acupuncture points and meridians with the connective tissue planes and the perivascular space has also been suggested. Several studies employing the human and animal models have shown that acupuncture enhances the generation of nitric oxide (NO) and increases local circulation. Specifically, electroacupuncture (EA) seems to prevent the reduction in NO production from endothelial NO synthetase (eNOS) and neuronal NO synthase (nNOS) that is associated with hypertension and this process involves a stomach-meridian organ but not a non-stomach-meridian organ such as the liver. How can we explain the phenomena of EA and meridian effect? Here, we proposed a neurovascular transmission model for acupuncture induced NO. In this proposed model, the acupuncture stimulus is able to influence connective tissue via mechanical force transfer to the extracellular matrix (ECM). Through the ECM, the mechanotransduction stimulus can be translated or travel from the acupuncture points, which involve local tissue and cells. Cells in the local tissue that have received mechanotransduction induce different types of NO production that can induce changes in blood flow and local circulation. The local mechanical stress produced is coupled to a cyclic strain of the blood vessels and this could then change the frequency of resonance. According to the resonance theory, an oscillatory

  18. Matrix Metalloproteinase Mmp-1a Is Dispensable for Normal Growth and Fertility in Mice and Promotes Lung Cancer Progression by Modulating Inflammatory Responses*

    PubMed Central

    Fanjul-Fernández, Miriam; Folgueras, Alicia R.; Fueyo, Antonio; Balbín, Milagros; Suárez, María F.; Fernández-García, M. Soledad; Shapiro, Steven D.; Freije, José M. P.; López-Otín, Carlos

    2013-01-01

    Human MMP-1 is a matrix metalloproteinase repeatedly associated with many pathological conditions, including cancer. Thus, MMP1 overexpression is a poor prognosis marker in a variety of advanced cancers, including colorectal, breast, and lung carcinomas. Moreover, MMP-1 plays a key role in the metastatic behavior of melanoma, breast, and prostate cancer cells. However, functional and mechanistic studies on the relevance of MMP-1 in cancer have been hampered by the absence of an in vivo model. In this work, we have generated mice deficient in Mmp1a, the murine ortholog of human MMP1. Mmp1a−/− mice are viable and fertile and do not exhibit obvious abnormalities, which has facilitated studies of cancer susceptibility. These studies have shown a decreased susceptibility to develop lung carcinomas induced by chemical carcinogens in Mmp1a−/− mice. Histopathological analysis indicated that tumors generated in Mmp1a−/− mice are smaller than those of wild-type mice, consistently with the idea that the absence of Mmp-1a hampers tumor progression. Proteomic analysis revealed decreased levels of chitinase-3-like 3 and accumulation of the receptor for advanced glycation end-products and its ligand S100A8 in lung samples from Mmp1a−/− mice compared with those from wild-type. These findings suggest that Mmp-1a could play a role in tumor progression by modulating the polarization of a Th1/Th2 inflammatory response to chemical carcinogens. On the basis of these results, we propose that Mmp1a knock-out mice provide an excellent in vivo model for the functional analysis of human MMP-1 in both physiological and pathological conditions. PMID:23548910

  19. Mandibular alveolar neurovascular bundle injury associated with impacted third molar surgery.

    PubMed

    Ruga, Emanuele; Gallesio, Cesare; Boffano, Paolo

    2010-07-01

    Inferior alveolar neurovascular bundle (IANB) injury is one of the most common complications of third molar removal and involves important medicolegal issues. An accurate preoperative radiographic assessment of surgical difficulty is necessary to correctly plan the removal of impacted third molars and to estimate the risk of IANB injury. Therefore, the preoperative knowledge of the exact location of the third molar roots in relation to the mandibular canal is mandatory. A direct contact between the tooth and neurovascular bundle is suggested by a radiotransparent band across the roots of the impacted third molar on panoramic radiograph. We present the management of a patient with IANB damage associated with third molar surgery.

  20. 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.

  1. Anterior transposition of the inferior oblique. Anatomic assessment of the neurovascular bundle.

    PubMed

    Stager, D R; Weakley, D R; Stager, D

    1992-03-01

    Anterior transposition of the inferior oblique insertion has been described as an effective procedure for weakening the inferior oblique and for decreasing dissociated vertical deviation. It has been postulated that this occurs by converting the inferior oblique muscle from an elevator to a depressor. We found histologic, radiologic, and clinical evidence that anterior transposition of the inferior oblique muscle converts it to a depressor by means of the firm posterior attachment of the inferior oblique muscle at the site of its neurovascular bundle. This new functional insertion at the neurovascular bundle created by the anterior transposition allows for the depressor effect seen after this procedure.

  2. Neurovascular abnormalities in brain disorders: highlights with angiogenesis and magnetic resonance imaging studies

    PubMed Central

    2013-01-01

    The coupling between neuronal activity and vascular responses is controlled by the neurovascular unit (NVU), which comprises multiple cell types. Many different types of dysfunction in these cells may impair the proper control of vascular responses by the NVU. Magnetic resonance imaging, which is the most powerful tool available to investigate neurovascular structures or functions, will be discussed in the present article in relation to its applications and discoveries. Because aberrant angiogenesis and vascular remodeling have been increasingly reported as being implicated in brain pathogenesis, this review article will refer to this hallmark event when suitable. PMID:23829868

  3. 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.

  4. Volumetric Spatial Correlations of Neurovascular Coupling Studied using Single Pulse Opto-fMRI

    PubMed Central

    Christie, Isabel N.; Wells, Jack A.; Kasparov, Sergey; Gourine, Alexander V.; Lythgoe, Mark F.

    2017-01-01

    Neurovascular coupling describes the link between neuronal activity and cerebral blood flow. This relationship has been the subject of intense scrutiny, with most previous work seeking to understand temporal correlations that describe neurovascular coupling. However, to date, the study of spatial correlations has been limited to two-dimensional mapping of neuronal or vascular derived signals emanating from the brain’s surface, using optical imaging techniques. Here, we investigate spatial correlations of neurovascular coupling in three dimensions, by applying a single 10 ms pulse of light to trigger optogenetic activation of cortical neurons transduced to express channelrhodopsin2, with concurrent fMRI. We estimated the spatial extent of increased neuronal activity using a model that takes into the account the scattering and absorption of blue light in brain tissue together with the relative density of channelrhodopsin2 expression across cortical layers. This method allows precise modulation of the volume of activated tissue in the cerebral cortex with concurrent three-dimensional mapping of functional hyperemia. Single pulse opto-fMRI minimizes adaptation, avoids heating artefacts and enables confined recruitment of the neuronal activity. Using this novel method, we present evidence for direct proportionality of volumetric spatial neurovascular coupling in the cerebral cortex. PMID:28176823

  5. Pathophysiological Interference with Neurovascular Coupling – When Imaging Based on Hemoglobin Might Go Blind

    PubMed Central

    Lindauer, Ute; Dirnagl, Ulrich; Füchtemeier, Martina; Böttiger, Caroline; Offenhauser, Nikolas; Leithner, Christoph; Royl, Georg

    2010-01-01

    Assessing neuronal activity by non-invasive functional brain imaging techniques which are based on the hemodynamic response depends totally on the physiological cascade of metabolism and blood flow. At present, functional brain imaging with near infrared spectroscopy (NIRS) or BOLD-fMRI is widely used in cognitive neuroscience in healthy subjects where neurovascular coupling and cerebrovascular reactivity can be assumed to be intact. Local activation studies as well as studies investigating functional connectivity between brain regions of the resting brain provide a rapidly increasing body of knowledge on brain function in humans and animals. Furthermore, functional NIRS and MRI techniques are increasingly being used in patients with severe brain diseases and this use might gain more and more importance for establishing their use in the clinical routine. However, more and more experimental evidence shows that changes in baseline physiological parameters, pharmacological interventions, or disease-related vascular changes may significantly alter the normal response of blood flow and blood oxygenation and thus may lead to misinterpretation of neuronal activity. In this article we present examples of recent experimental findings on pathophysiological changes of neurovascular coupling parameters in animals and discuss their potential implications for functional imaging based on hemodynamic signals such as fNIRS or BOLD-fMRI. To enable correct interpretation of neuronal activity by vascular signals, future research needs to deepen our understanding of the basic mechanisms of neurovascular coupling and the specific characteristics of disturbed neurovascular coupling in the diseased brain. PMID:20953238

  6. Glossopharyngeal neuralgia caused by a complex neurovascular conflict: Case report and review of the literature

    PubMed Central

    Alafaci, Concetta; Granata, Francesca; Cutugno, Mariano; Marino, Daniele; Conti, Alfredo; Tomasello, Francesco

    2015-01-01

    Background: Glossopharyngeal neuralgia (GN) is a rare condition characterized by severe, paroxysmal episodes of pain mainly localized to the external ear canal, pharynx, and tongue, usually caused by a neurovascular conflict between postero-inferior cerebellar artery (PICA) and IX cranial nerve. Sometimes there is also a compression of X c.n. Case Description: We present a case of a 71-year-old female with a 3-year history of intense pain localized in the pharynx and posterior portion of the tongue. Preoperative magnetic resonance imaging (MRI) documented a neurovascular conflict between a loop of PICA and IX left c.n. Surgery was performed through a retrosigmoid craniectomy. The intraoperative findings documented a loop of PICA compressing IX, X, and XI c.n. Microvascular decompression (MVD) of IX c.n. was performed using the interposing technique. No rhizotomy and MVD of the X c.n. was performed. Postoperative course showed the regression of all symptoms. Conclusions: The surgical treatment of patients with GN caused by complex neurovascular conflicts can be safely performed with the classical MVD of IX c.n. A double MVD of both IX and X c.n. has a role only in patients presenting symptoms from both nerves. Rhizotomy, in our opinion, has to be avoided in all cases. The authors review the literature concerning GN caused by complex neurovascular conflicts. PMID:25709856

  7. 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.

  8. The astrocytic contribution to neurovascular coupling--still more questions than answers?

    PubMed

    Kowiański, Przemysław; Lietzau, Grażyna; Steliga, Aleksandra; Waśkow, Monika; Moryś, Janusz

    2013-03-01

    Cerebral blood flow adequate for brain activity and metabolic demand is maintained through the processes of autoregulation and neurovascular coupling. Astrocytes undoubtedly make an important contribution to these processes. The critical factors that determine the polarity of astrocytic response include: metabolites (e.g., arachidonic acid and its derivatives, lactate and oxygen concentrations), ions (H(+), Ca(2+) and K(+)), gliotransmitters (glutamate, Glu; gamma-aminobutyric acid, GABA; d-serine; adenosine 5'-triphosphate, ATP and brain derived neurotrophic factor, BDNF), neuronal activity and vascular tone. Although the astrocytic contribution to neurovascular coupling has been intensively studied, a few important questions still remain, such as: (1) the modulatory function of astrocytes in tripartite synapses, including effects related to the strength of synaptic stimulation and the particular signaling pathway (astrocytic or neuronal) that becomes activated, (2) the significance of the vasoconstrictive reaction evoked by arachidonic acid metabolites (e.g., 20-hydroxyeicosatetraenoic acid, 20-HETE) under both physiological and pathological conditions, (3) the relationship between brain activity level and metabolic processes occurring in astrocytes, which is studied using neuroradiological techniques and (4) the astrocytic contribution to the neurovascular response under pathological conditions. Hence, the function of astrocytes in neurovascular coupling remains ambiguous. The function of astrocytes is beneficial and integrative in physiological conditions, but under definitive pathological conditions may become detrimental and involved in the development of diseases like ischemic stroke, arterial hypertension and Alzheimer's disease.

  9. Volumetric Spatial Correlations of Neurovascular Coupling Studied using Single Pulse Opto-fMRI.

    PubMed

    Christie, Isabel N; Wells, Jack A; Kasparov, Sergey; Gourine, Alexander V; Lythgoe, Mark F

    2017-02-08

    Neurovascular coupling describes the link between neuronal activity and cerebral blood flow. This relationship has been the subject of intense scrutiny, with most previous work seeking to understand temporal correlations that describe neurovascular coupling. However, to date, the study of spatial correlations has been limited to two-dimensional mapping of neuronal or vascular derived signals emanating from the brain's surface, using optical imaging techniques. Here, we investigate spatial correlations of neurovascular coupling in three dimensions, by applying a single 10 ms pulse of light to trigger optogenetic activation of cortical neurons transduced to express channelrhodopsin2, with concurrent fMRI. We estimated the spatial extent of increased neuronal activity using a model that takes into the account the scattering and absorption of blue light in brain tissue together with the relative density of channelrhodopsin2 expression across cortical layers. This method allows precise modulation of the volume of activated tissue in the cerebral cortex with concurrent three-dimensional mapping of functional hyperemia. Single pulse opto-fMRI minimizes adaptation, avoids heating artefacts and enables confined recruitment of the neuronal activity. Using this novel method, we present evidence for direct proportionality of volumetric spatial neurovascular coupling in the cerebral cortex.

  10. Towards a bimodal proximity sensor for in situ neurovascular bundle detection during dental implant surgery

    PubMed Central

    Weber, Jessie R.; Baribeau, François; Grenier, Paul; Émond, Frédéric; Dubois, Sylvain; Duchesne, François; Girard, Marc; Pope, Timothy; Gallant, Pascal; Mermut, Ozzy; Moghadam, Hassan Ghaderi

    2013-01-01

    Proof of concept results are presented towards an in situ bimodal proximity sensor for neurovascular bundle detection during dental implant surgery using combined near infrared absorption (NIR) and optical coherence tomography (OCT) techniques. These modalities are shown to have different sensitivity to the proximity of optical contrast from neurovascular bundles. NIR AC and DC signals from the pulsing of an artery enable qualitative ranging of the bundle in the millimeter range, with best sensitivity around 0.5-3mm distance in a custom phantom setup. OCT provides structural mapping of the neurovascular bundle at sub-millimeter distances in an ex vivo human jaw bone. Combining the two techniques suggests a novel ranging system for the surgeon that could be implemented in a “smart drill.” The proximity to the neurovascular bundle can be tracked in real time in the range of a few millimeters with NIR signals, after which higher resolution imaging OCT to provide finer ranging in the sub-millimeter distances. PMID:24466473

  11. The Cannabinoid Use in Progressive Inflammatory brain Disease (CUPID) trial: a randomised double-blind placebo-controlled parallel-group multicentre trial and economic evaluation of cannabinoids to slow progression in multiple sclerosis.

    PubMed

    Ball, Susan; Vickery, Jane; Hobart, Jeremy; Wright, Dave; Green, Colin; Shearer, James; Nunn, Andrew; Cano, Mayam Gomez; MacManus, David; Miller, David; Mallik, Shahrukh; Zajicek, John

    2015-02-01

    The Cannabinoid Use in Progressive Inflammatory brain Disease (CUPID) trial aimed to determine whether or not oral Δ(9)-tetrahydrocannabinol (Δ(9)-THC) slowed the course of progressive multiple sclerosis (MS); evaluate safety of cannabinoid administration; and, improve methods for testing treatments in progressive MS. There were three objectives in the CUPID study: (1) to evaluate whether or not Δ(9)-THC could slow the course of progressive MS; (2) to assess the long-term safety of Δ(9)-THC; and (3) to explore newer ways of conducting clinical trials in progressive MS. The CUPID trial was a randomised, double-blind, placebo-controlled, parallel-group, multicentre trial. Patients were randomised in a 2 : 1 ratio to Δ(9)-THC or placebo. Randomisation was balanced according to Expanded Disability Status Scale (EDSS) score, study site and disease type. Analyses were by intention to treat, following a pre-specified statistical analysis plan. A cranial magnetic resonance imaging (MRI) substudy, Rasch measurement theory (RMT) analyses and an economic evaluation were undertaken. Twenty-seven UK sites. Adults aged 18-65 years with primary or secondary progressive MS, 1-year evidence of disease progression and baseline EDSS 4.0-6.5. Oral Δ(9)-THC (maximum 28 mg/day) or matching placebo. Three and 6 months, and then 6-monthly up to 36 or 42 months. Primary outcomes were time to EDSS progression, and change in Multiple Sclerosis Impact Scale-29 version 2 (MSIS-29v2) 20-point physical subscale (MSIS-29phys) score. Various secondary patient- and clinician-reported outcomes and MRI outcomes were assessed. RMT analyses examined performance of MS-specific rating scales as measurement instruments and tested for a symptomatic or disease-modifying treatment effect. Economic evaluation estimated mean incremental costs and quality-adjusted life-years (QALYs). Effectiveness - recruitment targets were achieved. Of the 498 randomised patients (332 to active and 166 to placebo

  12. Control of the neurovascular coupling by nitric oxide-dependent regulation of astrocytic Ca(2+) signaling.

    PubMed

    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 Ca(2+) signaling that propagates to the endfeet, activating the release of vasoactive factors and arteriolar dilation. The astrocyte Ca(2+) 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 Ca(2+) waves are propagated among neighboring astrocytes directly via gap junctions or through ATP release via connexin hemichannels or pannexin channels. In addition, Ca(2+) 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 Ca(2+)-dependent NO-synthesizing enzymes endothelial NO synthase (eNOS) and neuronal NOS (nNOS) are expressed in astrocytes. Therefore, the astrocytic Ca(2+) signaling triggered in neurovascular coupling may activate NO production, which, in turn, may lead to Ca(2+) 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 Ca(2+) signaling that mediates neurovascular coupling, with a special emphasis in the possible participation of NO in

  13. Neurovascular relationships of the approaches for arthroscopic total trapeziectomy with ligamentous stabilization.

    PubMed

    Durand, S; Gagey, O; Masquelet, A C; Thoreux, P

    2005-08-01

    The aim of this study was to define the neurovascular relationships of the approaches used during arthroscopic total trapeziectomy with the Thompson "suspension-plasty." Fifteen fresh cadavers in which trapezio-metacarpal arthritis had been confirmed by preoperative radiographs were chosen. There were 12 women and 3 men (average age: 87 years), and small joint arthroscopy equipment was used. Two approaches for the trapezio-metacarpal joint were used: an ulnar approach situated at the ulnar border of the extensor pollicis brevis tendon and a radial approach placed at the middle of a line joining the tendons of the flexor carpi radialis and the abductor pollicis longus. A new transosseous approach at the base of the first metacarpal ("trans-M1" approach) is suggested and was used to do the ligamento-plasty. After the operation, a large skin flap was elevated in order to measure the distance between each surgical approach and the different neurovascular structures (radial artery, dividing branches of the superficial branch of the radial nerve and the end of the lateral cutaneous nerve of the forearm) and to verify the absence of neurovascular lesions. The different neurovascular structures at risk during this arthroscopic maneuver were the radial artery for the ulnar approach, the branches of the superficial branch of the radial nerve for all of the approaches and the ending of the lateral cutaneous nerve of the forearm for the radial and "trans-M1" approaches. The use of the approaches described allows arthroscopic trapeziectomy with the Thompson suspension-plasty without us having noted neurovascular lesion.

  14. Predictive Factors of Neurovascular and Tendon Injuries Following Dog Bites to the Upper Extremity.

    PubMed

    Alluri, Ram K; Pannell, William; Heckmann, Nathanael; Sivasundaram, Lakshmanan; Stevanovic, Milan; Ghiassi, Alidad

    2016-12-01

    Background: Dog bite injuries to the upper extremity can result in traumatic neurovascular and musculotendinous damage. Currently, there are no clear guidelines dictating which patients may benefit from early operative exploration. The purpose of this study was to identify clinical variables that were predictive of abnormal intraoperative findings in patients who sustained an upper extremity dog bite injury. Methods: All patients who presented to a level I trauma center between 2007 and 2015 with an upper extremity dog bite injury who underwent subsequent surgical exploration were retrospectively screened for inclusion in our study. Patients with inadequate documentation or preexisting neurovascular or motor deficits were excluded. Abnormalities on physical exam and injuries encountered during surgical exploration were recorded for each patient. Contingency tables were constructed comparing normal and abnormal nerve, tendon, and vascular physical exam findings with intact or disrupted neurovascular and musculotendinous structures identified during surgical exploration. Results: Between 2007 and 2014, 117 patients sustained a dog bite injury to the upper extremity, of which 39 underwent subsequent surgical exploration and were included in our analysis. Sixty-nine percent of patients with neuropraxia on exam had intraoperative nerve damage. Seventy-seven percent of patients with an abnormal tendon exam had intraoperative musculotendinous damage. One hundred percent of patients with an abnormal vascular physical exam had intraoperative arterial injury. Conclusions: To date, there are no clear guidelines on what clinical criteria indicate the need for operative exploration and possible repair of neurovascular structures in upper extremity dog bite injuries. In our study, nerve, tendon, and vascular abnormalities noted on physical exam were strongly predictive of discovering neurovascular and musculotendinous damage during surgical exploration.

  15. Biphasic direct current shift, haemoglobin desaturation and neurovascular uncoupling in cortical spreading depression

    PubMed Central

    Chang, Joshua C.; Shook, Lydia L.; Biag, Jonathan; Nguyen, Elaine N.; Toga, Arthur W.; Charles, Andrew C.

    2010-01-01

    Cortical spreading depression is a propagating wave of depolarization that plays important roles in migraine, stroke, subarachnoid haemorrhage and brain injury. Cortical spreading depression is associated with profound vascular changes that may be a significant factor in the clinical response to cortical spreading depression events. We used a combination of optical intrinsic signal imaging, electro-physiology, potassium sensitive electrodes and spectroscopy to investigate neurovascular changes associated with cortical spreading depression in the mouse. We identified two distinct phases of altered neurovascular function, one during the propagating cortical spreading depression wave and a second much longer phase after passage of the wave. The direct current shift associated with the cortical spreading depression wave was accompanied by marked arterial constriction and desaturation of cortical haemoglobin. After recovery from the initial cortical spreading depression wave, we observed a second phase of prolonged, negative direct current shift, arterial constriction and haemoglobin desaturation, lasting at least an hour. Persistent disruption of neurovascular coupling was demonstrated by a loss of coherence between electro-physiological activity and perfusion. Extracellular potassium concentration increased during the cortical spreading depression wave, but recovered and remained at baseline after passage of the wave, consistent with different mechanisms underlying the first and second phases of neurovascular dysfunction. These findings indicate that cortical spreading depression is associated with a multiphasic alteration in neurovascular function, including a novel second direct current shift accompanied by arterial constriction and decrease in tissue oxygen supply, that is temporally and mechanistically distinct from the initial propagated cortical spreading depression wave. Vascular/metabolic uncoupling with cortical spreading depression may have important

  16. 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

  17. Low-energy Shock Wave Therapy Ameliorates Erectile Dysfunction in a Pelvic Neurovascular Injuries Rat Model.

    PubMed

    Li, Huixi; Matheu, Melanie P; Sun, Fionna; Wang, Lin; Sanford, Melissa T; Ning, Hongxiu; Banie, Lia; Lee, Yung-Chin; Xin, Zhongcheng; Guo, Yinglu; Lin, Guiting; Lue, Tom F

    2016-01-01

    Erectile dysfunction (ED) caused by pelvic injuries is a common complication of civil and battlefield trauma with multiple neurovascular factors involved, and no effective therapeutic approach is available. To test the effect and mechanisms of low-energy shock wave (LESW) therapy in a rat ED model induced by pelvic neurovascular injuries. Thirty-two male Sprague-Dawley rats injected with 5-ethynyl-2'-deoxyuridine (EdU) at newborn were divided into 4 groups: sham surgery (Sham), pelvic neurovascular injury by bilateral cavernous nerve injury and internal pudendal bundle injury (PVNI), PVNI treated with LESW at low energy (Low), and PVNI treated with LESW at high energy (High). After LESW treatment, rats underwent erectile function measurement and the tissues were harvested for histologic and molecular study. To examine the effect of LESW on Schwann cells, in vitro studies were conducted. The intracavernous pressure (ICP) measurement, histological examination, and Western blot (WB) were conducted. Cell cycle, Schwann cell activation-related markers were examined in in vitro experiments. LESW treatment improves erectile function in a rat model of pelvic neurovascular injury by leading to angiogenesis, tissue restoration, and nerve generation with more endogenous EdU(+) progenitor cells recruited to the damaged area and activation of Schwann cells. LESW facilitates more complete re-innervation of penile tissue with regeneration of neuronal nitric oxide synthase (nNOS)-positive nerves from the MPG to the penis. In vitro experiments demonstrated that LESW has a direct effect on Schwann cell proliferation. Schwann cell activation-related markers including p-Erk1/2 and p75 were upregulated after LESW treatment. LESW-induced endogenous progenitor cell recruitment and Schwann cell activation coincides with angiogenesis, tissue, and nerve generation in a rat model of pelvic neurovascular injuries. Copyright © 2016 International Society for Sexual Medicine. Published by

  18. Rapid Postnatal Expansion of Neural Networks Occurs in an Environment of Altered Neurovascular and Neurometabolic Coupling

    PubMed Central

    Ma, Ying; Shaik, Mohammed A.; Kim, Sharon H.

    2016-01-01

    In the adult brain, increases in neural activity lead to increases in local blood flow. However, many prior measurements of functional hemodynamics in the neonatal brain, including functional magnetic resonance imaging (fMRI) in human infants, have noted altered and even inverted hemodynamic responses to stimuli. Here, we demonstrate that localized neural activity in early postnatal mice does not evoke blood flow increases as in the adult brain, and elucidate the neural and metabolic correlates of these altered functional hemodynamics as a function of developmental age. Using wide-field GCaMP imaging, the development of neural responses to somatosensory stimulus is visualized over the entire bilaterally exposed cortex. Neural responses are observed to progress from tightly localized, unilateral maps to bilateral responses as interhemispheric connectivity becomes established. Simultaneous hemodynamic imaging confirms that spatiotemporally coupled functional hyperemia is not present during these early stages of postnatal brain development, and develops gradually as cortical connectivity is established. Exploring the consequences of this lack of functional hyperemia, measurements of oxidative metabolism via flavoprotein fluorescence suggest that neural activity depletes local oxygen to below baseline levels at early developmental stages. Analysis of hemoglobin oxygenation dynamics at the same age confirms oxygen depletion for both stimulus-evoked and resting-state neural activity. This state of unmet metabolic demand during neural network development poses new questions about the mechanisms of neurovascular development and its role in both normal and abnormal brain development. These results also provide important insights for the interpretation of fMRI studies of the developing brain. SIGNIFICANCE STATEMENT This work demonstrates that the postnatal development of neuronal connectivity is accompanied by development of the mechanisms that regulate local blood flow in

  19. Inflammatory biomarkers for AMD.

    PubMed

    Stanton, Chloe M; Wright, Alan F

    2014-01-01

    Age-related macular degeneration (AMD) is the leading cause of blindness worldwide, affecting an estimated 50 million individuals aged over 65 years.Environmental and genetic risk-factors implicate chronic inflammation in the etiology of AMD, contributing to the formation of drusen, retinal pigment epithelial cell dysfunction and photoreceptor cell death. Consistent with a role for chronic inflammation in AMD pathogenesis, several inflammatory mediators, including complement components, chemokines and cytokines, are elevated at both the local and systemic levels in AMD patients. These mediators have diverse roles in the alternative complement pathway, including recruitment of inflammatory cells, activation of the inflammasome, promotion of neovascularisation and in the resolution of inflammation. The utility of inflammatory biomarkers in assessing individual risk and progression of the disease is controversial. However, understanding the role of these inflammatory mediators in AMD onset, progression and response to treatment may increase our knowledge of disease pathogenesis and provide novel therapeutic options in the future.

  20. 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

  1. 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

  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. The role of ABCB1 and ABCA1 in beta-amyloid clearance at the neurovascular unit in Alzheimer's disease

    PubMed Central

    ElAli, Ayman; Rivest, Serge

    2013-01-01

    Alzheimer's disease (AD) is a progressive neurodegenerative disorder that affects elderly persons, evolving with age to reach severe cognitive impairment. Amyloid deposits and neurofibrillary tangles constitute the main pathological hallmarks of AD. Amyloid deposits are initiated by the excessive production and accumulation of beta-amyloid (Aβ) peptides in the brain. The dysfunction of the Neurovascular Unit (NVU) has been proposed to be causative in AD development, due to an impaired clearance of Aβ from the brain. Cells forming the NVU express several Adenosine Triphosphate ATP-Binding Cassette (ABC) transporters, among which ABCB1 and ABCA1 play an important role in Aβ processing. The drug transporter ABCB1 directly transports Aβ from the brain into the blood circulation, whereas the cholesterol transporter ABCA1 neutralizes Aβ aggregation capacity in an Apolipoprotein E (ApoE)-dependent manner, facilitating Aβ subsequent elimination from the brain. In the present minireview, we will summarize the contribution of ABCB1, and ABCA1 at the NVU in Aβ clearance. Moreover, we will outline and discuss the possible collaboration of ABCB1, and ABCA1 at the NVU in mediating an efficient clearance of Aβ from the brain. PMID:23494712

  4. EMCCD-based high resolution dynamic x-ray detector for neurovascular interventions.

    PubMed

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

    2011-01-01

    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 μm(2), 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.

  5. 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

  6. 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

  7. 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.

  8. 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.

  9. The effects of focal epileptic activity on regional sensory-evoked neurovascular coupling and postictal modulation of bilateral sensory processing

    PubMed Central

    Harris, Sam; Bruyns-Haylett, Michael; Kennerley, Aneurin; Boorman, Luke; Overton, Paul G; Ma, Hongtao; Zhao, Mingrui; Schwartz, Theodore H; Berwick, Jason

    2013-01-01

    While it is known that cortical sensory dysfunction may occur in focal neocortical epilepsy, it is unknown whether sensory-evoked neurovascular coupling is also disrupted during epileptiform activity. Addressing this open question may help to elucidate both the effects of focal neocortical epilepsy on sensory responses and the neurovascular characteristics of epileptogenic regions in sensory cortex. We therefore examined bilateral sensory-evoked neurovascular responses before, during, and after 4-aminopyridine (4-AP, 15 mmol/L, 1 μL) induced focal neocortical seizures in right vibrissal cortex of the rat. Stimulation consisted of electrical pulse trains (16 seconds, 5 Hz, 1.2 mA) presented to the mystacial pad. Consequent current-source density neural responses and epileptic activity in both cortices and across laminae were recorded via two 16-channel microelectrodes bilaterally implanted in vibrissal cortices. Concurrent two-dimensional optical imaging spectroscopy was used to produce spatiotemporal maps of total, oxy-, and deoxy-hemoglobin concentration. Compared with control, sensory-evoked neurovascular coupling was altered during ictal activity, but conserved postictally in both ipsilateral and contralateral vibrissal cortices, despite neurovascular responses being significantly reduced in the former, and enhanced in the latter. Our results provide insights into sensory-evoked neurovascular dynamics and coupling in epilepsy, and may have implications for the localization of epileptogenic foci and neighboring eloquent cortex. PMID:23860375

  10. Multi-modal assessment of neurovascular coupling during cerebral ischaemia and reperfusion using remote middle cerebral artery occlusion.

    PubMed

    Sutherland, Brad A; Fordsmann, Jonas C; Martin, Chris; Neuhaus, Ain A; Witgen, Brent M; Piilgaard, Henning; Lønstrup, Micael; Couch, Yvonne; Sibson, Nicola R; Lauritzen, Martin; Buchan, Alastair M

    2017-07-01

    Hyperacute changes in cerebral blood flow during cerebral ischaemia and reperfusion are important determinants of injury. Cerebral blood flow is regulated by neurovascular coupling, and disruption of neurovascular coupling contributes to brain plasticity and repair problems. However, it is unknown how neurovascular coupling is affected hyperacutely during cerebral ischaemia and reperfusion. We have developed a remote middle cerebral artery occlusion model in the rat, which enables multi-modal assessment of neurovascular coupling immediately prior to, during and immediately following reperfusion. Male Wistar rats were subjected to remote middle cerebral artery occlusion, where a long filament was advanced intraluminally through a guide cannula in the common carotid artery. Transcallosal stimulation evoked increases in blood flow, tissue oxygenation and neuronal activity, which were diminished by middle cerebral artery occlusion and partially restored during reperfusion. These evoked responses were not affected by administration of the thrombolytic alteplase at clinically used doses. Evoked cerebral blood flow responses were fully restored at 24 h post-middle cerebral artery occlusion indicating that neurovascular dysfunction was not sustained. These data show for the first time that the rat remote middle cerebral artery occlusion model coupled with transcallosal stimulation provides a novel method for continuous assessment of hyperacute neurovascular coupling changes during ischaemia and reperfusion, and offers unique insight into hyperacute ischaemic pathophysiology.

  11. Determining a magnetic resonance imaging inflammatory activity acceptable state without subsequent radiographic progression in rheumatoid arthritis: results from a followup MRI study of 254 patients in clinical remission or low disease activity.

    PubMed

    Gandjbakhch, Frédérique; Haavardsholm, Espen A; Conaghan, Philip G; Ejbjerg, Bo; Foltz, Violaine; Brown, Andrew K; Døhn, Uffe Møller; Lassere, Marissa; Freeston, Jane E; Olsen, Inge Christoffer; Bøyesen, Pernille; Bird, Paul; Fautrel, Bruno; Hetland, Merete Lund; Emery, Paul; Bourgeois, Pierre; Hørslev-Petersen, Kim; Kvien, Tore K; McQueen, Fiona M; Østergaard, Mikkel

    2014-02-01

    To assess the predictive value of magnetic resonance imaging (MRI)-detected subclinical inflammation for subsequent radiographic progression in a longitudinal study of patients with rheumatoid arthritis (RA) in clinical remission or low disease activity (LDA), and to determine cutoffs for an MRI inflammatory activity acceptable state in RA in which radiographic progression rarely occurs. Patients with RA in clinical remission [28-joint Disease Activity Score-C-reactive protein (DAS28-CRP) < 2.6, n = 185] or LDA state (2.6 ≤ DAS28-CRP < 3.2, n = 69) with longitudinal MRI and radiographic data were included from 5 cohorts (4 international centers). MRI were assessed according to the Outcome Measures in Rheumatology (OMERACT) RA MRI scoring system (RAMRIS). Statistical analyses included an underlying conditional logistic regression model stratified per cohort, with radiographic progression as dependent variable. A total of 254 patients were included in the multivariate analyses. At baseline, synovitis was observed in 95% and osteitis in 49% of patients. Radiographic progression was observed in 60 patients (24%). RAMRIS synovitis was the only independent predictive factor in multivariate analysis. ROC analysis identified a cutoff value for baseline RAMRIS synovitis score of 5 (maximum possible score 21). Rheumatoid factor (RF) status yielded a significant interaction with synovitis (p value = 0.044). RF-positive patients with a RAMRIS synovitis score of > 5 vs ≤ 5, had an OR of 4.4 (95% CI 1.72-11.4) for radiographic progression. High MRI synovitis score predicts radiographic progression in patients in clinical remission/LDA. A cutoff point for determining an MRI inflammatory activity acceptable state based on the RAMRIS synovitis score was established. Incorporating MRI in future remission criteria should be considered.

  12. Reappraisal of the inferior epigastric flap: a new neurovascular flap model in the rat.

    PubMed

    Hirigoyen, M B; Rhee, J S; Weisz, D J; Zhang, W X; Urken, M L; Weinberg, H

    1996-09-01

    An anatomic, histologic, and electrophysiologic study was carried out in order to determine the distribution and cutaneous sensory territory of the epigastric nerve in the rat. Results for nerve staining (Sihler's method) and electrophysiologic nerve mapping indicate that the neurosome of the epigastric nerve has a different autonomy than the vascular territory of the inferior epigastric artery. Based on these findings, an experimental model for neurovascular free-tissue transfer is proposed.

  13. Exposed inferior alveolar neurovascular bundle during surgical removal of a residual cyst.

    PubMed

    Boffano, Paolo; Gallesio, Cesare

    2010-01-01

    Iatrogenic neurodeficiency is one of the most distressing complications to any surgical procedure. The prediction of close proximity of the oral lesions to the inferior alveolar neurovascular bundle is extremely important. Furthermore, iatrogenic neurosensory dysfunctions of the facial region involve important medicolegal issues. In this report, we describe the case of a patient who did not show either paresthesia or anesthesia after the surgical removal of a mandibular residual cyst that exhibited adherence to the inferior alveolar nerve bundle.

  14. Hemichannels in the neurovascular unit and white matter under normal and inflamed conditions.

    PubMed

    Orellana, Juan A; Figueroa, Xavier F; Sánchez, Helmuth A; Contreras-Duarte, Susana; Velarde, Victoria; Sáez, Juan C

    2011-05-01

    In the normal brain, cellular types that compose the neurovascular unit, including neurons, astrocytes and endothelial cells express pannexins and connexins, which are protein subunits of two families that form plasma membrane channels. Most available evidence in mammals indicated that endogenously expressed pannexins only form hemichannels, and connexins form both gap junction channels and hemichannels. While gap junction channels connect the cytoplasm of contacting cells and coordinate electrical and metabolic activities, hemichannels communicate intra- and extracellular compartments and serve as diffusional pathways for ions and small molecules. Here, evidence supporting the functional role of hemichannels in the neurovascular unit and white matter under physiological and pathological conditions are reviewed. A sub-threshold acute pathological threatening condition (e.g., stroke and brain infection) leads to glial cell activation, which maintains an active defense and restores the normal function of the neurovascular unit. However, if the stimulus is deleterious, microglia and the endothelium become overactivated, both releasing bioactive molecules (e.g., glutamate, cytokines, prostaglandins and ATP) that increase the activity of astroglial hemichannels, reducing the astrocyte neuroprotective functions, and further reducing neuronal cell viability. Moreover, ATP is known to contribute to myelin degeneration of axons. Consequently, hemichannels might play a relevant role in the excitotoxic response of oligodendrocytes observed in ischemia and encephalomyelitis. Regulated changes in hemichannel permeability in healthy brain cells can have positive consequences in terms of paracrine/autocrine signaling, whereas persistent changes in cells affected by neurological disorders can be detrimental. Therefore, blocking hemichannels expressed by glial cells and/or neurons of the inflamed central nervous system might prevent neurovascular unit dysfunction and

  15. 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

  16. A model of neurovascular coupling and the BOLD response PART II.

    PubMed

    Mathias, E J; Plank, M J; David, T

    2017-04-01

    A mathematical model is developed which describes a signalling mechanism of neurovascular coupling with a model of a pyramidal neuron and its corresponding fMRI BOLD response. In the first part of two papers (Part I) we described the integration of the neurovascular coupling unit extended to include a complex neuron model, which includes the important Na/K ATPase pump, with a model that provides a BOLD signal taking its input from the cerebral blood flow and the metabolic rate of oxygen consumption. We showed that this produced a viable signal in terms of initial dip, positive and negative BOLD signals. In this paper (PART II) our model predicts the variations of the BOLD response due to variations in neuronal activity and indicates that the BOLD signal could be used as an initial biomarker for neuronal dysfunction or variations in the perfusion of blood to the cerebral tissue. We have compared the simulated hypoxic BOLD response to experimental BOLD signals observed in the hippocampus during hypoxia showing good agreement. This approach of combined quantitative modelling of neurovascular coupling response and its BOLD response will enable more specific assessment of a brain region.

  17. A model of neurovascular coupling and the BOLD response: PART I.

    PubMed

    Mathias, E J; Plank, M J; David, T

    2017-04-01

    The mechanisms with which neurons communicate with the vasculature to increase blood flow, termed neurovascular coupling is still unclear primarily due to the complex interactions between many parameters and the difficulty in accessing, monitoring and measuring them in the highly heterogeneous brain. Hence a solid theoretical framework based on existing experimental knowledge is necessary to study the relation between neural activity, the associated vasoactive factors released and their effects on the vasculature. Such a framework should also be related to experimental data so that it can be validated against repetitive experiments and generate verifiable hypothesis. We have developed a mathematical model which describes a signaling mechanism of neurovascular coupling with a model of pyramidal neuron and its corresponding fMRI BOLD response. In the first part of two papers we describe the integration of the neurovascular coupling unit extended to include a complex neuron model, which includes the important Na/K ATPase pump, with a model that provides a BOLD signal taking its input from the cerebral blood flow and the metabolic rate of oxygen consumption. We show that this produces a viable signal in terms of initial dip, positive and negative BOLD signals.

  18. Bayesian Comparison of Neurovascular Coupling Models Using EEG-fMRI

    PubMed Central

    Rosa, Maria J.; Kilner, James M.; Penny, Will D.

    2011-01-01

    Functional magnetic resonance imaging (fMRI), with blood oxygenation level-dependent (BOLD) contrast, is a widely used technique for studying the human brain. However, it is an indirect measure of underlying neuronal activity and the processes that link this activity to BOLD signals are still a topic of much debate. In order to relate findings from fMRI research to other measures of neuronal activity it is vital to understand the underlying neurovascular coupling mechanism. Currently, there is no consensus on the relative roles of synaptic and spiking activity in the generation of the BOLD response. Here we designed a modelling framework to investigate different neurovascular coupling mechanisms. We use Electroencephalographic (EEG) and fMRI data from a visual stimulation task together with biophysically informed mathematical models describing how neuronal activity generates the BOLD signals. These models allow us to non-invasively infer the degree of local synaptic and spiking activity in the healthy human brain. In addition, we use Bayesian model comparison to decide between neurovascular coupling mechanisms. We show that the BOLD signal is dependent upon both the synaptic and spiking activity but that the relative contributions of these two inputs are dependent upon the underlying neuronal firing rate. When the underlying neuronal firing is low then the BOLD response is best explained by synaptic activity. However, when the neuronal firing rate is high then both synaptic and spiking activity are required to explain the BOLD signal. PMID:21698175

  19. MRI Markers of Neurodegenerative and Neurovascular Changes in Relation to Postoperative Delirium and Postoperative Cognitive Decline.

    PubMed

    Kant, Ilse M J; de Bresser, Jeroen; van Montfort, Simone J T; Slooter, Arjen J C; Hendrikse, Jeroen

    2017-06-28

    Postoperative delirium (POD) and postoperative cognitive decline (POCD) are common in elderly patients. The aim of the present review was to explore the association of neurodegenerative and neurovascular changes with the occurrence of POD and POCD. Fifteen MRI studies were identified by combining multiple search terms for POD, POCD, and brain imaging. These studies described a total of 1,422 patients and were all observational in design. Neurodegenerative changes (global and regional brain volumes) did not show a consistent association with the occurrence of POD (four studies) or POCD (two studies). In contrast, neurovascular changes (white matter hyperintensities and cerebral infarcts) were more consistently associated with the occurrence of POD (seven studies) and POCD (five studies). In conclusion, neurovascular changes appear to be consistently associated with the occurrence of POD and POCD, and may identify patients at increased risk of these conditions. Larger prospective studies are needed to study the consistency of these findings and to unravel the underlying pathophysiological mechanisms. Copyright © 2017 The Authors. Published by Elsevier Inc. All rights reserved.

  20. [THE MODEL OF NEUROVASCULAR UNIT IN VITRO CONSISTING OF THREE CELLS TYPES].

    PubMed

    Khilazheva, E D; Boytsova, E B; Pozhilenkova, E A; Solonchuk, Yu R; Salmina, A B

    2015-01-01

    There are many ways to model blood brain barrier and neurovascular unit in vitro. All existing models have their disadvantages, advantages and some peculiarities of preparation and usage. We obtained the three-cells neurovascular unit model in vitro using progenitor cells isolated from the rat embryos brain (Wistar, 14-16 d). After withdrawal of the progenitor cells the neurospheres were cultured with subsequent differentiation into astrocytes and neurons. Endothelial cells were isolated from embryonic brain too. During the differentiation of progenitor cells the astrocytes monolayer formation occurs after 7-9 d, neurons monolayer--after 10-14 d, endothelial cells monolayer--after 7 d. Our protocol for simultaneous isolation and cultivation of neurons, astrocytes and endothelial cells reduces the time needed to obtain neurovascular unit model in vitro, consisting of three cells types and reduce the number of animals used. It is also important to note the cerebral origin of all cell types, which is also an advantage of our model in vitro.

  1. Erythropoietin receptor expression in the human urogenital tract: immunolocalization in the prostate, neurovascular bundle and penis.

    PubMed

    Liu, Tongyun; Allaf, Mohamad E; Lagoda, Gwen; Burnett, Arthur L

    2007-11-01

    To investigate whether the erythropoietin (EPO) receptor is expressed in human periprostatic (including the neurovascular bundles) and penile tissues, and define its distribution in these tissues, as the administration of exogenous EPO in cavernous nerve injury promoted the recovery of erectile function in a rat model. Human prostate (six samples) and penile (two) tissue were collected and paraffin-embedded. Tissue was sectioned and processed for immunohistochemical studies using an antibody for the EPO receptor; immunolocalization was assessed using light microscopy. There was prominent staining for the EPO receptor in neuronal cell bodies of the periprostatic neurovascular bundles, and in the axons emanating from these ganglia. The glandular epithelium of the prostate also had weak staining. There was EPO receptor immunoreactivity in the penile specimens in the penile dorsal nerves, sinusoidal endothelium of the corpus cavernosum, and endothelial cells lining the dorsal veins and arteries. All slides processed with no primary antibody or blocking peptide showed no staining. EPO receptor expression was identified and localized in human penile tissues and in the periprostatic neurovascular bundles responsible for erectile function. This suggests a likely role for endogenous EPO within these tissues, and provides the rationale for its clinical use as a protective agent locally.

  2. 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.

  3. Ly49E Expression on CD8αα-Expressing Intestinal Intraepithelial Lymphocytes Plays No Detectable Role in the Development and Progression of Experimentally Induced Inflammatory Bowel Diseases

    PubMed Central

    Van Acker, Aline; Filtjens, Jessica; Van Welden, Sophie; Taveirne, Sylvie; Van Ammel, Els; Vanhees, Mandy; Devisscher, Lindsey; Kerre, Tessa; Taghon, Tom; Vandekerckhove, Bart; Plum, Jean; Leclercq, Georges

    2014-01-01

    The Ly49E NK receptor is a unique inhibitory receptor, presenting with a high degree of conservation among mouse strains and expression on both NK cells and intraepithelial-localised T cells. Amongst intraepithelial-localised T cells, the Ly49E receptor is abundantly expressed on CD8αα-expressing innate-like intestinal intraepithelial lymphocytes (iIELs), which contribute to front-line defense at the mucosal barrier. Inflammatory bowel diseases (IBDs), encompassing Crohn's disease and ulcerative colitis, have previously been suggested to have an autoreactive origin and to evolve from a dysbalance between regulatory and effector functions in the intestinal immune system. Here, we made use of Ly49E-deficient mice to characterize the role of Ly49E receptor expression on CD8αα-expressing iIELs in the development and progression of IBD. For this purpose we used the dextran sodium sulphate (DSS)- and trinitrobenzenesulfonic-acid (TNBS)-induced colitis models, and the TNFΔARE ileitis model. We show that Ly49E is expressed on a high proportion of CD8αα-positive iIELs, with higher expression in the colon as compared to the small intestine. However, Ly49E expression on small intestinal and colonic iIELs does not influence the development or progression of inflammatory bowel diseases. PMID:25310588

  4. 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. Copyright © 2015 The Authors. Published by Elsevier Ltd.. All rights reserved.

  5. A Critical Role for the Vascular Endothelium in Functional Neurovascular Coupling in the Brain

    PubMed Central

    Chen, Brenda R.; Kozberg, Mariel G.; Bouchard, Matthew B.; Shaik, Mohammed A.; Hillman, Elizabeth M. C.

    2014-01-01

    Background The functional modulation of blood flow in the brain is critical for brain health and is the basis of contrast in functional magnetic resonance imaging. There is evident coupling between increases in neuronal activity and increases in local blood flow; however, many aspects of this neurovascular coupling remain unexplained by current models. Based on the rapid dilation of distant pial arteries during cortical functional hyperemia, we hypothesized that endothelial signaling may play a key role in the long‐range propagation of vasodilation during functional hyperemia in the brain. Although well characterized in the peripheral vasculature, endothelial involvement in functional neurovascular coupling has not been demonstrated. Methods and Results We combined in vivo exposed‐cortex multispectral optical intrinsic signal imaging (MS‐OISI) with a novel in vivo implementation of the light‐dye technique to record the cortical hemodynamic response to somatosensory stimulus in rats before and after spatially selective endothelial disruption. We demonstrate that discrete interruption of endothelial signaling halts propagation of stimulus‐evoked vasodilation in pial arteries, and that wide‐field endothelial disruption in pial arteries significantly attenuates the hemodynamic response to stimulus, particularly the early, rapid increase and peak in hyperemia. Conclusions Involvement of endothelial pathways in functional neurovascular coupling provides new explanations for the spatial and temporal features of the hemodynamic response to stimulus and could explain previous results that were interpreted as evidence for astrocyte‐mediated control of functional hyperemia. Our results unify many aspects of blood flow regulation in the brain and body and prompt new investigation of direct links between systemic cardiovascular disease and neural deficits. PMID:24926076

  6. 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

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

    PubMed

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

    2016-07-12

    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. 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. 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. 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.

  8. 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

  9. Hyperglycaemic memory affects the neurovascular unit of the retina in a diabetic mouse model.

    PubMed

    Friedrichs, Patrick; Schlotterer, Andrea; Sticht, Carsten; Kolibabka, Matthias; Wohlfart, Paulus; Dietrich, Axel; Linn, Thomas; Molema, Grietje; Hammes, Hans-Peter

    2017-07-01

    The aim of this study was to evaluate damage to the neurovascular unit in a mouse model of hyperglycaemic memory. A streptozotocin-induced mouse model of diabetes (C57BL/6J background) received insulin-releasing pellets and pancreatic islet-cell transplantation. Damage to the neurovascular unit was studied by quantitative retinal morphometry for microvascular changes and microarray analysis, with subsequent functional annotation clustering, for changes of the retinal genome. Sustained microvascular damage was confirmed by persistent loss of pericytes in the retinal vasculature (PC/mm(2)): compared with healthy controls (1981 ± 404 PC/mm(2)), the pericyte coverage of the retinal vasculature was significantly reduced in diabetic mice (1571 ± 383 PC/mm(2), p < 0.001) and transplanted mice (1606 ± 268 PC/mm(2), p < 0.001). Genes meeting the criteria for hyperglycaemic memory were attributed to the cytoskeletal and nuclear cell compartments of the neurovascular unit. The most prominent regulated genes in the cytoskeletal compartment were Ddx51, Fgd4, Pdlim7, Utp23, Cep57, Csrp3, Eml5, Fhl3, Map1a, Mapk1ip1, Mnda, Neil2, Parp2, Myl12b, Dynll1, Stag3 and Sntg2, and in the nuclear compartment were Ddx51, Utp23, Mnda, Kmt2e, Nr6a1, Parp2, Cdk8, Srsf1 and Zfp326. We demonstrated that changes in gene expression and microvascular damage persist after euglycaemic re-entry, indicating memory. The datasets generated during and/or analysed during the current study are available in the GEO repository, GSE87433, www.ncbi.nlm.nih.gov/geo/query/acc.cgi?token=idmbysgctluxviv&acc=GSE87433 .

  10. Towards spatial frequency domain optical imaging of neurovascular coupling in a mouse model of Alzheimer's disease

    NASA Astrophysics Data System (ADS)

    Lin, Alexander J.; Konecky, Soren D.; Rice, Tyler B.; Green, Kim N.; Choi, Bernard; Durkin, Anthony J.; Tromberg, Bruce J.

    2012-02-01

    Early neurovascular coupling (NVC) changes in Alzheimer's disease can potentially provide imaging biomarkers to assist with diagnosis and treatment. Previous efforts to quantify NVC with intrinsic signal imaging have required assumptions of baseline optical pathlength to calculate changes in oxy- and deoxy-hemoglobin concentrations during evoked stimuli. In this work, we present an economical spatial frequency domain imaging (SFDI) platform utilizing a commercially available LED projector, camera, and off-the-shelf optical components suitable for imaging dynamic optical properties. The fast acquisition platform described in this work is validated on silicone phantoms and demonstrated in neuroimaging of a mouse model.

  11. Continuous multi-modality brain imaging reveals modified neurovascular seizure response after intervention

    PubMed Central

    Ringuette, Dene; Jeffrey, Melanie A.; Dufour, Suzie; Carlen, Peter L.; Levi, Ofer

    2017-01-01

    We developed a multi-modal brain imaging system to investigate the relationship between blood flow, blood oxygenation/volume, intracellular calcium and electrographic activity during acute seizure-like events (SLEs), both before and after pharmacological intervention. Rising blood volume was highly specific to SLE-onset whereas blood flow was more correlated with all eletrographic activity. Intracellular calcium spiked between SLEs and at SLE-onset with oscillation during SLEs. Modified neurovascular and ionic SLE responses were observed after intervention and the interval between SLEs became shorter and more inconsistent. Comparison of artery and vein pulsatile flow suggest proximal interference and greater vascular leakage prior to intervention. PMID:28270990

  12. Impact of Altered Cholinergic Tones on the Neurovascular Coupling Response to Whisker Stimulation.

    PubMed

    Lecrux, Clotilde; Sandoe, Claire H; Neupane, Sujaya; Kropf, Pascal; Toussay, Xavier; Tong, Xin-Kang; Lacalle-Aurioles, María; Shmuel, Amir; Hamel, Edith

    2017-02-08

    Brain imaging techniques that use vascular signals to map changes in neuronal activity rely on the coupling between electrophysiology and hemodynamics, a phenomenon referred to as "neurovascular coupling" (NVC). It is unknown whether this relationship remains reliable under altered brain states associated with acetylcholine (ACh) levels, such as attention and arousal and in pathological conditions such as Alzheimer's disease. We therefore assessed the effects of varying ACh tone on whisker-evoked NVC responses in rat barrel cortex, measured by cerebral blood flow (CBF) and neurophysiological recordings (local field potentials, LFPs). We found that acutely enhanced ACh tone significantly potentiated whisker-evoked CBF responses through muscarinic ACh receptors and concurrently facilitated neuronal responses, as illustrated by increases in the amplitude and power in high frequencies of the evoked LFPs. However, the cellular identity of the activated neuronal network within the responsive barrel was unchanged, as characterized by c-Fos upregulation in pyramidal cells and GABA interneurons coexpressing vasoactive intestinal polypeptide. In contrast, chronic ACh deprivation hindered whisker-evoked CBF responses and the amplitude and power in most frequency bands of the evoked LFPs and reduced the rostrocaudal extent and area of the activated barrel without altering its identity. Correlations between LFP power and CBF, used to estimate NVC, were enhanced under high ACh tone and disturbed significantly by ACh depletion. We conclude that ACh is not only a facilitator but also a prerequisite for the full expression of sensory-evoked NVC responses, indicating that ACh may alter the fidelity of hemodynamic signals in assessing changes in evoked neuronal activity.SIGNIFICANCE STATEMENT Neurovascular coupling, defined as the tight relationship between activated neurons and hemodynamic responses, is a fundamental brain function that underlies hemodynamic-based functional brain

  13. 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

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

    PubMed

    Chen, W; Liu, P; Volkow, N D; Pan, Y; Du, C

    2016-10-01

    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 electroencephalography recordings and CBF with laser Doppler flowmetry in the rat's somatosensory cortex for both resting state and forepaw stimulation before and following cocaine administration (1 mg kg(-1), intravenously). 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 ∼20 min after 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 neurovascular regulation for both stimulation and spontaneous activity. The greater reductions by cocaine to the stimulation-induced CBF increases than to the background CBF should be considered when interpreting functional MRI studies comparing activation responses between controls and cocaine abusers. Neurovascular uncoupling could contribute to cocaine

  15. 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.

  16. The endovascular operating room as an extension of the intensive care unit: changing strategies in the management of neurovascular disease.

    PubMed

    Bell, Randy S; Vo, Alexander H; Veznedaroglu, Erol; Armonda, Rocco A

    2006-11-01

    Technological advances within the field of endovascular neurosurgery have influenced the management of the neurovascular patient within the intensive care unit (ICU). The endovascular operating room has, in fact, become an extension of the ICU in certain cases. Given the rapid development of new endovascular technologies, it is more important than ever for neurosurgeons to remain intimately involved with the care of their patients within the ICU. This article offers an overview of the evolution in ICU management of neurovascular disease and provides a framework for the incorporation of the endovascular operating room in the intensive care management of patients with this disease.

  17. Our experience of neurovascular bundles surgical treatment interposition at transcondylar and supracondylar fractures of humeral bone at children.

    PubMed

    Ahmedov, R; Masharipov, F; Hakimov, A

    2012-10-01

    The main aim of the study was to discuss the modern approach to the diagnoses and surgical treatment of fractures of humerus in children, associated with compromised neurovascular status and signs of acute ischemia. The 10 year experience was analyzed, with frequency of complications, varied from 0, 68% to 9% between the group. The age, sex, mechanism of injury and neurovascular status were recorded in all 31 patients. Our data suggested, that aggressive surgical approach, when indicated, is corresponding with well-reduced fracture in proper alignment with a viable and warm functional extremity in 93,5% of cases.

  18. Novel Wavelet Real Time Analysis of Neurovascular Coupling in Neonatal Encephalopathy

    PubMed Central

    Chalak, Lina F.; Tian, Fenghua; Adams-Huet, Beverley; Vasil, Diana; Laptook, Abbot; Tarumi, Takashi; Zhang, Rong

    2017-01-01

    Birth asphyxia constitutes a major global public health burden for millions of infants, despite hypothermia therapy. There is a critical need for real time surrogate markers of therapeutic success, to aid in patient selection and/or modification of interventions in neonatal encephalopathy (NE). This is a proof of concept study aiming to quantify neurovascular coupling (NVC) using wavelet analysis of the dynamic coherence between amplitude-integrated electroencephalography (aEEG) and near-infrared spectroscopy in NE. NVC coupling is assessed by a wavelet metric estimation of percent time of coherence between NIRS SctO2 and aEEG for 78 hours after birth. An abnormal outcome was predefined by a Bayley III score <85 by 18–24 m. We observed high coherence, intact NVC, between the oscillations of SctO2 and aEEG in the frequency range of 0.00025–0.001 Hz in the non-encephalopathic newborns. NVC coherence was significantly decreased in encephalopathic newborns who were cooled vs. non-encephalopathic controls (median IQR 3[2–9] vs.36 [33–39]; p < 0.01), and was significantly lower in those with abnormal 24 months outcomes relative to those with normal outcomes (median IQR 2[1–3] vs 28[19–26], p = 0.04). Wavelet coherence analysis of neurovascular coupling in NE may identify infants at risk for abnormal outcomes. PMID:28393884

  19. 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

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

    PubMed

    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

    2013-07-02

    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 [(11)C]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.

  1. Neurovascular stalk of the superficial sural flap: human fetus anatomical study.

    PubMed

    Sladjana, Ugrenović Z; Ivan, Jovanović D; Ljiljana, Vasović P; Natalija, Stefanović J; Predrag, Kovacević T; Vesna, Stojanović R

    2005-08-01

    The neurovascular stalk of the superficial sural flap, which is the most frequently used, is composed of the lesser saphenous vein, the sural nerve, and the median superficial sural artery. However, it has many variations. This is very important for its application in the reconstruction of soft-tissue defects. The aim of the authors' research was to detect the presence of the superficial sural blood vessels and to investigate their relationships with the sural nerve and the lesser saphenous vein. The study group consisted of 42 fetal lower extremities. Fetuses were fixed in 10% formalin and their blood vessels were injected with Micropaque solution (barium sulfate). The median superficial sural artery was detected in 83.3 percent of the cases, whereas the sural nerve and lesser saphenous vein were detected in all cases. The median superficial sural artery was located lateral to the medial cutaneous sural nerve and sural nerve, whereas the lesser saphenous vein was located medially. All three superficial sural arteries (medial, median, and lateral) were detected in fetuses with different gestational ages. The median superficial sural artery was the most frequently detected one and had the constant relationship with the other elements of the neurovascular stalk of the superficial sural arteries.

  2. Astrocytes mediate neurovascular signaling to capillary pericytes but not to arterioles

    PubMed Central

    Mishra, Anusha; Reynolds, James P.; Chen, Yang; Gourine, Alexander V.; Rusakov, Dmitri A.; Attwell, David

    2016-01-01

    Active neurons increase their energy supply by dilating nearby arterioles and capillaries. This neurovascular coupling underlies BOLD functional imaging signals, but its mechanism is controversial. Canonically, neurons release glutamate to activate metabotropic glutamate receptors (mGluR5) on astrocytes, evoking Ca2+ release from internal stores, activating phospholipase A2 and generating vasodilatory arachidonic acid derivatives. However, adult astrocytes lack mGluR5, and knock-out of the IP3 receptors that release Ca2+ from stores does not affect neurovascular coupling. We now show that buffering astrocyte Ca2+ inhibits neuronally-evoked capillary dilation, that astrocyte [Ca2+]i is raised not by release from stores but by entry through ATP-gated channels, and that Ca2+ generates arachidonic acid via phospholipase D2 and diacylglycerol kinase rather than phospholipase A2. In contrast, dilation of arterioles depends on NMDA receptor activation and Ca2+-dependent NO generation by interneurons. These results reveal that different signalling cascades regulate cerebral blood flow at the capillary and arteriole levels. PMID:27775719

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

    PubMed Central

    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

    2015-01-01

    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

  4. Prediction of surgical view of neurovascular decompression using interactive computer graphics.

    PubMed

    Kin, Taichi; Oyama, Hiroshi; Kamada, Kyousuke; Aoki, Shigeki; Ohtomo, Kuni; Saito, Nobuhito

    2009-07-01

    To assess the value of an interactive visualization method for detecting the offending vessels in neurovascular compression syndrome in patients with facial spasm and trigeminal neuralgia. Computer graphics models are created by fusion of fast imaging employing steady-state acquisition and magnetic resonance angiography. High-resolution magnetic resonance angiography and fast imaging employing steady-state acquisition were performed preoperatively in 17 patients with neurovascular compression syndromes (facial spasm, n = 10; trigeminal neuralgia, n = 7) using a 3.0-T magnetic resonance imaging scanner. Computer graphics models were created with computer software and observed interactively for detection of offending vessels by rotation, enlargement, reduction, and retraction on a graphic workstation. Two-dimensional images were reviewed by 2 radiologists blinded to the clinical details, and 2 neurosurgeons predicted the offending vessel with the interactive visualization method before surgery. Predictions from the 2 imaging approaches were compared with surgical findings. The vessels identified during surgery were assumed to be the true offending vessels. Offending vessels were identified correctly in 16 of 17 patients (94%) using the interactive visualization method and in 10 of 17 patients using 2-dimensional images. These data demonstrated a significant difference (P = 0.015 by Fisher's exact method). The interactive visualization method data corresponded well with surgical findings (surgical field, offending vessels, and nerves). Virtual reality 3-dimensional computer graphics using fusion magnetic resonance angiography and fast imaging employing steady-state acquisition may be helpful for preoperative simulation.

  5. Augmented reality in neurovascular surgery: feasibility and first uses in the operating room.

    PubMed

    Kersten-Oertel, Marta; Gerard, Ian; Drouin, Simon; Mok, Kelvin; Sirhan, Denis; Sinclair, David S; Collins, D Louis

    2015-11-01

    The aim of this report is to present a prototype augmented reality (AR) intra-operative brain imaging system. We present our experience of using this new neuronavigation system in neurovascular surgery and discuss the feasibility of this technology for aneurysms, arteriovenous malformations (AVMs), and arteriovenous fistulae (AVFs). We developed an augmented reality system that uses an external camera to capture the live view of the patient on the operating room table and to merge this view with pre-operative volume-rendered vessels. We have extensively tested the system in the laboratory and have used the system in four surgical cases: one aneurysm, two AVMs and one AVF case. The developed AR neuronavigation system allows for precise patient-to-image registration and calibration of the camera, resulting in a well-aligned augmented reality view. Initial results suggest that augmented reality is useful for tailoring craniotomies, localizing vessels of interest, and planning resection corridors. Augmented reality is a promising technology for neurovascular surgery. However, for more complex anomalies such as AVMs and AVFs, better visualization techniques that allow one to distinguish between arteries and veins and determine the absolute depth of a vessel of interest are needed.

  6. 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

  7. Perivascular macrophages mediate the neurovascular and cognitive dysfunction associated with hypertension

    PubMed Central

    Faraco, Giuseppe; Sugiyama, Yukio; Garcia-Bonilla, Lidia; Chang, Haejoo; Santisteban, Monica M.; Racchumi, Gianfranco; Murphy, Michelle; Anrather, Joseph

    2016-01-01

    Hypertension is a leading risk factor for dementia, but the mechanisms underlying its damaging effects on the brain are poorly understood. Due to a lack of energy reserves, the brain relies on continuous delivery of blood flow to its active regions in accordance with their dynamic metabolic needs. Hypertension disrupts these vital regulatory mechanisms, leading to the neuronal dysfunction and damage underlying cognitive impairment. Elucidating the cellular bases of these impairments is essential for developing new therapies. Perivascular macrophages (PVMs) represent a distinct population of resident brain macrophages that serves key homeostatic roles but also has the potential to generate large amounts of reactive oxygen species (ROS). Here, we report that PVMs are critical in driving the alterations in neurovascular regulation and attendant cognitive impairment in mouse models of hypertension. This effect was mediated by an increase in blood-brain barrier permeability that allowed angiotensin II to enter the perivascular space and activate angiotensin type 1 receptors in PVMs, leading to production of ROS through the superoxide-producing enzyme NOX2. These findings unveil a pathogenic role of PVMs in the neurovascular and cognitive dysfunction associated with hypertension and identify these cells as a putative therapeutic target for diseases associated with cerebrovascular oxidative stress. PMID:27841763

  8. 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. PMID:27579245

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

    PubMed

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

    2015-01-07

    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.

  10. Pericyte-Mediated Regulation of Capillary Diameter: A Component of Neurovascular Coupling in Health and Disease

    PubMed Central

    Hamilton, Nicola B.; Attwell, David; Hall, Catherine N.

    2010-01-01

    Because regional blood flow increases in association with the increased metabolic demand generated by localized increases in neural activity, functional imaging researchers often assume that changes in blood flow are an accurate read-out of changes in underlying neural activity. An understanding of the mechanisms that link changes in neural activity to changes in blood flow is crucial for assessing the validity of this assumption, and for understanding the processes that can go wrong during disease states such as ischaemic stroke. Many studies have investigated the mechanisms of neurovascular regulation in arterioles but other evidence suggests that blood flow regulation can also occur in capillaries, because of the presence of contractile cells, pericytes, on the capillary wall. Here we review the evidence that pericytes can modulate capillary diameter in response to neuronal activity and assess the likely importance of neurovascular regulation at the capillary level for functional imaging experiments. We also discuss evidence suggesting that pericytes are particularly sensitive to damage during pathological insults such as ischaemia, Alzheimer's disease and diabetic retinopathy, and consider the potential impact that pericyte dysfunction might have on the development of therapeutic interventions and on the interpretation of functional imaging data in these disorders. PMID:20725515

  11. Neurovascular Compression at the Root Entry Zone Correlates with Trigeminal Neuralgia and Early Microvascular Decompression Outcome.

    PubMed

    Mistry, Akshitkumar M; Niesner, Kurt J; Lake, Wendell B; Forbes, Jonathan A; Shannon, Chevis N; Kasl, Rebecca A; Konrad, Peter E; Neimat, Joseph S

    2016-11-01

    Trigeminal neurovascular contact (NVC) is hypothesized to be the etiology of classical trigeminal neuralgia (TGN). We aimed to seek a correlation between types of NVCs and the presence of TGN as well as early surgical outcome in patients with TGN treated with trigeminal microvascular decompression (MVD). We blindly analyzed preoperative high-resolution magnetic resonance images with respect to the degree (none, "touch," or compression) and location of bilateral NVC in 57 retrospectively identified Burchiel Type 1 TGN patients treated by MVD. Location of NVC was noted as either at the root entry zone or distal to it. Using a logistic regression model, we assessed the degree and location of trigeminal NVC for correlation with the symptomatic side. Furthermore, the NVC characteristics on the symptomatic side were correlated with early postoperative pain relief. Although the degree and location of NVC were not statistically correlative independently, a combined interaction analysis of both statistically correlated with the symptomatic side and with early postoperative pain relief. We conclude that in TGN patients treated with MVD, magnetic resonance imaging identified neurovascular compression at the root entry zone (correlates with the affected side and early postoperative pain relief. Copyright © 2016 Elsevier Inc. All rights reserved.

  12. Dopamine receptors and the persistent neurovascular dysregulation induced by methamphetamine self-administration in rats.

    PubMed

    Kousik, Sharanya M; Napier, T Celeste; Ross, Ryan D; Sumner, D Rick; Carvey, Paul M

    2014-11-01

    Recently abstinent methamphetamine (Meth) abusers showed neurovascular dysregulation within the striatum. The factors that contribute to this dysregulation and the persistence of these effects are unclear. The current study addressed these knowledge gaps. First, we evaluated the brains of rats with a history of Meth self-administration following various periods of forced abstinence. Micro-computed tomography revealed a marked reduction in vessel diameter and vascular volume uniquely within the striatum between 1 and 28 days after Meth self-administration. Microvessels showed a greater impairment than larger vessels. Subsequently, we determined that dopamine (DA) D2 receptors regulated Meth-induced striatal vasoconstriction via acute noncontingent administration of Meth. These receptors likely regulated the response to striatal hypoxia, as hypoxia inducible factor 1α was elevated. Acute Meth exposure also increased striatal levels of endothelin receptor A and decreased neuronal nitric oxide synthase. Collectively, the data provide novel evidence that Meth-induced striatal neurovascular dysregulation involves DA receptor signaling that results in vasoconstriction via endothelin receptor A and nitric oxide signaling. As these effects can lead to hypoxia and trigger neuronal damage, these findings provide a mechanistic explanation for the selective striatal toxicity observed in the brains of Meth-abusing humans. Copyright © 2014 by The American Society for Pharmacology and Experimental Therapeutics.

  13. Low prevalence of human herpesvirus-6 and varicella zoster virus in blood of multiple sclerosis patients, irrespective of inflammatory status or disease progression.

    PubMed

    Hon, Gloudina M; Erasmus, Rajiv T; Matsha, Tandi

    2014-08-01

    Herpesviruses, including human herpesvirus-6 and varicella zoster virus, have been implicated in the disease aetiology of multiple sclerosis. These viruses are capable of reactivation, reminiscent of the relapsing-remitting nature of multiple sclerosis. However, viral DNA has also been reported present in healthy controls, often at similar prevalence rates. This study aimed to determine whether prevalence could be associated with different stages of activity of the disease as well as the inflammatory status of the patients. Polymerase chain reaction assays were used to screen for human herpesvirus-6 and varicella zoster virus DNA in blood from 31 Caucasian patients with multiple sclerosis and 30 healthy age, sex and race matched control subjects. The patients were screened for inflammation using C-reactive protein as a marker and were also categorized according to their remitting/relapsing status. Results were positive for human herpesvirus-6 in blood from only one patient (3.2%) and human herpesvirus-6 DNA was not present in any control subjects. Varicella zoster virus was not detected in either the patients or control subjects. Similar to some other studies we saw an absence or very low viral positivity in blood from both patients and controls. These findings were irrespective of relapse episodes, increased inflammatory status or duration of the disease. Results therefore do not support a causative role for either human herpesvirus-6 or varicella zoster virus in the disease aetiology of multiple sclerosis, but rather that prevalence in patients may be linked to that of the general population.

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

    PubMed

    Grammas, Paula

    2011-03-25

    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.

  15. 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

  16. Fisetin inhibits IL-1β-induced inflammatory response in human osteoarthritis chondrocytes through activating SIRT1 and attenuates the progression of osteoarthritis in mice.

    PubMed

    Zheng, Wenhao; Feng, Zhenhua; You, Shengban; Zhang, Hui; Tao, Zhenyu; Wang, Quan; Chen, Hua; Wu, Yaosen

    2017-04-01

    Osteoarthritis (OA) is a degenerative joint disease characterized by cartilage degradation and inflammation. Fisetin, a polyphenol extracted from fruits and vegetables, has been reported to have anti-inflammatory effects. Our study aimed to investigate the effect of fisetin on OA both in vitro and in vivo. In vitro, chondrocytes were pretreated with fisetin alone or fisetin combined with sirtinol (an inhibitor of SIRT1) for 2h before IL-1β stimulation. Production of NO, PGE2, TNF-α and IL-6 were evaluated by the Griess reaction and ELISAs. The mRNA (COX-2, iNOS, MMP-3, MMP-13, ADAMTS-5, Sox-9, aggrecan and collagen-II) and protein expression (COX-2, iNOS, MMP-3, MMP-13, ADAMTS-5 and SIRT1) were measured by qRT-PCR and Western blot respectively. Immunofluorescence was used to assess the expression of collagen-II and SIRT1. SIRT1 activity was quantified with SIRT1 fluorometric assay kit. The in vivo effect of fisetin was evaluated by gavage in mice OA models induced by destabilization of the medial meniscus (DMM). We found that fisetin inhibited IL-1β-induced expression of NO, PGE2, TNF-α, IL-6, COX-2, iNOS, MMP-3, MMP-13, ADAMTS-5. Besides, fisetin remarkably decreased IL-1β-induced degradation of Sox-9, aggrecan and collagen-II. Furthermore, fisetin significantly inhibited IL-1β-induced SIRT1 decrease and inactivation. However, the inhibitory effect of fisetin was obvious abolished by sirtinol, suggesting that fisetin exerts anti-inflammatory effects through activating SIRT1. In vivo, fisetin-treated mice exhibited less cartilage destruction and lower OARSI scores. Moreover, fisetin reduced subchondral bone plate thickness and alleviated synovitis. Taken together, these findings indicate that fisetin may be a potential agent in the treatment of OA. Copyright © 2017 Elsevier B.V. All rights reserved.

  17. Hepatocyte-stellate cell cross-talk in the liver engenders a permissive inflammatory microenvironment that drives progression in hepatocellular carcinoma.

    PubMed

    Coulouarn, Cédric; Corlu, Anne; Glaise, Denise; Guénon, Isabelle; Thorgeirsson, Snorri S; Clément, Bruno

    2012-05-15

    Many solid malignant tumors arise on a background of inflamed and/or fibrotic tissues, features that are found in more than 80% hepatocellular carcinomas (HCC). Activated hepatic stellate cells (HSC) play a critical role in fibrogenesis associated with HCC onset and progression, yet their functional impact on hepatocyte fate remains largely unexplored. Here, we used a coculture model to investigate the cross-talk between hepatocytes (human hepatoma cells) and activated human HSCs. Unsupervised genome-wide expression profiling showed that hepatocyte-HSC cross-talk is bidirectional and results in the deregulation of functionally relevant gene networks. Notably, coculturing increased the expression of proinflammatory cytokines and modified the phenotype of hepatocytes toward motile cells. Hepatocyte-HSC cross-talk also generated a permissive proangiogenic microenvironment, particularly by inducing VEGFA and matrix metalloproteinase (MMP)9 expression in HSCs. An integrative genomic analysis revealed that the expression of genes associated with hepatocyte-HSC cross-talk correlated with HCC progression in mice and was predictive of a poor prognosis and metastasis propensity in human HCCs. Interestingly, the effects of cross-talk on migration and angiogenesis were reversed by the histone deacetylase inhibitor trichostatin A. Our findings, therefore, indicate that the cross-talk between hepatoma cells and activated HSCs is an important feature of HCC progression, which may be targeted by epigenetic modulation.

  18. Inflammatory Manifestations of Lymphedema

    PubMed Central

    Ly, Catherine L.; Kataru, Raghu P.; Mehrara, Babak J.

    2017-01-01

    Lymphedema results from lymphatic insufficiency leading to a progressive inflammatory process that ultimately manifests as discomfort, recurrent infections, and, at times, secondary malignancy. Collectively, these morbidities contribute to an overall poor quality of life. Although there have been recent advances in microsurgical interventions, a conservative palliative approach remains the mainstay of treatment for this disabling disease. The absence of a cure is due to an incomplete understanding of the pathophysiological changes that result in lymphedema. A histological hallmark of lymphedema is inflammatory cell infiltration and recent studies with animal models and clinical biopsy specimens have suggested that this response plays a key role in the pathology of the disease. The purpose of this report is to provide an overview of the ongoing research in and the current understanding of the inflammatory manifestations of lymphedema. PMID:28106728

  19. 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

  20. 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

  1. The establishment of endovascular aneurysm coiling at a neurovascular unit: report of experience during early years.

    PubMed

    Norbäck, O; Gál, G; Johansson, M; Solander, S; Tovi, M; Persson, L; Ronne-Engström, E; Enblad, P

    2005-02-01

    The treatment of cerebral aneurysms is changing from surgical clipping to endovascular coiling (EVC) in many neurovascular centres. The aim of this study was to evaluate the technical results and clinical outcome at 6 months in a consecutive series of subarachnoid hemorrhage (SAH) patients treated with EVC, in a situation when the EVC had been established very rapidly as the first line of treatment at a neurovascular centre. The patient material comprised 239 SAH patients (155 women and 84 men, mean age 55 years, age range 16-81) allocated to EVC as the first line of treatment in the acute stage (within 3 weeks of rupture) between September 1996 and December 2000. Clinical grade on admission was Hunt & Hess (H&H) I and II in 42%, H&H III in 25% and H&H grade IV and V in 33% of the patients. The aneurysm was located in the anterior circulation in 82% of the cases. EVC was performed on days 0-3 in 77% of the cases. EVC of the target aneurysm was able to be completed in 222 patients (93%). Complete occlusion was achieved in 126 patients (53%). Procedural complications occurred in 39 patients (16%). Favourable clinical outcome was observed in 57%, severe disability in 28% and poor outcome in 14% of the patients. Favourable outcome was achieved in 77% of H&H I and II patients and in 43% of H&H III-V patients. The multivariate logistic regression analysis revealed that younger age, good neurological grade on admission, absence of intracerebral hematoma and intraventricular hematoma respectively, ICA-PcomA aneurysm location, later treatment and absence of complications were significant predictors of favourable outcome. After interventional training and installation of the X-ray system, the introduction and establishment of EVC at a neurovascular unit can be done in a short period of time and with favourable results. Future studies must concentrate on identifying factors of importance for the choice of interventional or surgical therapy. The results of this study indicate

  2. Computerized analysis of the greater palatine foramen to gain the palatine neurovascular bundle during palatal surgery.

    PubMed

    Cagimni, Pınar; Govsa, Figen; Ozer, Mehmet Asim; Kazak, Zuhal

    2017-02-01

    Investigation of the computerized dimensional anatomic location of the greater palatine foramen (GPF) and lesser palatine foramens (LPF) is important indicating site to collect palatal donor tissue, reconstructioning the orofacial area of the oncology patient and applying the greater palatine nerve block anesthesia. The aim of this study is to determine a patient-friendly landmark and to specify the precise location of the GPF in order to standardise certain anatomical marks of safe neurovascular bundle. 120 bony palates were examined to detect the position of the GPF and the LPF related to adjacent anatomical landmarks using a computer software program. The GPF was assessed regarding the position, the diameter and the distances between each foramen and the midline maxillary suture (MMS), the inner border of alveolar ridge (AR), posterior palatal border (PBB), and incisive foramen (IF). The GPF was identified as single in 81 %, double in 16 %, triple in 2 % and absent in 2 % of the specimens. The mean distances between the GPF and the MSS, the GPF and the AR, the GPF and the PPB, the GPF and the IF were 16, 4, 4, and 40 mm, respectively. In majority of the cases, the GPF was seen between the distal surfaces of the third maxillary molar (78 %). Single LPF was observed in 53.45 % of the skulls, two LPF were observed in 31 % of the skulls bilaterally and five LPF were rare in 2.1 % of the specimens. The LPF was most commonly at the junction of the palatine bone and the inner lamella of the pterygoid plate (71.9 %). This study made possible to investigate the variability of the GPF and the feasibility of the greater palatine neurovascular bundle, and to calculate the lengths of some parameters with the help of certain software. To collect the donor tissue of the neurovascular greater palatine network, each distance among the AR-GPF-PPB were equal to 4 mm. To estimate the possible length of the graft, the incision was made along the third and the second molar

  3. Sural artery perforator flap with posterior tibial neurovascular decompression for recurrent foot ulcer in leprosy patients

    PubMed Central

    Ismail, Hossam El-din Ali; El Fahar, Mohamed Hassan

    2017-01-01

    Introduction: The sensory loss and alteration of the shape of the foot make the foot liable to trauma and pressure, and subsequently cause more callus formation, blisters, and ulcers. Foot ulcers usually are liable to secondary infection as cellulitis or osteomyelitis, and may result in amputations. Foot ulcers are a major problem and a major cause of handicaps in leprosy patients. The current study is to present our clinical experience and evaluate the use of sural flap with posterior tibial neurovascular decompression (PTND) in recurrent foot ulcers in leprosy patients. Patient and methods: A total number of 9 patients were suffering from chronic sequelae of leprosy as recurrent foot ulcers. All the patients were reconstructed with the reverse sural artery fasciocutaneous flap with posterior tibial neurovascular decompression from September 2012 to August 2015. Six patients were male and three were female with a mean age of 39.8 years (range, 30–50 years). All the soft tissue defects were in the weight-bearing area of the inside of the foot. The flap sizes ranged from 15/4 to 18/6 cm. Mean follow-up period was 21.2 months (range, 35–2 months). Results: All the flaps healed uneventfully. There was no major complication as total flap necrosis. Only minor complications occurred which were treated without surgical intervention except in two patients who developed superficial necrosis of the skin paddle. Surgical debridement was done one week later. The flap was completely viable after surgery, and the contour of the foot was restored. We found that an improvement of sensation occurred in those patients in whom the anesthesia started one year ago or less and no sensory recovery in patient in whom the anesthesia had lasted for more than two years. Conclusion: The reverse sural artery flap with posterior tibial neurovascular decompression provides a reliable method for recurrent foot soft tissue reconstruction in leprosy patients with encouraging function and

  4. Injury patterns and the role of tendons in protecting neurovascular structures in wrist injuries.

    PubMed

    Lee, Chul Hyung; Cha, Soo Min; Shin, Hyun Dae

    2016-06-01

    The purpose of this study was to evaluate the anatomical features of injured structures, investigate the protection provided by the specific tendon of each corresponding important neurovascular structure (radial artery, median nerve, and ulnar nerve/artery) and to compare the results among the three categories of wrist injuries. This study included 114 patients who underwent primary repair for damaged wrist structures; 40 patients sustained accidental damage without intention (group 1), 40 had self-inflicted damage (group 2), and 34 patients had a stab or penetrating wound caused by a sharp instrument during a conflict or violent event involving another person (group 3). The basic demographic factors, distribution pattern, area, and depth of the injured structures were investigated and compared. The barrier roles of the flexor carpi radialis (FCR) for the radial artery, palmaris longus (PL) for the median nerve, and flexor carpi ulnaris (FCU) for the ulnar nerve were estimated. In group 1, FCU injury was the most common single-structure injury. In group 2, PL±median nerve injuries were the most common. Multiple-structure injuries involving more than five structures occurred more frequently in group 3 than in the other groups. FCU±ulnar nerve injuries were more common in group 3 than in the other groups. Radial-side structures were injured most frequently in group 3, and central-side injuries occurred most frequently in groups 1 and 2. Superficial- and middle-layer injuries occurred at similar frequencies among the three groups. Particularly, deep-layer injuries were most weakly related to group 2 injuries. The barrier effects of the FCR, PL, and FCU were confirmed, respectively. Wrist soft tissue injuries showed particular patterns of injured structures and depths according to the injury mechanism. These patterns included features such as single-structure injuries and the locations and depths of multiple-structure injuries with or without neurovascular injuries

  5. 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

  6. Diagnosis and neurosurgical treatment of glossopharyngeal neuralgia: clinical findings and 3-D visualization of neurovascular compression in 19 consecutive patients.

    PubMed

    Gaul, C; Hastreiter, P; Duncker, A; Naraghi, R

    2011-10-01

    Glossopharyngeal neuralgia is a rare condition with neuralgic sharp pain in the pharyngeal and auricular region. Classical glossopharyngeal neuralgia is caused by neurovascular compression at the root entry zone of the nerve. Regarding the rare occurrence of glossopharyngeal neuralgia, we report clinical data and magnetic resonance imaging (MRI) findings in a case series of 19 patients, of whom 18 underwent surgery. Two patients additionally suffered from trigeminal neuralgia and three from additional symptomatic vagal nerve compression. In all patients, ipsilateral neurovascular compression syndrome of the IX cranial nerve could be shown by high-resolution MRI and image processing, which was confirmed intraoperatively. Additional neurovascular compression of the V cranial nerve was shown in patients suffering from trigeminal neuralgia. Vagal nerve neurovascular compression could be seen in all patients during surgery. Sixteen patients were completely pain free after surgery without need of anticonvulsant treatment. As a consequence of the operation, two patients suffered from transient cerebrospinal fluid hypersecretion as a reaction to Teflon implants. One patient suffered postoperatively from deep vein thrombosis and pulmonary embolism. Six patients showed transient cranial nerve dysfunctions (difficulties in swallowing, vocal cord paresis), but all recovered within 1 week. One patient complained of a gnawing and burning pain in the cervical area. Microvascular decompression is a second-line treatment after failure of standard medical treatment with high success in glossopharyngeal neuralgia. High-resolution MRI and 3D visualization of the brainstem and accompanying vessels as well as the cranial nerves is helpful in identifying neurovascular compression before microvascular decompression procedure.

  7. Regional Homogeneity of Resting-state fMRI Contributes to Both Neurovascular and Task Activation Variations

    PubMed Central

    Yuan, Rui; Di, Xin; Kim, Eun H.; Barik, Sabrina; Rypma, Bart; Biswal, Bharat B.

    2013-01-01

    The task induced blood oxygenation level dependent signal changes observed using functional magnetic resonance imaging (fMRI) is critically dependent on the relationship between neuronal activity and hemodynamic response. Therefore, understanding the nature of neurovascular coupling is important when interpreting fMRI signal changes evoked via task. In this study, we used regional homogeneity (ReHo), a measure of local synchronization of the BOLD time series, to investigate whether the similarities of one voxel with the surrounding voxels is a property of neurovascular coupling. FMRI scans were obtained from fourteen subjects during bilateral finger tapping (FTAP), digit-symbol substitution (DSST) and periodic breath holding (BH) paradigm. A resting-state scan was also obtained for each of the subjects for 4 minutes using identical imaging parameters. Inter-voxel correlation analyses were conducted between the resting-state ReHo, resting-state amplitude of low frequency fluctuations (ALFF), breath hold (BH) responses and task activations within the masks related to task activations. There was a reliable mean voxel-wise spatial correlation between ReHo and other neurovascular variables (BH responses and ALFF). We observed a moderate correlation between ReHo and task activations (FTAP: r = 0.32; DSST: r = 0.22) within the task positive network and a small yet reliable correlation within the default mode network (DSST: r = −0.08). Subsequently, a linear regression was used to estimate the contribution of ReHo, ALFF and BH responses to the task activated voxels. The unique contribution of ReHo was minimal. The results suggest that regional synchrony of the BOLD activity is a property that can explain the variance of neurovascular coupling and task activations; but its contribution to task activations can be accounted for by other neurovascular factors such as the ALFF. PMID:23969197

  8. Resveratrol treatment rescues neurovascular coupling in aged mice: role of improved cerebromicrovascular endothelial function and downregulation of NADPH oxidase.

    PubMed

    Toth, Peter; Tarantini, Stefano; Tucsek, Zsuzsanna; Ashpole, Nicole M; Sosnowska, Danuta; Gautam, Tripti; Ballabh, Praveen; Koller, Akos; Sonntag, William E; Csiszar, Anna; Ungvari, Zoltan

    2014-02-01

    Moment-to-moment adjustment of cerebral blood flow (CBF) to neuronal activity via neurovascular coupling is essential for the maintenance of normal neuronal function. Increased oxidative stress that occurs with aging was shown to impair neurovascular coupling, which likely contributes to a significant age-related decline in higher cortical function, increasing the risk for vascular cognitive impairment. Resveratrol is a polyphenolic compound that exerts significant antiaging protective effects in large vessels, but its effects on the cerebromicrovasculature remain poorly defined. The present study was undertaken to investigate the capacity of resveratrol to improve neurovascular coupling in aging. In aged (24-mo-old) C57BL/6 mice N(ω)-nitro-l-arginine methyl ester-sensitive, nitric oxide-mediated CBF responses to whisker stimulation and to the endothelium-dependent dilator acethylcholine (ACh) were impaired compared with those in young (3-mo-old) mice. Treatment of aged mice with resveratrol rescued neurovascular coupling and ACh-induced responses, which was associated with downregulation of cortical expression of NADPH oxidase and decreased levels of biomarkers of oxidative/nitrative stress (3-nitrotyrosine, 8-isoprostanes). Resveratrol also attenuated age-related increases in reactive oxygen species (ROS) production in cultured cerebromicrovascular endothelial cells (DCF fluorescence, flow cytometry). In conclusion, treatment with resveratrol rescues cortical neurovascular coupling responses to increased neuronal activity in aged mice, likely by restoring cerebromicrovascular endothelial function via downregulation of NADPH oxidase-derived ROS production. Beneficial cerebromicrovascular effects of resveratrol may contribute to its protective effects on cognitive function in aging.

  9. Resveratrol treatment rescues neurovascular coupling in aged mice: role of improved cerebromicrovascular endothelial function and downregulation of NADPH oxidase

    PubMed Central

    Toth, Peter; Tarantini, Stefano; Tucsek, Zsuzsanna; Ashpole, Nicole M.; Sosnowska, Danuta; Gautam, Tripti; Ballabh, Praveen; Koller, Akos; Sonntag, William E.; Csiszar, Anna

    2013-01-01

    Moment-to-moment adjustment of cerebral blood flow (CBF) to neuronal activity via neurovascular coupling is essential for the maintenance of normal neuronal function. Increased oxidative stress that occurs with aging was shown to impair neurovascular coupling, which likely contributes to a significant age-related decline in higher cortical function, increasing the risk for vascular cognitive impairment. Resveratrol is a polyphenolic compound that exerts significant antiaging protective effects in large vessels, but its effects on the cerebromicrovasculature remain poorly defined. The present study was undertaken to investigate the capacity of resveratrol to improve neurovascular coupling in aging. In aged (24-mo-old) C57BL/6 mice Nω-nitro-l-arginine methyl ester-sensitive, nitric oxide-mediated CBF responses to whisker stimulation and to the endothelium-dependent dilator acethylcholine (ACh) were impaired compared with those in young (3-mo-old) mice. Treatment of aged mice with resveratrol rescued neurovascular coupling and ACh-induced responses, which was associated with downregulation of cortical expression of NADPH oxidase and decreased levels of biomarkers of oxidative/nitrative stress (3-nitrotyrosine, 8-isoprostanes). Resveratrol also attenuated age-related increases in reactive oxygen species (ROS) production in cultured cerebromicrovascular endothelial cells (DCF fluorescence, flow cytometry). In conclusion, treatment with resveratrol rescues cortical neurovascular coupling responses to increased neuronal activity in aged mice, likely by restoring cerebromicrovascular endothelial function via downregulation of NADPH oxidase-derived ROS production. Beneficial cerebromicrovascular effects of resveratrol may contribute to its protective effects on cognitive function in aging. PMID:24322615

  10. Influence of magnetic resonance imaging in the decision to preserve or resect neurovascular bundles at robotic assisted laparoscopic radical prostatectomy.

    PubMed

    Park, Bong Hee; Jeon, Hwang Gyun; Jeong, Byong Chang; Seo, Seong Il; Lee, Hyun Moo; Choi, Han Yong; Jeon, Seong Soo

    2014-07-01

    We evaluated the accuracy of preoperative multiparametric 3.0-T magnetic resonance imaging for local staging of prostate cancer and its influence in the decision to preserve neurovascular bundles at robotic assisted laparoscopic radical prostatectomy. The study included 353 patients who had confirmed prostate cancer and underwent preoperative magnetic resonance imaging and robotic assisted laparoscopic radical prostatectomy between 2008 and 2011. The extent of neurovascular bundle sparing was initially determined on the basis of the clinical information and the nerve sparing surgical plan was reevaluated after review of the magnetic resonance imaging report. The value of preoperative magnetic resonance imaging in the prediction of extracapsular extension and in the decision of surgical plan according to D'Amico risk classification was analyzed. The magnetic resonance imaging performed correct staging, over staging and under staging in 261 (73.9%), 43 (12.2%), and 49 (13.9%) patients, respectively. After review of the magnetic resonance imaging reports, the initial surgical plan was not changed in 260 patients (74%) and was changed in 93 patients (26%). Robotic assisted laparoscopic radical prostatectomy was changed to a more preservable neurovascular bundle sparing procedure in 53 patients (57%) and changed to a more aggressive neurovascular bundle resecting procedure in 40 patients (43%). For the patients with a change to more conservative surgery, the appropriateness was 91%. The sensitivity of magnetic resonance imaging in predicting extracapsular extension showed a tendency to increase from low to high risk groups (33%, 46%, 80%, respectively, p <0.001). In intermediate and high risk groups, there was a surgical plan change in 40 patients (of 129, 31%) and 27 patients (of 67, 40%), respectively. Preoperative magnetic resonance imaging significantly improves the decision making to preserve or resect the neurovascular bundle at robotic assisted laparoscopic

  11. Regional homogeneity of resting-state fMRI contributes to both neurovascular and task activation variations.

    PubMed

    Yuan, Rui; Di, Xin; Kim, Eun H; Barik, Sabrina; Rypma, Bart; Biswal, Bharat B

    2013-11-01

    The task induced blood oxygenation level dependent signal changes observed using functional magnetic resonance imaging (fMRI) are critically dependent on the relationship between neuronal activity and hemodynamic response. Therefore, understanding the nature of neurovascular coupling is important when interpreting fMRI signal changes evoked via task. In this study, we used regional homogeneity (ReHo), a measure of local synchronization of the BOLD time series, to investigate whether the similarities of one voxel with the surrounding voxels are a property of neurovascular coupling. FMRI scans were obtained from fourteen subjects during bilateral finger tapping (FTAP), digit-symbol substitution (DSST) and periodic breath holding (BH) paradigm. A resting-state scan was also obtained for each of the subjects for 4min using identical imaging parameters. Inter-voxel correlation analyses were conducted between the resting-state ReHo, resting-state amplitude of low frequency fluctuations (ALFF), BH responses and task activations within the masks related to task activations. There was a reliable mean voxel-wise spatial correlation between ReHo and other neurovascular variables (BH responses and ALFF). We observed a moderate correlation between ReHo and task activations (FTAP: r=0.32; DSST: r=0.22) within the task positive network and a small yet reliable correlation within the default mode network (DSST: r=-0.08). Subsequently, a linear regression was used to estimate the contribution of ReHo, ALFF and BH responses to the task activated voxels. The unique contribution of ReHo was minimal. The results suggest that regional synchrony of the BOLD activity is a property that can explain the variance of neurovascular coupling and task activations; but its contribution to task activations can be accounted for by other neurovascular factors such as the ALFF. © 2013.

  12. A Longitudinal Analysis of the Effect of Mass Drug Administration on Acute Inflammatory Episodes and Disease Progression in Lymphedema Patients in Léogane, Haiti

    PubMed Central

    Eddy, Brittany A.; Blackstock, Anna J.; Williamson, John M.; Addiss, David G.; Streit, Thomas G.; Beau de Rochars, Valery M.; Fox, LeAnne M.

    2014-01-01

    We conducted a longitudinal analysis of 117 lymphedema patients in a filariasis-endemic area of Haiti during 1995–2008. No difference in lymphedema progression between those who received or did not receive mass drug administration (MDA) was found on measures of foot (P = 0.24), ankle (P = 0.87), or leg (P = 0.46) circumference; leg volume displacement (P = 0.09), lymphedema stage (P = 0.93), or frequency of adenolymphangitis (ADL) episodes (P = 0.57). Rates of ADL per year were greater after initiation of MDA among both groups (P < 0.01). Nevertheless, patients who received MDA reported improvement in four areas of lymphedema-related quality of life (P ≤ 0.01). Decreases in foot and ankle circumference and ADL episodes were observed during the 1995-1998 lymphedema management study (P ≤ 0.01). This study represents the first longitudinal, quantitative, leg-specific analysis examining the clinical effect of diethylcarbamazine on lymphedema progression and ADL episodes. PMID:24218408

  13. 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

  14. 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

  15. 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.

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

    PubMed

    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.

  17. 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

  18. 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.

  19. Unusual Branching Pattern of the Lateral Cord of the Brachial Plexus Associated with Neurovascular Compression

    PubMed Central

    Loh, Hitendra K.; Singh, Shikha; Suri, Rajesh K.

    2017-01-01

    The brachial plexus consists of a network of nerves that innervates the upper limbs and its musculature. We report a rare formation of the lateral cord of the brachial plexus observed during the dissection of a 47-year-old male cadaver at the Department of Anatomy, Vardhman Mahavir Medical College, New Delhi, India, in 2016. The lateral cord was exceptionally long with twin lateral pectoral nerves and twin lateral roots of the median nerve. The proximal lateral root of the median nerve was thin in comparison to the medial root of the median nerve. The distal lateral root of the median nerve was thicker and followed an unusual course through the coracobrachialis muscle. In the lower third of the arm, the median nerve and the brachial artery—along with its vena comitans—spanned through the brachialis muscle. Surgeons, anaesthesiologists, radiologists and anatomists should be aware of such anatomical variations as they may result in neurovascular compression. PMID:28417040

  20. Granular Layer Neurons Control Cerebellar Neurovascular Coupling Through an NMDA Receptor/NO-Dependent System.

    PubMed

    Mapelli, Lisa; Gagliano, Giuseppe; Soda, Teresa; Laforenza, Umberto; Moccia, Francesco; D'Angelo, Egidio U

    2017-02-01

    Neurovascular coupling (NVC) is the process whereby neuronal activity controls blood vessel diameter. In the cerebellum, the molecular layer is regarded as the main NVC determinant. However, the granular layer is a region with variable metabolic demand caused by large activity fluctuations that shows a prominent expression of NMDA receptors (NMDARs) and nitric oxide synthase (NOS) and is therefore much more suitable for effective NVC. Here, we show, in the granular layer of acute rat cerebellar slices, that capillary diameter changes rapidly after mossy fiber stimulation. Vasodilation required neuronal NMDARs and NOS stimulation and subsequent guanylyl cyclase activation that probably occurred in pericytes. Vasoconstriction required metabotropic glutamate receptors and CYP ω-hydroxylase, the enzyme regulating 20-hydroxyeicosatetraenoic acid production. Therefore, granular layer capillaries are controlled by the balance between vasodilating and vasoconstricting systems that could finely tune local blood flow depending on neuronal activity changes at the cerebellar input stage.

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

    PubMed

    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.

  2. Neurovascular Study of the Trigeminal Nerve at 3 T MRI

    PubMed Central

    Gonzalez, Nadia; Muñoz, Alexandra; Bravo, Fernando; Sarroca, Daniel; Morales, Carlos

    2015-01-01

    This study aimed to show a novel visualization method to investigate neurovascular compression of the trigeminal nerve (TN) using a volume-rendering fusion imaging technique of 3D fast imaging employing steady-state acquisition (3D FIESTA) and coregistered 3D time of flight MR angiography (3D TOF MRA) sequences, which we called “neurovascular study of the trigeminal nerve”. We prospectively studied 30 patients with unilateral trigeminal neuralgia (TN) and 50 subjects without symptoms of TN (control group), on a 3 Tesla scanner. All patients were assessed using 3D FIESTA and 3D TOF MRA sequences centered on the pons, as well as a standard brain protocol including axial T1, T2, FLAIR and GRE sequences to exclude other pathologies that could cause TN. Post-contrast T1-weighted sequences were also performed. All cases showing arterial imprinting on the trigeminal nerve (n = 11) were identified on the ipsilateral side of the pain. No significant relationship was found between the presence of an artery in contact with the trigeminal nerve and TN. Eight cases were found showing arterial contact on the ipsilateral side of the pain and five cases of arterial contact on the contralateral side. The fusion imaging technique of 3D FIESTA and 3D TOF MRA sequences, combining the high anatomical detail provided by the 3D FIESTA sequence with the 3D TOF MRA sequence and its capacity to depict arterial structures, results in a tool that enables quick and efficient visualization and assessment of the relationship between the trigeminal nerve and the neighboring vascular structures. PMID:25924169

  3. The Latarjet coracoid process transfer procedure: alterations in the neurovascular structures.

    PubMed

    Freehill, Michael T; Srikumaran, Umasuthan; Archer, Kristin R; McFarland, Edward G; Petersen, Steve A

    2013-05-01

    The Latarjet coracoid process transfer procedure is an established, reliable treatment for glenoid deficiency associated with recurrent anterior shoulder instability, but changes in neurovascular anatomy resulting from the procedure are a concern. The purpose of our cadaveric study was to identify changes in the neurovascular anatomy after a Latarjet procedure. We obtained 4 paired, fresh-frozen cadaveric forequarters (8 shoulders) from the Maryland State Anatomy Board. In each shoulder, we preoperatively measured the distances from the midanterior glenoid rim to the musculocutaneous nerve, axillary nerve, and axillary artery in 2 directions (lateral to medial and superior to inferior) and with the arm in 2 positions (0° abduction/neutral rotation; 30° abduction/30° external rotation), for a total of 12 measurements. We then created a standardized bony defect in the anterior-inferior glenoid, reconstructed it with the Latarjet procedure, and repeated the same measurements. Two examiners independently took each measurement twice. Inter-rater reliability was adequate, allowing pre-Latarjet measurements to be combined, averaged, and compared with combined and averaged post-Latarjet measurements by using paired Student t tests (significance, P ≤ .05). We found (1) significant differences in the location of the musculocutaneous nerve in the superior-to-inferior direction for both arm positions, (2) notably lax and consistently overlapping musculocutaneous and axillary nerves, and (3) an unchanged axillary artery location. The Latarjet procedure resulted in consistent and clinically significant alterations in the anatomic relationships of the musculocutaneous and axillary nerves, which may make them vulnerable to injury during revision surgery. Copyright © 2013 Journal of Shoulder and Elbow Surgery Board of Trustees. Published by Mosby, Inc. All rights reserved.

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

    PubMed

    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 hyperhomocysteinemia (HHcy), was associated with neurovascular diseases. At physiological levels, hydrogen sulfide (H(2)S) protected the neurovascular system. Because Hcy was also a precursor of hydrogen sulfide (H(2)S), we sought to test whether the H(2)S protected the brain during HHcy. Cystathionine-beta-synthase heterozygous (CBS+/-) and wild type (WT) mice were supplemented with or without NaHS (30 microM/L, H(2)S 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 H(2)S) 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 H(2)S 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 H(2)S and suggested that physiological levels of H(2)S supplementation may have therapeutic potential against HHcy-induced microvascular permeability, in part, by normalizing the MMP/TIMP ratio in the brain.

  5. Systematic review on randomized controlled clinical trials of acupuncture therapy for neurovascular headache.

    PubMed

    Zhao, Lei; Guo, Yi; Wang, Wei; Yan, Li-juan

    2011-08-01

    To evaluate the effectiveness of acupuncture as a treatment for neurovascular headache and to analyze the current situation related to acupuncture treatment. PubMed database (1966-2010), EMBASE database (1986-2010), Cochrane Library (Issue 1, 2010), Chinese Biomedical Literature Database (1979-2010), China HowNet Knowledge Database (1979-2010), VIP Journals Database (1989-2010), and Wanfang database (1998-2010) were retrieved. Randomized or quasi-randomized controlled studies were included. The priority was given to high-quality randomized, controlled trials. Statistical outcome indicators were measured using RevMan 5.0.20 software. A total of 16 articles and 1 535 cases were included. Meta-analysis showed a significant difference between the acupuncture therapy and Western medicine therapy [combined RR (random efficacy model)=1.46, 95% CI (1.21, 1.75), Z=3.96, P<0.0001], indicating an obvious superior effect of the acupuncture therapy; significant difference also existed between the comprehensive acupuncture therapy and acupuncture therapy alone [combined RR (fixed efficacy model)=3.35, 95% CI (1.92, 5.82), Z=4.28, P<0.0001], indicating that acupuncture combined with other therapies, such as points injection, scalp acupuncture, auricular acupuncture, etc., were superior to the conventional body acupuncture therapy alone. The inclusion of limited clinical studies had verified the efficacy of acupuncture in the treatment of neurovascular headache. Although acupuncture or its combined therapies provides certain advantages, most clinical studies are of small sample sizes. Large sample size, randomized, controlled trials are needed in the future for more definitive results.

  6. 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

  7. 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.

  8. Typical and atypical neurovascular relations of the trigeminal nerve in the cerebellopontine angle: an anatomical study.

    PubMed

    Rusu, M C; Ivaşcu, R V; Cergan, R; Păduraru, D; Podoleanu, L

    2009-08-01

    The aim of the present study was to anatomically evaluate in adults the neurovascular trigeminal relations in the cerebellopontine angle (CPA), from a morphological and topographical perspective and thus to improve, detail and debate the pre-existing information, with educational and surgical implications. For the present anatomical study we performed bilateral dissections on 20 human adult skull bases, in formalin-fixed cadavers, at the level of the cerebellopontine angle, using the anatomical superior approach; we also studied 20 additional drawn specimens-cerebellum and brainstems, from autopsied cadavers, in order to better document the vasculature at the trigeminal root entry zone (REZ). The most constant but not exclusive neurovascular relations of the trigeminal nerves were those with the superior cerebellar artery (SCA) and the superior petrosal vein (the petrosal vein of Dandy). The regular possibility for the SCA to appear divided into a medial and a lateral branch and these to represent individual trigeminal relations at the level of the pontine cistern or REZ must not be neglected. The petrosal vein tributaries can also represent superior, inferior, or interradicular trigeminal relations. Arterioles emerging from the SCA or the anterior inferior cerebellar artery (AICA) represented trigeminal relations either at the REZ or were coursing between the trigeminal roots. A dissected specimen presented a radicular trigeminal artery emerging from the basilar artery and entering the trigeminal cavum inferior to the nerve. Another specimen presented two bony lamellae superior to the trigeminal nerve at the entrance in the trigeminal cavum-these lamellae were embedded within the lateral border of tentorium cerebelli and the posterior petroclinoid ligament. So we bring here an evidence-based support extremely useful not only for specialists dealing with this area but also for educational purposes. It appears important not only to consider the typical anatomy at

  9. 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

  10. [Neurovascular infrahyoidal myofascial flap. Anatomic and topographic study of the innervation and blood supply].

    PubMed

    Remmert, S; Meyer, S; Majocco, A

    1998-06-01

    The neurovascular infrahyoidal myofascial flap: An anatomical and topographical study of the innervation and blood supply. 15 cadavers had bilaterally been examined for the topography of the upper thyroid artery and vein and of the lower cervical ansa, as an axial bundle of vessels and nerves for the infrahyoidal myofascial flap. With the injection of methylene blue the vascular territories of the upper thyroid artery had been demonstrated. The upper thyroid artery and vein could be found in all cases. This artery was deriving in 47% from the external carotid artery, in 30% from the bifurcation and in 23% from the common carotid artery. The vein flowed in 43% into the facial vein and in 37% into the internal jugular vein. In the remaining 20% several segmental veins were found, which flowed into the jugular vein separately. In case of a far caudally situated vascular bundle the radius of rotation can be limited in cranial direction. The voluntary innervation of the muscles of this flap is derived from the lower cervical ansa. The upper radix of the ansa can be found 1 cm in latero-cranial direction of the greater horn of the hyoid bone, where it is separating from the hypoglossal nerve. The upper thyroid artery is supplying the infrahyoidal musculature in the whole extension from the hyoid bone to the sternum. Therefore it is possible to develop a myofascial flap of 3.5 cm x 11.5 cm in size, which is pedicled at an upper vascular and nerval bundle. Depending on the radius of rotation defects of the floor of mouth, of the tongue and of the oro- and hypopharynx can well be covered with this new neurovascular myofascial flap.

  11. Brain Perivascular Macrophages Initiate the Neurovascular Dysfunction of Alzheimer Aβ Peptides.

    PubMed

    Park, Laibaik; Uekawa, Ken; Garcia-Bonilla, Lidia; Koizumi, Kenzo; Murphy, Michelle; Pistik, Rose; Younkin, Linda; Younkin, Steven; Zhou, Ping; Carlson, George; Anrather, Josef; Iadecola, Costantino

    2017-07-21

    Increasing evidence indicates that alterations of the cerebral microcirculation may play a role in Alzheimer disease, the leading cause of late-life dementia. The amyloid-β peptide (Aβ), a key pathogenic factor in Alzheimer disease, induces profound alterations in neurovascular regulation through the innate immunity receptor CD36 (cluster of differentiation 36), which, in turn, activates a Nox2-containing NADPH oxidase, leading to cerebrovascular oxidative stress. Brain perivascular macrophages (PVM) located in the perivascular space, a major site of brain Aβ collection and clearance, are juxtaposed to the wall of intracerebral resistance vessels and are a powerful source of reactive oxygen species. We tested the hypothesis that PVM are the main source of reactive oxygen species responsible for the cerebrovascular actions of Aβ and that CD36 and Nox2 in PVM are the molecular substrates of the effect. Selective depletion of PVM using intracerebroventricular injection of clodronate abrogates the reactive oxygen species production and cerebrovascular dysfunction induced by Aβ applied directly to the cerebral cortex, administered intravascularly, or overproduced in the brain of transgenic mice expressing mutated forms of the amyloid precursor protein (Tg2576 mice). In addition, using bone marrow chimeras, we demonstrate that PVM are the cells expressing CD36 and Nox2 responsible for the dysfunction. Thus, deletion of CD36 or Nox2 from PVM abrogates the deleterious vascular effects of Aβ, whereas wild-type PVM reconstitute the vascular dysfunction in CD36-null mice. The data identify PVM as a previously unrecognized effector of the damaging neurovascular actions of Aβ and unveil a new mechanism by which brain-resident innate immune cells and their receptors may contribute to the pathobiology of Alzheimer disease. © 2017 American Heart Association, Inc.

  12. Magnetic Resonance Imaging of Ischemia Viability Thresholds and the Neurovascular Unit

    PubMed Central

    Barber, Philip A.

    2013-01-01

    Neuroimaging has improved our understanding of the evolution of stroke at discreet time points helping to identify irreversibly damaged and potentially reversible ischemic brain. Neuroimaging has also contributed considerably to the basic premise of acute stroke therapy which is to salvage some portion of the ischemic region from evolving into infarction, and by doing so, maintaining brain function and improving outcome. The term neurovascular unit (NVU) broadens the concept of the ischemic penumbra by linking the microcirculation with neuronal-glial interactions during ischemia reperfusion. Strategies that attempt to preserve the individual components (endothelium, glia and neurons) of the NVU are unlikely to be helpful if blood flow is not fully restored to the microcirculation. Magnetic resonance imaging (MRI) is the foremost imaging technology able to bridge both basic science and the clinic via non-invasive real time high-resolution anatomical delineation of disease manifestations at the molecular and ionic level. Current MRI based technologies have focused on the mismatch between perfusion-weighted imaging (PWI) and diffusion weighted imaging (DWI) signals to estimate the tissue that could be saved if reperfusion was achieved. Future directions of MRI may focus on the discordance of recanalization and reperfusion, providing complimentary pathophysiological information to current compartmental paradigms of infarct core (DWI) and penumbra (PWI) with imaging information related to cerebral blood flow, BBB permeability, inflammation, and oedema formation in the early acute phase. In this review we outline advances in our understanding of stroke pathophysiology with imaging, transcending animal stroke models to human stroke, and describing the potential translation of MRI to image important interactions relevant to acute stroke at the interface of the neurovascular unit. PMID:23711462

  13. A Working Module for the Neurovascular Unit in the Sexually Dimorphic Nucleus of the Preoptic Area.

    PubMed

    He, Zhen; Cui, Li; Ferguson, Sherry A; Paule, Merle G

    2017-08-24

    The neurovascular unit (NVU) can be conceptualized as a functional entity consisting of neurons, astrocytes, pericytes, and endothelial and smooth muscle cells that operate in concert to affect blood flow to a very circumscribed area. Although we are currently in a "golden era" of bioengineering, there are, as yet, no living NVUs-on-a-chip modules available and the development of a neural chip that would mimic NVUs is a seemingly lofty goal. The sexually dimorphic nucleus of the preoptic area (SDN-POA) is a tiny brain structure (between 0.001~0.007 mm(3) in rats) with an assessable biological function (i.e., male sexual behavior). The present effort was undertaken to determine whether there are identifiable NVUs in the SDN-POA by assessing its vasculature relative to its known neural components. First, a thorough and systematic review of thousands of histologic and immunofluorescent images from 201 weanling and adult rats was undertaken to define the characteristics of the vessels supplying the SDN-POA: its primary supply artery/arteriole and capillaries are physically inseparable from their neural elements. A subsequent immunofluorescent study targeting α-smooth muscle actin confirmed the identity of an artery/arteriole supplying the SDN-POA. In reality, the predominant components of the SDN-POA are calbindin D28k-positive neurons that are comingled with tyrosine hydroxylase-positive projections. Finally, a schematic of an SDN-POA NVU is proposed as a working model of the basic building block of the CNS. Such modules could serve the study of neurovascular mechanisms and potentially inform the development of next generation bioengineered neural transplants, i.e., the construct of an NVU neural chip.

  14. Three-dimensional digitalized virtual planning for retrograde sural neurovascular island flaps: a comparative study.

    PubMed

    Li, Ya-Guang; Chen, Xiang-Jun; Zhang, Yuan-Zhi; Han, De-Zhi; Yan, De-Xiong; Gao, Guo-Zhen; Zhao, Xiao-Chun; Sun, Wei-Jing

    2014-08-01

    The purpose of this study was to explore the effectiveness and safety of three-dimensional (3D) digitalized planning for the sural neurovascular island flap in repair of soft tissue defects in the ankle and foot. This study included 40 patients with soft tissue defects of the ankle and foot who underwent soft tissue reconstruction between October 2008 and June 2012. The patients were randomly assigned into two groups: 3D-reconstruction group (Group A, n=20) and control group (Group B, n=20). Three-dimensional, digitalized virtual planning was performed in the patients in Group A, who underwent computed topographic angiography. The survival rate, operation time, and surgical accuracy were compared between the two groups. All flaps in Group A survived and the recipient site primarily healed, but 4 flaps in Group B had marginal necrosis after the operation. During the 6-12 month follow-up period, all flaps in Group A had good skin quality. In Group B, hard scarring and mild contracture occurred in 4 cases, and the patients experienced pain when walking. The survival rate of the flap in Group A (100%) was significantly higher than in Group B (70%). The operation time in Group A was significantly less than in Group B. The surgical accuracy in Group A was significantly better than in Group B. The preoperative use of 3D digitalized virtual planning for the sural neurovascular island flap improves the surgical accuracy, decreases the operation time, and increases the survival rate of the flap. Therapeutic III. Copyright © 2013 Elsevier Ltd and ISBI. All rights reserved.

  15. 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

  16. [Neurovascular compression of the medulla oblongata: a rare cause of secondary hypertension].

    PubMed

    Nádas, Judit; Czirják, Sándor; Igaz, Péter; Vörös, Erika; Jermendy, György; Rácz, Károly; Tóth, Miklós

    2014-05-25

    Compression of the rostral ventrolateral medulla oblongata is one of the rarely identified causes of refractory hypertension. In patients with severe, intractable hypertension caused by neurovascular compression, neurosurgical decompression should be considered. The authors present the history of a 20-year-old man with severe hypertension. After excluding other possible causes of secondary hypertension, the underlying cause of his high blood pressure was identified by the demonstration of neurovascular compression shown by magnetic resonance angiography and an increased sympathetic activity (sinus tachycardia) during the high blood pressure episodes. Due to frequent episodes of hypertensive crises, surgical decompression was recommended, which was performed with the placement of an isograft between the brainstem and the left vertebral artery. In the first six months after the operation, the patient's blood pressure could be kept in the normal range with significantly reduced doses of antihypertensive medication. Repeat magnetic resonance angiography confirmed the cessation of brainstem compression. After six months, increased blood pressure returned periodically, but to a smaller extent and less frequently. Based on the result of magnetic resonance angiography performed 22 months after surgery, re-operation was considered. According to previous literature data long-term success can only be achieved in one third of patients after surgical decompression. In the majority of patients surgery results in a significant decrease of blood pressure, an increased efficiency of antihypertensive therapy as well as a decrease in the frequency of highly increased blood pressure episodes. Thus, a significant improvement of the patient's quality of life can be achieved. The case of this patient is an example of the latter scenario.

  17. 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

  18. 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

    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

    2016-03-22

    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.

  19. Inflammatory myopathies.

    PubMed

    Podell, Michael

    2002-01-01

    Inflammatory myopathies are the result of infiltration of inflammatory cells into striated muscle, with or without an association with an underlying cause. Two broad classifications are IIMs and secondary inflammatory myopathies associated with other diseases. Standard diagnostic criteria for inflammatory myopathy include the presence of weakness or loss of specific muscle group function, an increase in CK, EMG changes associated with muscle membrane instability, and histologic evidence of inflammation. Not all these criteria, however, must be present. Fresh-frozen biopsy from two proximal muscles is recommended for biopsy confirmation. IIM can either focally affect head or neck muscles or be more diffuse. MMM is an immune-mediated disease characterized by a humoral antibody produced against the unique type IIM and type I variant mvofibers of masticatory muscles of dogs, which causes inflammation and loss of function of the muscles of mastication. Idiopathic polymyositis can affect focal muscle groups (extraocular, laryngeal) or present as multifocal or diffuse involvement of skeletal muscle in the cat and dog. Familial canine DM is an inflammatory disease of the striated muscle, skin, and vasculature in young Collies, Shetland Sheepdogs (Shelties), and, rarely, Collie-crossbred dogs. Immunosuppressive therapy is the key to successful treatment. Protozoal parasitic myopathies are the most common cause of clinically relevant secondary inflammatory myopathies. The degree of systemic involvement is often the limiting factor to successful treatment. Early recognition of the clinical signs for proper diagnostic testing and institution of appropriate therapy can result in a rewarding outcome in treating inflammatory myopathies in the cat and dog.

  20. 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

  1. The differential anti-inflammatory effects of exercise modalities and their association with early carotid atherosclerosis progression in patients with type 2 diabetes.

    PubMed

    Kadoglou, N P E; Fotiadis, G; Kapelouzou, A; Kostakis, A; Liapis, C D; Vrabas, I S

    2013-02-01

    Adipokines, visfatin, apelin, vaspin and ghrelin have emerged as novel cardiovascular risk factors. We aimed to evaluate the effects of different exercise modalities on the aforementioned novel adipokines and carotid intima-media thickness in patients with Type 2 diabetes mellitus. One hundred patients with Type 2 diabetes were equivalently (n = 25) randomized into four groups: (1) a control group with patients encouraged to perform self-controlled exercise; (2) a supervised aerobic exercise group (exercise four times/week, 60 min/session, 60-75% of maximum heart rate); (3) a resistance training group (60-80% baseline maximum load achieved in one repetition); and (4) a combined aerobic exercise plus resistance training group, as in groups 2 and 3. All participants had HbA(1c) levels ≥ 48 mmol/mol (≥ 6.5%), without overt diabetic vascular complications. Blood samples, clinical characteristics, peak oxygen uptake and carotid intima-media thickness measurements were obtained at baseline and at the end of the study, after 6 months. At baseline, there were non-significant differences between groups. All active groups significantly ameliorated glycaemic profile, insulin sensitivity and triglycerides levels compared with the control group (P < 0.05). Aerobic training further improved lipids, systolic blood pressure and exercise capacity compared with the resistance training and the control groups (P < 0.05). Moreover, high-sensitivity C-reactive protein and visfatin decreased, while vaspin and apelin circulating levels increased within the aerobic exercise group and the aerobic exercise plus resistance training group, and compared with the other groups (P < 0.05). Within- and between-group comparisons showed negligible alterations in ghrelin serum levels and body weight after all exercise modalities. Finally, aerobic training attenuated the carotid intima-media thickness progression (0.017 ± 0.006 mm) compared with the control subjects (0.129

  2. miRNA-133a-UCP2 pathway regulates inflammatory bowel disease progress by influencing inflammation, oxidative stress and energy metabolism

    PubMed Central

    Jin, Xi; Chen, Dong; Zheng, Ruo-Heng; Zhang, Hong; Chen, Yi-Peng; Xiang, Zun

    2017-01-01

    AIM To investigate the role of the miR-133a-UCP2 pathway in the pathogenesis of inflammatory bowel disease (IBD) and to explore the potential downstream mechanisms with respect to inflammation, oxidative stress and energy metabolism. METHODS C57BL/6 mice were fed dextran sulfate sodium (DSS) liquid for 7 consecutive days, followed by the administration of saline to the DSS group, UCP2 siRNA to the UCP2 group and a miR-133a mimic to the miR-133a group on days 8 and 11. Body weight, stool consistency and rectal bleeding were recorded daily, and these composed the disease activity index (DAI) score for the assessment of disease severity. After cervical dislocation was performed on day 14, the length of the colon in each mouse was measured, and colonic tissue was collected for further study, which included the following: haematoxylin and eosin staining, UCP2 and miR-133a detection by immunohistochemical staining, western blot and quantitative real-time PCR, measurement of apoptosis by TUNEL assay, and the assessment of inflammation (TNF-α, IL-1β, IL-6 and MCP1), oxidative stress (H2O2 and MDA) and metabolic parameters (ATP) by ELISA and colorimetric methods. RESULTS An animal model of IBD was successfully established, as shown by an increased DAI score, shortened colon length and specific pathologic changes, along with significantly increased UCP2 and decreased miR-133a levels. Compared with the DSS group, the severity of IBD was alleviated in the UCP2 and the miR-133a groups after successful UCP2 knockdown and miR-133a overexpression. The extent of apoptosis, as well as the levels of TNF-α, IL-1β, MDA and ATP, were significantly increased in both the UCP2 and miR-133a groups compared with the DSS group. CONCLUSION The miR-133a-UCP2 pathway participates in IBD by altering downstream inflammation, oxidative stress and markers of energy metabolism, which provides novel clues and potential therapeutic targets for IBD. PMID:28104982

  3. [Inflammatory myopathies].

    PubMed

    Maurer, Britta

    2017-02-01

    Inflammatory myopathies comprise heterogeneous, often multisystemic autoimmune diseases with muscle involvement as a common feature. The prognosis largely depends on a timely diagnosis and initiation of therapy. Given the complexity of these rare diseases, when an inflammatory myopathy is suspected patients should be referred to an expert center with established algorithms for the diagnostic work-up. The differential diagnostic exclusion of myositis mimics should ideally be carried out in close collaboration with neurologists and neuropathologists. The choice of immunosuppressive treatment should primarily depend on disease severity and organ involvement but age and comorbidities also have to be taken into account.

  4. Neurovascular mechanisms underlying augmented cold-induced reflex cutaneous vasoconstriction in human hypertension.

    PubMed

    Greaney, Jody L; Kenney, W Larry; Alexander, Lacy M

    2017-03-01

    In hypertensive adults (HTN), cardiovascular risk increases disproportionately during environmental cold exposure. Despite ample evidence of dysregulated sympathetic control of the peripheral vasculature in hypertension, no studies have examined integrated neurovascular function during cold stress in HTN. The findings of the present study show that whole-body cold stress elicits greater increases in sympathetic outflow directed to the cutaneous vasculature and, correspondingly, greater reductions in skin blood flow in HTN. We further demonstrate an important role for non-adrenergic sympathetic co-transmitters in mediating the vasoconstrictor response to cold stress in hypertension. In the context of thermoregulation and the maintenance of core temperature, sympathetically-mediated control of the cutaneous vasculature is not only preserved, but also exaggerated in hypertension. Given the increasing prevalence of hypertension, clarifying the mechanistic underpinnings of hypertension-induced alterations in neurovascular function during cold exposure is clinically relevant. Despite ample evidence of dysregulated sympathetic control of the peripheral vasculature in hypertension, no studies have examined integrated neurovascular function during cold stress in hypertensive adults (HTN). We hypothesized that (i) whole-body cooling would elicit greater cutaneous vasoconstriction and greater increases in skin sympathetic nervous system activity (SSNA) in HTN (n = 14; 56 ± 2 years) compared to age-matched normotensive adults (NTN; n = 14; 55 ± 2 years) and (ii) augmented reflex vasoconstriction in HTN would be mediated by an increase in cutaneous vascular adrenergic sensitivity and a greater contribution of non-adrenergic sympathetic co-transmitters. SSNA (peroneal microneurography) and red cell flux (laser Doppler flowmetry; dorsum of foot) were measured during whole-body cooling (water-perfused suit). Sympathetic adrenergic- and non

  5. 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.

  6. Focal deformity of the cranial nerves observed on multislice motion-sensitized driven equilibrium (MSDE) in patients with neurovascular compression.

    PubMed

    Kanoto, Masafumi; Hosoya, Takaaki; Oda, Atsuko; Honma, Tsuguo; Sugai, Yukio

    2012-01-01

    Our purpose is to demonstrate the deformity of the cranial nerves by arterial compression using a novel technique, multislice motion-sensitized driven equilibrium (MSDE). Subjects were 10 patients with neurovascular compression (5 patients with trigeminal neuralgia and 5 patients with hemifacial spasm). We observed the existence and extent of deformity of nerves by MSDE. Afterward, we compared operative findings with preoperative imaging findings and evaluated the validity of the latter. All compressing, blood vessels could be correctly identified through preoperative evaluation. Of all patients, 7 showed deformity of the cranial nerves, which was consistent with operative findings except in one case. In postoperative evaluation, patients' neurological symptoms improved and the deformity disappeared. Three patients did not show deformity on preoperative MSDE images. In these patients, neural compression was also not observed during the operation. The deformity of cranial nerves in patients with neurovascular compression was clearly shown using MSDE.

  7. Detection of neurovascular structures using injection pressure in blockade of brachial plexus in rat.

    PubMed

    Vucković, Ilvana; Hadzić, Admir; Dilberović, Faruk; Kulenović, Amela; Mornjaković, Zakira; Zulić, Irfan; Divanović, Kucuk-Alija; Kapur, Eldan; Cosović, Esad; Voljevica, Alma

    2005-08-01

    In the last few decades there has been a great development of regional anesthesia; all the postulates are defined and all the techniques of usage are perfected. However, like any other medical procedure, the block of brachial plexus carries a risk of certain unwanted complications, like possible intraneural and intravascular injections. The reason for great discrepancy between the injury of brachial plexus and other periphery nerves while performing the nerve blockade is the frequent usage of this block, but also the specific proximity of neurovascular structures in axilla. The purpose of this work is to determine the values of pressures which appear in para-neural, intraneural and intravascular injection applications of local anesthetic, and to compare those values in order to avoid cases of intraneural and intravascular injections in clinical practice with consequential complications. In experimental study there have been used 12 Wistar rats of both genders. After anesthesia with ether and mid-humoral access to the neurovascular structures in axilla, the injection of 2% lidocaine with epinephrine was performed with the help of automatic syringe charge. The needle was at first placed para-neural, and then also intraneural and intravascular. During every application the pressure values were monitored using the manometer, and then they were analyzed by special software program. All para-neural injections resulted with the pressure between 13,96-27,92 kPa. The majority of intraneural injections were combined with the injection pressure greater than 69,8 kPa, while the intravascular injections were combined with injection pressure less than 6,98 kPa. Based on the available data it can be noticed that so far none of the methods of prevention from unwanted complications of regional anesthesia can insure the avoidance of intraneural and intravascular injection of local anesthetic. Based on our research it is obvious that the measuring of pressure during the nerve

  8. 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

  9. 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

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

    PubMed Central

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

    2015-01-01

    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

  11. Preservation of the inferior alveolar neurovascular bundle in the osteotomy of benign lesions of the mandible using a digital template.

    PubMed

    Huang, Dong; Chen, MinJie; He, DongMei; Yang, Chi; Yuan, JianBing; Bai, Guo; Wang, YiWen; Wei, WenBin; Chen, ZhuoZhi

    2015-09-01

    Our aim was to evaluate the effect of a digital template in the preservation of the inferior alveolar neurovascular bundle during osteotomy for benign lesions of the mandible in 6 patients who were treated with mandibular osteotomies during 2013. Computed tomographic (CT) data were imported into ProPlan CMF 1.4 software. The borders of the lesion and the inferior alveolar canal were marked, and a digital template designed to mark the borders, outline the canal, and guide the osteotomy. A mirror image of the unaffected mandible was used to make a stereolithographic model by a rapid prototyping technique to prefabricate the reconstruction plate for the bone graft. The accuracy of the designs and the templates was evaluated during operation and postoperatively by CT. The sensation of the skin was tested using a Neurometer® CPT (current perception threshold) sensory detector (Neurotron Inc, Baltimore USA) to evaluate the function of the preserved inferior alveolar neurovascular bundle during follow up. With the digital template it was possible to guide removal of the bony lesion while accurately protecting the neurovascular bundle. Follow up for a mean of 8 months (range 5 -12) showed good facial symmetry, a stable occlusion, and recovery of sensation in the lower lip on the affected side. We conclude that a digital template can successfully help the resection of benign lesions of the mandible while preserving the function of the inferior alveolar neurovascular bundle. Copyright © 2015 The British Association of Oral and Maxillofacial Surgeons. Published by Elsevier Ltd. All rights reserved.

  12. 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. © The Author(s) 2015.

  13. 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

  14. Toward the era of a one-stop imaging service using an angiography suite for neurovascular disorders.

    PubMed

    Hung, Sheng-Che; Lin, Chung-Jung; Guo, Wan-Yuo; 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.

  15. Investigation of the neurovascular coupling in positive and negative BOLD responses in human brain at 7 T.

    PubMed

    Huber, Laurentius; Goense, Jozien; Kennerley, Aneurin J; Ivanov, Dimo; Krieger, Steffen N; Lepsien, Jöran; Trampel, Robert; Turner, Robert; Möller, Harald E

    2014-08-15

    Decreases in stimulus-dependent blood oxygenation level dependent (BOLD) signal and their underlying neurovascular origins have recently gained considerable interest. In this study a multi-echo, BOLD-corrected vascular space occupancy (VASO) functional magnetic resonance imaging (fMRI) technique was used to investigate neurovascular responses during stimuli that elicit positive and negative BOLD responses in human brain at 7 T. Stimulus-induced BOLD, cerebral blood volume (CBV), and cerebral blood flow (CBF) changes were measured and analyzed in 'arterial' and 'venous' blood compartments in macro- and microvasculature. We found that the overall interplay of mean CBV, CBF and BOLD responses is similar for tasks inducing positive and negative BOLD responses. Some aspects of the neurovascular coupling however, such as the temporal response, cortical depth dependence, and the weighting between 'arterial' and 'venous' contributions, are significantly different for the different task conditions. Namely, while for excitatory tasks the BOLD response peaks at the cortical surface, and the CBV change is similar in cortex and pial vasculature, inhibitory tasks are associated with a maximum negative BOLD response in deeper layers, with CBV showing strong constriction of surface arteries and a faster return to baseline. The different interplays of CBV, CBF and BOLD during excitatory and inhibitory responses suggests different underlying hemodynamic mechanisms.

  16. 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

  17. Preoperative evaluation of neurovascular relationships for microvascular decompression in the cerebellopontine angle in a virtual reality environment.

    PubMed

    Du, Zhuo-Ying; Gao, Xiang; Zhang, Xiao-Luo; Wang, Zhi-Qiu; Tang, Wei-Jun

    2010-09-01

    In this paper the authors' goal was to evaluate the feasibility and efficacy of a virtual reality (VR) system in preoperative planning for microvascular decompression (MVD) procedures treating idiopathic trigeminal neuralgia and hemifacial spasm. The system's role in surgical simulation and training was also assessed. Between May 2008 and April 2009, the authors used the Dextroscope system to visualize the neurovascular complex and simulate MVD in the cerebellopontine angle in a VR environment in 16 patients (6 patients had trigeminal neuralgia and 10 had hemifacial spasm). Reconstructions were carried out 2-3 days before MVD. Images were printed in a red-blue stereoscopic format for teaching and discussion and were brought into the operating room to be compared with real-time intraoperative findings. The VR environment was a powerful aid for spatial understanding of the neurovascular relationship in MVD for operating surgeons and trainees. Through an initial series of comparison/confirmation experiences, the senior neurosurgeon became accustomed to the system. He could predict intraoperative problems and simulate surgical maneuvering, which increased his confidence in performing the procedure. The Dextroscope system is an easy and rapid method to create a stereoscopic neurovascular model for MVD that is highly concordant with intraoperative findings. It effectively shortens the learning curve and adds to the surgeon's confidence.

  18. 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.

  19. Inflammatory cytokines.

    PubMed

    Cerami, A

    1992-01-01

    The immune system produces cytokines and other humoral factors to protect the host when threatened by inflammatory agents, microbial invasion, or injury. In some cases this complex defense network successfully restores normal homeostasis, but at other times the overproduction of immunoregulatory mediators may actually prove deleterious to the host. Some examples of immune system-mediated injury have been extensively investigated including anaphylactic shock, autoimmune disease, and immune complex disorders. More recently it has become clear that the cytokine cachectin/tumor necrosis factor (TNF) occupies a key role in the pathophysiology associated with diverse inflammatory states and other serious illnesses including septic shock and cachexia. For example, when cachectin/TNF is produced by resident macrophages during early microbial infection, it mediates an inflammatory response that may alienate and repel the attacking organisms. If the infection spreads, however, the subsequent release of large quantities of cachectin/TNF into the circulation may be catastrophic and trigger a state of lethal shock. These toxic effects occur by direct action of TNF on host cells and by the interaction with a cascade of other endogenous mediators including interleukin-1 and interferon-gamma. The biology of cachectin/TNF will be reviewed, along with the potential for modulating the effects of this pluripotent molecule in a variety of pathologic states.

  20. Exploring neuro-vascular and neuro-metabolic coupling in rat somatosensory cortex

    NASA Astrophysics Data System (ADS)

    Mesquita, R. C.; Huppert, T. J.; Boas, D. A.

    2009-01-01

    The existence of a coupling between changes in neuronal activity, cerebral blood flow and blood oxygenation is well known. The explicit relationship between these systems, however, is complex and remains a subject of intense research. Here, we use direct electrophysiological recordings to predict blood flow and oxygenation changes measured with optical methods during parametric stimulation applied to the somatosensory cortex in rat brain. Using a multimodal model of the cerebral functional unit, we estimate a neuro-vascular and a neuro-metabolic transfer function relating the experimentally measured neural responses with the inputs to a vascular model predicting hemodynamic and blood oxygenation changes. We show that our model can accurately predict experimentally measured parametric hemodynamic evoked responses by using a single linear transfer function relationship with a reduced number of state parameters to relate the level of neural activity to evoked cerebral blood flow and oxygen metabolism changes. At the same time, we characterize the metabolic and vascular neural response functions and interpret their physiological significance.

  1. 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.

  2. Upregulation of neurovascular communication through filamin abrogation promotes ectopic periventricular neurogenesis

    PubMed Central

    Houlihan, Shauna L; Lanctot, Alison A; Guo, Yan; Feng, Yuanyi

    2016-01-01

    Neuronal fate-restricted intermediate progenitors (IPs) are derived from the multipotent radial glia (RGs) and serve as the direct precursors for cerebral cortical neurons, but factors that control their neurogenic plasticity remain elusive. Here we report that IPs’ neuron production is enhanced by abrogating filamin function, leading to the generation of periventricular neurons independent of normal neocortical neurogenesis and neuronal migration. Loss of Flna in neural progenitor cells (NPCs) led RGs to undergo changes resembling epithelial-mesenchymal transition (EMT) along with exuberant angiogenesis that together changed the microenvironment and increased neurogenesis of IPs. We show that by collaborating with β-arrestin, Flna maintains the homeostatic signaling between the vasculature and NPCs, and loss of this function results in escalated Vegfa and Igf2 signaling, which exacerbates both EMT and angiogenesis to further potentiate IPs’ neurogenesis. These results suggest that the neurogenic potential of IPs may be boosted in vivo by manipulating Flna-mediated neurovascular communication. DOI: http://dx.doi.org/10.7554/eLife.17823.001 PMID:27664421

  3. Zika virus infection disrupts neurovascular development and results in postnatal microcephaly with brain damage.

    PubMed

    Shao, Qiang; Herrlinger, Stephanie; Yang, Si-Lu; Lai, Fan; Moore, Julie M; Brindley, Melinda A; Chen, Jian-Fu

    2016-11-15

    Zika virus (ZIKV) infection of pregnant women can result in fetal brain abnormalities. It has been established that ZIKV disrupts neural progenitor cells (NPCs) and leads to embryonic microcephaly. However, the fate of other cell types in the developing brain and their contributions to ZIKV-associated brain abnormalities remain largely unknown. Using intracerebral inoculation of embryonic mouse brains, we found that ZIKV infection leads to postnatal growth restriction including microcephaly. In addition to cell cycle arrest and apoptosis of NPCs, ZIKV infection causes massive neuronal death and axonal rarefaction, which phenocopy fetal brain abnormalities in humans. Importantly, ZIKV infection leads to abnormal vascular density and diameter in the developing brain, resulting in a leaky blood-brain barrier (BBB). Massive neuronal death and BBB leakage indicate brain damage, which is further supported by extensive microglial activation and astrogliosis in virally infected brains. Global gene analyses reveal dysregulation of genes associated with immune responses in virus-infected brains. Thus, our data suggest that ZIKV triggers a strong immune response and disrupts neurovascular development, resulting in postnatal microcephaly with extensive brain damage.

  4. Advanced in vitro approach to study neurovascular coupling mechanisms in the brain microcirculation

    PubMed Central

    Kim, Ki Jung; Filosa, Jessica A

    2012-01-01

    An understanding of the signalling events underlying neurovascular coupling mechanisms in the brain is a crucial step in the development of novel therapeutic approaches for the treatment of cerebrovascular-associated disorders. In this study we present an enhanced in vitro brain slice preparation from male Wistar rat cortical slices that incorporates haemodynamic variables (flow and pressure) into parenchymal arterioles resulting in the development of myogenic tone (28% from maximum dilatation). Moreover, we characterized flow-induced vascular responses, resulting in various degrees of vasoconstrictions and the response to 10 mm K+ or astrocytic activation with the mGluR agonist, t-ACPD (100 μm), resulting in vasodilatations of 33.6 ± 4.7% and 38.6 ± 4.6%, respectively. Using fluorescence recovery, we determined perfusate velocity to calculate diameter changes under different experimental pH conditions. Using this approach, we demonstrate no significant differences between diameter changes measured using video microscopy or predicted from the velocity values obtained using fluorescence recovery after photobleaching. The model is further validated by demonstrating our ability to cannulate arterioles in two brain regions (cortex and supraoptic nucleus of the hypothalamus). Altogether, we believe this is the first study demonstrating successful cannulation and perfusion of parenchymal arterioles while monitoring/estimating luminal diameter and pressure under conditions where flow rates are controlled. PMID:22310311

  5. Exhaustive Exercise Attenuates the Neurovascular Coupling by Blunting the Pressor Response to Visual Stimulation

    PubMed Central

    Ikemura, Tsukasa; Hayashi, Naoyuki

    2015-01-01

    Neurovascular coupling (NVC) is assessed as an increase response to visual stimulation, and is monitored by blood flow of the posterior cerebral artery (PCA). To investigate whether exhaustive exercise modifies NVC, and more specifically, the relative contributions of vasodilatation in the downstream of PCA and the pressor response on NVC, we measured blood flow velocity in the PCA (PCAv) in 13 males using transcranial Doppler ultrasound flowmetry during a leg-cycle exercise at 75% of maximal heart rate until exhaustion. NVC was estimated as the relative change in PCAv from the mean value obtained during 20-s with the eyes closed to the peak value obtained during 40-s of visual stimulation involving looking at a reversed checkerboard. Conductance index (CI) was calculated by dividing PCAv by mean arterial pressure (MAP) to evaluate the vasodilatation. At exhaustion, PCAv was significantly decreased relative to baseline measurements, and the PCAv response to visual stimulation significantly decreased. Compared to baseline, exhaustive exercise significantly suppressed the increase in MAP to visual stimulation, while the CI response did not significantly change by the exercise. These results suggest that exhaustive exercise attenuates the magnitude of NVC by blunting the pressor response to visual stimulation. PMID:25866801

  6. Improving neurovascular outcomes with bilateral forepaw stimulation in a rat photothrombotic ischemic stroke model

    PubMed Central

    Liao, Lun-De; Bandla, Aishwarya; Ling, Ji Min; Liu, Yu-Hang; Kuo, Li-Wei; Chen, You-Yin; King, Nicolas KK; Lai, Hsin-Yi; Lin, Yan-Ren; Thakor, Nitish V.

    2014-01-01

    Abstract. Restoring perfusion to the penumbra during the hyperacute phase of ischemic stroke is a key goal of neuroprotection. Thrombolysis is currently the only approved treatment for ischemic stroke. However, its use is limited by the narrow therapeutic window and side effect of bleeding. Therefore, other interventions are desired that could potentially increase the perfusion of the penumbra. Here, we hypothesized that bilateral peripheral electrical stimulation will improve cerebral perfusion and restore cortical neurovascular response. We assess the outcomes of bilateral forepaw electrical stimulation at intensities of 2 and 4 mA, administered either unilaterally or bilaterally. We developed a combined electrocorticogram (ECoG)-functional photoacoustic microscopy (fPAM) system to evaluate the relative changes in cerebral hemodynamic function and electrophysiologic response to acute, focal stroke. The fPAM system is used for cerebral blood volume (CBV) and hemoglobin oxygen saturation (SO2) and the ECoG for neural activity, namely somatosensory-evoked potential (SSEP), interhemispheric coherence, and alpha-delta ratio (ADR) in response to forepaw stimulation. Our results confirmed the neuroprotective effect of bilateral forepaw stimulation at 2 mA as indicated by the 82% recovery of ADR and 95% improvement in perfusion into the region of penumbra. This experimental model can be used to study other potential interventions such as therapeutic hypertension and hypercarbia. PMID:26157965

  7. Neurovascular complications due to the Hippocrates method for reducing anterior shoulder dislocations.

    PubMed

    Regauer, Markus; Polzer, Hans; Mutschler, Wolf

    2014-01-18

    In spite of the fact that the Hippocrates method hardly has been evaluated in a scientific manner and numerous associated iatrogenic complications have been reported, this method remains to be one of the most common techniques for reducing anterior shoulder dislocations. We report the case of a 69-year-old farmer under coumarin anticoagulant therapy who sustained acute first time anterior dislocation of his dominant right shoulder. By using the Hippocrates method with the patient under general anaesthesia, the brachial vein was injured and an increasing hematoma subsequently caused brachial plexus paresis by pressure. After surgery for decompression and vascular suturing, symptoms declined rapidly, but brachial plexus paresis still was not fully reversible after 3 mo of follow-up. The hazardousness of using the Hippocrates method can be explained by traction on the outstretched arm with force of the operator's body weight, direct trauma to the axillary region by the physician's heel, and the topographic relations of neurovascular structures and the dislocated humeral head. As there is a variety of alternative reduction techniques which have been evaluated scientifically and proofed to be safe, we strongly caution against the use of the Hippocrates method as a first line technique for reducing anterior shoulder dislocations, especially in elder patients with fragile vessels or under anticoagulant therapy, and recommend the scapular manipulation technique or the Milch technique, for example, as a first choice.

  8. A dynamic model of neurovascular coupling: implications for blood vessel dilation and constriction.

    PubMed

    Zheng, Ying; Pan, Yi; Harris, Sam; Billings, Steve; Coca, Daniel; Berwick, Jason; Jones, Myles; Kennerley, Aneurin; Johnston, David; Martin, Chris; Devonshire, Ian M; Mayhew, John

    2010-09-01

    Neurovascular coupling in response to stimulation of the rat barrel cortex was investigated using concurrent multichannel electrophysiology and laser Doppler flowmetry. The data were used to build a linear dynamic model relating neural activity to blood flow. Local field potential time series were subject to current source density analysis, and the time series of a layer IV sink of the barrel cortex was used as the input to the model. The model output was the time series of the changes in regional cerebral blood flow (CBF). We show that this model can provide excellent fit of the CBF responses for stimulus durations of up to 16 s. The structure of the model consisted of two coupled components representing vascular dilation and constriction. The complex temporal characteristics of the CBF time series were reproduced by the relatively simple balance of these two components. We show that the impulse response obtained under the 16-s duration stimulation condition generalised to provide a good prediction to the data from the shorter duration stimulation conditions. Furthermore, by optimising three out of the total of nine model parameters, the variability in the data can be well accounted for over a wide range of stimulus conditions. By establishing linearity, classic system analysis methods can be used to generate and explore a range of equivalent model structures (e.g., feed-forward or feedback) to guide the experimental investigation of the control of vascular dilation and constriction following stimulation. Copyright (c) 2010 Elsevier Inc. All rights reserved.

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

    PubMed

    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

    2015-09-01

    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.

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

    PubMed Central

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

    2013-01-01

    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

  11. Ectopic vesicular neurotransmitter release along sensory axons mediates neurovascular coupling via glial calcium signaling.

    PubMed

    Thyssen, Anne; Hirnet, Daniela; Wolburg, Hartwig; Schmalzing, Günther; Deitmer, Joachim W; Lohr, Christian

    2010-08-24

    Neurotransmitter release generally is considered to occur at active zones of synapses, and ectopic release of neurotransmitters has been demonstrated in a few instances. However, the mechanism of ectopic neurotransmitter release is poorly understood. We took advantage of the intimate morphological and functional proximity of olfactory receptor axons and specialized glial cells, olfactory ensheathing cells (OECs), to study ectopic neurotransmitter release. Axonal stimulation evoked purinergic and glutamatergic Ca(2+) responses in OECs, indicating ATP and glutamate release. In axons expressing synapto-pHluorin, stimulation evoked an increase in synapto-pHluorin fluorescence, indicative of vesicle fusion. Transmitter release was dependent on Ca(2+) and could be inhibited by bafilomycin A1 and botulinum toxin A. Ca(2+) transients in OECs evoked by ATP, axonal stimulation, and laser photolysis of NP-EGTA resulted in constriction of adjacent blood vessels. Our results indicate that ATP and glutamate are released ectopically by vesicles along axons and mediate neurovascular coupling via glial Ca(2+) signaling.

  12. Apelin-13 protects neurovascular unit against ischemic injuries through the effects of vascular endothelial growth factor.

    PubMed

    Huang, Chuyi; Dai, Chuanfu; Gong, Kai; Zuo, Huancong; Chu, Heling

    2016-12-01

    Apelin-13 has protective effects on many neurological diseases, including cerebral ischemia. Here, we aimed to test Apelin-13's effects on ischemic neurovascular unit (NVU) injuries and investigate whether the effects were dependent on vascular endothelial growth factor (VEGF). We detected the expression of VEGF and its receptors (VEGFRs) induced by Apelin-13 injection at 1d, 3d, 7d and 14d after middle cerebral artery occlusion (MCAO). Meanwhile, we examined the effects of Apelin-13 on NVU in both in vivo and in vitro experiments as well as whether the effects were VEGF dependent by using VEGF antibody. We also assessed the related signal transduction pathways via multiple inhibitors. We demonstrated Apelin-13 highly increased VEGF and VEGFR-2 expression, not VEGFR-1. Importantly, Apelin-13 led to neurological functions improvement by associating with promotion of angiogenesis as well as reduction of neuronal death and astrocyte activation, which was markedly blocked by VEGF antibody. In cell cultures, Apelin-13 protected neurons, astrocytes and endothelial cells against oxygen-glucose deprivation (OGD) injuries. Moreover, the effect of Apelin-13 to up-regulate VEGF was suppressed by extracellular signal-regulated kinase (ERK) inhibitor U0126 and phosphatidylinositol 3'-kinase (PI3K) inhibitor LY294002. Our data suggest protective effects of Apelin-13 on ischemic NVU injuries are highly associated with the increase of VEGF binding to VEGFR-2, possibly acting through activation of ERK and PI3K/Akt pathways. Copyright © 2016. Published by Elsevier Ltd.

  13. Reliability of the nitroglycerin provocative test in the diagnosis of neurovascular headaches.

    PubMed

    Sances, G; Tassorelli, C; Pucci, E; Ghiotto, N; Sandrini, G; Nappi, G

    2004-02-01

    Nitroglycerin administration provokes spontaneous-like migraine attacks in migraine and cluster headache (CH) patients. Nitroglycerin-induced migraine-like headache has been used as an experimental model of migraine. In this paper, we evaluate the possibility of using the nitroglycerin provocative test (NPT) as a supportive measure in the diagnosis of primary neurovascular headaches by assessing its reliability on a large population and adopting strict criteria for rating the response as positive or negative. Our population consisted of 197 migraineurs, 42 subjects suffering from cluster headache and 53 healthy controls. In migraine without aura, the test sensitivity was 82.1%, specificity 96.2% and accuracy 85.5%, while in subjects suffering from migraine with aura, the reliability of the NPT was less satisfactory (sensitivity 13.6%, specificity 96.2% and accuracy 72%). In CH patients tested during the active phase of the disease the sensitivity was 80.6%, specificity 100% and accuracy 92.9%. NPT is an easy, low-cost and reliable method for supporting the diagnosis of migraine without aura and cluster headache.

  14. Molecular contributions to neurovascular unit dysfunctions after brain injuries: lessons for target-specific drug development

    PubMed Central

    Jullienne, Amandine; Badaut, Jérôme

    2014-01-01

    The revised ‘expanded’ neurovascular unit (eNVU) is a physiological and functional unit encompassing endothelial cells, pericytes, smooth muscle cells, astrocytes and neurons. Ischemic stroke and traumatic brain injury are acute brain injuries directly affecting the eNVU with secondary damage, such as blood–brain barrier (BBB) disruption, edema formation and hypoperfusion. BBB dysfunctions are observed at an early postinjury time point, and are associated with eNVU activation of proteases, such as tissue plasminogen activator and matrix metalloproteinases. BBB opening is accompanied by edema formation using astrocytic AQP4 as a key protein regulating water movement. Finally, nitric oxide dysfunction plays a dual role in association with BBB injury and dysregulation of cerebral blood flow. These mechanisms are discussed including all targets of eNVU encompassing endothelium, glial cells and neurons, as well as larger blood vessels with smooth muscle. In fact, the feeding blood vessels should also be considered to treat stroke and traumatic brain injury. This review underlines the importance of the eNVU in drug development aimed at improving clinical outcome after stroke and traumatic brain injury. PMID:24489483

  15. Clavicle fracture with thoracic penetration and hemopneumothorax but without neurovascular compromise.

    PubMed

    Tjoumakaris, Fotios P; Matzon, Jonas L; Williams, Gerald R

    2011-10-05

    Clavicle fractures are rarely associated with more severe neurologic or vascular injuries. When these associated injuries are encountered, prompt recognition and treatment are paramount to optimize outcome. The majority of fractures that result in neurovascular compromise are from high-energy trauma; however, a high index of suspicion should be present in all cases as low-energy trauma can also result in more catastrophic injury. This article describes a case of a low-energy clavicle fracture in a 28-year-old woman that resulted in intrathoracic penetration of the fracture fragment with hemopneumothorax. The patient underwent successful chest tube placement and open reduction and internal fixation of the fracture. A multidisciplinary team was used during surgery, including cardiothoracic, trauma, and orthopedic surgery. Two years postoperatively, the patient was back to normal activities with no neurologic, pulmonary, or vascular sequelae. This case highlights the importance of a comprehensive physical examination and inspection of all radiographs so that associated injuries are not missed.

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

    PubMed Central

    Simon, Matthew J.; Iliff, Jeffrey J.

    2015-01-01

    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. PMID:26499397

  17. Pivotal role for beta-1 integrin in neurovascular remodelling after ischemic stroke.

    PubMed

    Lathia, Justin D; Chigurupati, Srinivasulu; Thundyil, John; Selvaraj, Pradeep K; Mughal, Mohamed R; Woodruff, Trent M; Chan, Sic L; Karamyan, Vardan T; Mattson, Mark P; Arumugam, Thiruma V

    2010-01-01

    beta1 integrin is a cell surface molecule that is critical for endothelial cell adhesion, migration and survival during angiogenesis. In the present study we employed in vivo and in vitro models to elucidate the role of beta1 integrin in vascular remodelling and stroke outcomes. At 24 h after cerebral ischemia and reperfusion (I/R), the ischemic cortex (ipsilateral area) exhibited modest beta1 integrin immunoreactivity and a robust increase was observed at 72 h. Double-label immunohistochemical analysis for beta1 integrin with neuronal (NeuN), microglial (Iba-1), astrocyte (GFAP), progenitor cell (Ng2) and blood vessel (collagen 4) markers showed that beta1 integrin expression only localized to blood vessels. In vitro studies using cultured endothelial cells and a beta1 integrin blocking antibody confirmed that beta1 integrin is required for endothelial cell migration, proliferation and blood vessel formation. In vivo studies in the cerebral I/R model using the beta1 integrin blocking antibody further confirmed that beta1 integrin signaling is involved in vascular formation and recovery following ischemic stroke. Finally, we found that beta1 integrin is critically involved in functional deficits and survival after a stroke. These results suggest that beta1 integrin plays important roles in neurovascular remodelling and functional outcomes following stroke, and that targeting the beta1 integrin signalling may provide a novel strategy for modulating angiogenesis in ischemic stroke and other pathological conditions.

  18. Neurovascular complications due to the Hippocrates method for reducing anterior shoulder dislocations

    PubMed Central

    Regauer, Markus; Polzer, Hans; Mutschler, Wolf

    2014-01-01

    In spite of the fact that the Hippocrates method hardly has been evaluated in a scientific manner and numerous associated iatrogenic complications have been reported, this method remains to be one of the most common techniques for reducing anterior shoulder dislocations. We report the case of a 69-year-old farmer under coumarin anticoagulant therapy who sustained acute first time anterior dislocation of his dominant right shoulder. By using the Hippocrates method with the patient under general anaesthesia, the brachial vein was injured and an increasing hematoma subsequently caused brachial plexus paresis by pressure. After surgery for decompression and vascular suturing, symptoms declined rapidly, but brachial plexus paresis still was not fully reversible after 3 mo of follow-up. The hazardousness of using the Hippocrates method can be explained by traction on the outstretched arm with force of the operator’s body weight, direct trauma to the axillary region by the physician’s heel, and the topographic relations of neurovascular structures and the dislocated humeral head. As there is a variety of alternative reduction techniques which have been evaluated scientifically and proofed to be safe, we strongly caution against the use of the Hippocrates method as a first line technique for reducing anterior shoulder dislocations, especially in elder patients with fragile vessels or under anticoagulant therapy, and recommend the scapular manipulation technique or the Milch technique, for example, as a first choice. PMID:24649415

  19. Aging Exacerbates Obesity-induced Cerebromicrovascular Rarefaction, Neurovascular Uncoupling, and Cognitive Decline in Mice

    PubMed Central

    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.; Csiszar, Anna

    2014-01-01

    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

  20. Identification of neurovascular changes associated with cerebral amyloid angiopathy from subject-specific hemodynamic response functions.

    PubMed

    Williams, Rebecca J; Goodyear, Bradley G; Peca, Stefano; McCreary, Cheryl R; Frayne, Richard; Smith, Eric E; Pike, G Bruce

    2017-01-01

    Cerebral amyloid angiopathy (CAA) is a small-vessel disease preferentially affecting posterior brain regions. Recent evidence has demonstrated the efficacy of functional MRI in detecting CAA-related neurovascular injury, however, it is unknown whether such perturbations are associated with changes in the hemodynamic response function (HRF). Here we estimated HRFs from two different brain regions from block design activation data, in light of recent findings demonstrating how block designs can accurately reflect HRF parameter estimates while maximizing signal detection. Patients with a diagnosis of probable CAA and healthy controls performed motor and visual stimulation tasks. Time-to-peak (TTP), full-width at half-maximum (FWHM), and area under the curve (AUC) of the estimated HRFs were compared between groups and to MRI features associated with CAA including cerebral microbleed (CMB) count. Motor HRFs in CAA patients showed significantly wider FWHM ( P = 0.006) and delayed TTP ( P = 0.03) compared to controls. In the patient group, visual HRF FWHM was positively associated with CMB count ( P = 0.03). These findings indicate that hemodynamic abnormalities in patients with CAA may be reflected in HRFs estimated from block designs across different brain regions. Moreover, visual FWHM may be linked to structural MR indications associated with CAA.

  1. CD44 expression in endothelial colony-forming cells regulates neurovascular trophic effect

    PubMed Central

    Sakimoto, Susumu; Marchetti, Valentina; Aguilar, Edith; Lee, Kelsey; Usui, Yoshihiko; Bucher, Felicitas; Trombley, Jennifer K.; Fallon, Regis; Wagey, Ravenska; Peters, Carrie; Scheppke, Elizabeth L.; Westenskow, Peter D.

    2017-01-01

    Vascular abnormalities are a common component of eye diseases that often lead to vision loss. Vaso-obliteration is associated with inherited retinal degenerations, since photoreceptor atrophy lowers local metabolic demands and vascular support to those regions is no longer required. Given the degree of neurovascular crosstalk in the retina, it may be possible to use one cell type to rescue another cell type in the face of severe stress, such as hypoxia or genetically encoded cell-specific degenerations. Here, we show that intravitreally injected human endothelial colony-forming cells (ECFCs) that can be isolated and differentiated from cord blood in xeno-free media collect in the vitreous cavity and rescue vaso-obliteration and neurodegeneration in animal models of retinal disease. Furthermore, we determined that a subset of the ECFCs was more effective at anatomically and functionally preventing retinopathy; these cells expressed high levels of CD44, the hyaluronic acid receptor, and IGFBPs (insulin-like growth factor–binding proteins). Injection of cultured media from ECFCs or only recombinant human IGFBPs also rescued the ischemia phenotype. These results help us to understand the mechanism of ECFC-based therapies for ischemic insults and retinal neurodegenerative diseases. PMID:28138561

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

    PubMed

    Lecrux, C; Hamel, E

    2016-10-05

    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'.

  3. Cerebral abscess after neuro-vascular embolization: Own experience and review of the literature.

    PubMed

    Cossu, G; Daniel, R T; Messerer, M

    2017-03-01

    Cerebral abscesses are a rare complication after therapeutic neuro-endovascular procedures. The aim of this article is to report a case of cerebral abscess after the endovascular embolization of a cerebral aneurysm and to discuss and review all the cases of cerebral abscess secondary to neurovascular embolization described in the literature up to now. A 40-year-old female patient was treated using an endovascular embolization for a ruptured aneurysm of the basilar artery tip. After 2 months she presented with a cerebellar abscess. Antibiotic therapy was started, and a surgical drainage of the collection was performed, with a favorable postoperative outcome. Twelve other cases were reported in the literature, in five cases secondary to the treatment of a cerebral aneurysm, in six cases secondary to a cerebral arterio-venous malformation (AVM) and in one case secondary to a dural arterio-venous fistula (DAVF). The pathophysiology and risk factors of cerebral abscess formation are discussed in detail. The risk of cerebral abscesses after neuro-endovascular embolization is not negligible, and a growing number of patients affected by this complication may be expected in the near future because of the spreading of neuro-endovascular techniques. The role of prophylactic antibiotic therapy in specific subgroups of patients is still debated.

  4. Exhaustive exercise attenuates the neurovascular coupling by blunting the pressor response to visual stimulation.

    PubMed

    Yamaguchi, Yuji; Ikemura, Tsukasa; Hayashi, Naoyuki

    2015-01-01

    Neurovascular coupling (NVC) is assessed as an increase response to visual stimulation, and is monitored by blood flow of the posterior cerebral artery (PCA). To investigate whether exhaustive exercise modifies NVC, and more specifically, the relative contributions of vasodilatation in the downstream of PCA and the pressor response on NVC, we measured blood flow velocity in the PCA (PCAv) in 13 males using transcranial Doppler ultrasound flowmetry during a leg-cycle exercise at 75% of maximal heart rate until exhaustion. NVC was estimated as the relative change in PCAv from the mean value obtained during 20-s with the eyes closed to the peak value obtained during 40-s of visual stimulation involving looking at a reversed checkerboard. Conductance index (CI) was calculated by dividing PCAv by mean arterial pressure (MAP) to evaluate the vasodilatation. At exhaustion, PCAv was significantly decreased relative to baseline measurements, and the PCAv response to visual stimulation significantly decreased. Compared to baseline, exhaustive exercise significantly suppressed the increase in MAP to visual stimulation, while the CI response did not significantly change by the exercise. These results suggest that exhaustive exercise attenuates the magnitude of NVC by blunting the pressor response to visual stimulation.

  5. Micro Vascular Plug (MVP)-assisted vessel occlusion in neurovascular pathologies: technical results and initial clinical experience.

    PubMed

    Beaty, Narlin B; Jindal, Gaurav; Gandhi, Dheeraj

    2015-10-01

    Deconstructive approaches may be necessary to treat a variety of neurovascular pathologies. Recently, a new device has become available for endovascular arterial occlusion that may have unique applications in neurovascular disease. The Micro Vascular Plug (MVP, Reverse Medical, Irvine, California, USA) has been designed for vessel occlusion through targeted embolization. To report the results from our initial experience with eight consecutive patients in whom the MVP was used to achieve endovascular occlusion of an artery in the head and neck. Eight consecutive patients treated over a nine-month period were included. The patients' radiographic and electronic medical records were retrospectively reviewed. Specifically demographic information, clinical indication, site of arterial occlusion, size of MVP, time to vessel occlusion, clinical complications, use of other secondary embolic agents, and clinical outcome were recorded. Follow-up information when available is presented. The MVP was used in eight patients for the treatment of neurovascular disease. Indications for treatment included post-traumatic head/neck bleeding (n=3), carotid-cavernous fistula (1), vertebral-vertebral fistula (1), giant fusiform vertebral aneurysm (1), stump-emboli after carotid dissection (1), and iatrogenic vertebral artery penetrating injury (1). One device was used in five patients, two in two patients, and one patient with extensive vertebral-vertebral venous fistula required three plugs to effectively trap the fistula from proximal and distal aspects. Vessel occlusion was obtained in <2 min in each case and there were no procedural complications. Four patients were followed up and no incidence of plug migration or vessel recanalization was seen. To the best of our knowledge, this is the first series reporting the use of MVP in neurovascular disease. Use of this device may be associated with shorter procedural times and cost savings in comparison with the use of microcoils for

  6. Inflammatory Bowel Disease

    MedlinePlus

    ... work? How does inflammatory bowel disease interfere with digestion? Who gets inflammatory bowel disease? How is inflammatory ... top How does inflammatory bowel disease interfere with digestion? When the small intestine becomes inflamed, as in ...

  7. 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

  8. 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.

  9. Central cardiovascular circuits contribute to the neurovascular dysfunction in angiotensin II hypertension.

    PubMed

    Capone, Carmen; Faraco, Giuseppe; Peterson, Jeffrey R; Coleman, Christal; Anrather, Josef; Milner, Teresa A; Pickel, Virginia M; Davisson, Robin L; Iadecola, Costantino

    2012-04-04

    Hypertension, a powerful risk factor for stroke and dementia, has damaging effects on the brain and its vessels. In particular, hypertension alters vital cerebrovascular control mechanisms linking neural activity to cerebral perfusion. In experimental models of slow-developing hypertension, free radical signaling in the subfornical organ (SFO), one of the forebrain circumventricular organs, is critical for the hormonal release and sympathetic activation driving the elevation in arterial pressure. However, the contribution of this central mechanism to the cerebrovascular alterations induced by hypertension remains uncertain. We tested the hypothesis that free radical production in the SFO is involved in the alterations in cerebrovascular regulation produced by hypertension. In a mouse model of gradual hypertension induced by chronic administration of subpressor doses of angiotensin II (AngII), suppression of free radicals in the SFO by overexpression of CuZn-superoxide dismutase (CuZnSOD) prevented the alteration in neurovascular coupling and endothelium-dependent responses in somatosensory cortex induced by hypertension. The SFO mediates the dysfunction via two signaling pathways. One involves SFO-dependent activation of the paraventricular hypothalamic nucleus, elevations in plasma vasopressin, upregulation of endothelin-1 in cerebral resistance arterioles and activation of endothelin type A receptors. The other pathway depends on activation of cerebrovascular AngII type 1 (AT1) receptors by AngII. Both pathways mediate vasomotor dysfunction by inducing vascular oxidative stress. The findings implicate for the first time the SFO and its efferent hypothalamic pathways in the cerebrovascular alterations induced by AngII, and identify vasopressin and endothelin-1 as potential therapeutic targets to counteract the devastating effects of hypertension on the brain.

  10. Evidence for impaired neurovascular transmission in a murine model of Duchenne muscular dystrophy

    PubMed Central

    Bagher, Pooneh; Duan, Dongsheng

    2011-01-01

    Duchenne muscular dystrophy (DMD) is a muscle-wasting disease caused by mutations in the dystrophin gene. Little is known about how blood flow control is affected in arteriolar networks supplying dystrophic muscle. We tested the hypothesis that mdx mice, a murine model for DMD, exhibit defects in arteriolar vasomotor control. The cremaster muscle was prepared for intravital microscopy in pentobarbital sodium-anesthetized mdx and C57BL/10 control mice (n ≥ 5 per group). Spontaneous vasomotor tone increased similarly with arteriolar branch order in both mdx and C57BL/10 mice [pooled values: first order (1A), 6%; second order (2A), 56%; and third order (3A), 61%] with no difference in maximal diameters between groups measured during equilibration with topical 10 μM sodium nitroprusside (pooled values: 1A, 70 ± 3 μm; 2A, 31 ± 3 μm; and 3A, 19 ± 3 μm). Concentration-response curves to acetylcholine (ACh) and norepinephrine added to the superfusion solution did not differ between mdx and C57BL/10 mice, nor did constriction to elevated (21%) oxygen. In response to local stimulation from a micropipette, conducted vasodilation to ACh and conducted vasoconstriction to KCl were also not different between groups; however, constriction decayed with distance (P < 0.05) whereas dilation did not. Remarkably, arteriolar constriction to perivascular nerve stimulation (PNS) at 2, 4, and 8 Hz was reduced by ∼25–30% in mdx mice compared with C57BL/10 mice (P < 0.05). With intact arteriolar reactivity to agonists, attenuated constriction to perivascular nerve stimulation indicates impaired neurovascular transmission in arterioles controlling blood flow in mdx mice. PMID:21109597

  11. Design of catheter radio frequency coils using coaxial transmission line resonators for interventional neurovascular MR imaging

    PubMed Central

    Martin, Alastair; Jordan, Caroline; Lillaney, Prasheel; Losey, Aaron; Pang, Yong; Hu, Jeffrey; Wilson, Mark; Cooke, Daniel; Hetts, Steven W.

    2017-01-01

    Background It is technically challenging to design compact yet sensitive miniature catheter radio frequency (RF) coils for endovascular interventional MR imaging. Methods In this work, a new design method for catheter RF coils is proposed based on the coaxial transmission line resonator (TLR) technique. Due to its distributed circuit, the TLR catheter coil does not need any lumped capacitors to support its resonance, which simplifies the practical design and construction and provides a straightforward technique for designing miniature catheter-mounted imaging coils that are appropriate for interventional neurovascular procedures. The outer conductor of the TLR serves as an RF shield, which prevents electromagnetic energy loss, and improves coil Q factors. It also minimizes interaction with surrounding tissues and signal losses along the catheter coil. To investigate the technique, a prototype catheter coil was built using the proposed coaxial TLR technique and evaluated with standard RF testing and measurement methods and MR imaging experiments. Numerical simulation was carried out to assess the RF electromagnetic field behavior of the proposed TLR catheter coil and the conventional lumped-element catheter coil. Results The proposed TLR catheter coil was successfully tuned to 64 MHz for proton imaging at 1.5 T. B1 fields were numerically calculated, showing improved magnetic field intensity of the TLR catheter coil over the conventional lumped-element catheter coil. MR images were acquired from a dedicated vascular phantom using the TLR catheter coil and also the system body coil. The TLR catheter coil is able to provide a significant signal-to-noise ratio (SNR) increase (a factor of 200 to 300) over its imaging volume relative to the body coil. Conclusions Catheter imaging RF coil design using the proposed coaxial TLR technique is feasible and advantageous in endovascular interventional MR imaging applications. PMID:28516044

  12. Erythropoietin promotes neurovascular remodeling and long-term functional recovery in rats following traumatic brain injury

    PubMed Central

    Ning, Ruizhuo; Xiong, Ye; Mahmood, Asim; Zhang, Yanlu; Meng, Yuling; Qu, Changsheng; Chopp, Michael

    2011-01-01

    Erythropoietin (EPO) improves functional recovery after traumatic brain injury (TBI). This study was designed to investigate long-term (3 mo) effects of EPO on brain remodeling and functional recovery in rats after TBI. Young male Wistar rats were subjected to unilateral controlled cortical impact injury. TBI rats were divided into the following groups: 1) Saline group (n = 7); 2) EPO-6h group (n = 8); and 3) EPO-24h group (n = 8). EPO (5,000 U/kg in saline) was administered intraperitoneally at 6 h, and 1 and 2 days (EPO-6h group) or at 1, 2, and 3 days (EPO-24h group) post injury. Neurological function was assessed using a modified neurological severity score, footfault and Morris water maze tests. Animals were sacrificed at 3 mos after injury and brain sections stained for immunohistochemical analyses. Compared to the saline, EPO-6h treatment significantly reduced cortical lesion volume, while EPO-24h therapy did not affect the lesion volume (P<0.05). Both the EPO-6h and EPO-24h treatments significantly reduced hippocampal cell loss (P<0.05), promoted angiogenesis (P<0.05) and increased endogenous cellular proliferation (BrdU-positive cells) in the injury boundary zone and hippocampus (P<0.05) compared to saline controls. Significantly enhanced neurogenesis (BrdU/NeuN-positive cells) was seen in the dentate gyrus of both EPO groups compared to the saline group. Both EPO treatments significantly improved long-term sensorimotor and cognitive functional recovery after TBI. In conclusion, the beneficial effects of posttraumatic EPO treatment on injured brain persisted for at least 3 months. The long-term improvement in functional outcome may in part be related to the neurovascular remodeling induced by EPO. PMID:21295557

  13. Impaired neurovascular unit function contributes to persistent symptoms after concussion: a pilot study.

    PubMed

    Bartnik-Olson, Brenda L; Holshouser, Barbara; Wang, Harrison; Grube, Matthew; Tong, Karen; Wong, Valarie; Ashwal, Stephen

    2014-09-01

    Research shows that approximately 14% of school age children with mild traumatic brain injury (TBI) including sports-related concussions (SRCs) remain symptomatic three months after injury. Advanced imaging studies early after injury have shown evidence of axonal damage, reduced N-acetyl aspartate (NAA) and impaired cerebral blood flow (CBF) in individuals with mild TBI. This study was undertaken to determine whether these techniques can provide valuable information in pediatric SRC patients with persistent post-concussive symptoms. Fifteen pediatric subjects ages 8 to 17 years with persistent post-concussive symptoms were evaluated using perfusion-weighted imaging (PWI), three-dimensional (3D) magnetic resonance spectroscopic imaging, and diffusion tensor imaging (DTI) three to 12 months post-SRC. Data were compared with 15 demographically similar (age, gender, and body mass index) controls. In the bilateral thalami, SRC patients showed reduced CBF (p=0.02 and p=0.02) and relative cerebral blood volume (CBV; p=0.05 and p=0.03), compared with controls. NAA/creatine (Cr) and NAA/choline (Cho) ratios were reduced in the corpus callosum (p=0.003; p=0.05) and parietal white matter (p<0.001; p=0.006) of SRC subjects, compared with controls. Significant differences in DTI metrics differentiated patients with cognitive symptoms, compared with those without cognitive symptoms and controls. Advanced imaging methods detect a spectrum of injury including impaired axonal function, neuronal metabolism and perfusion, suggesting involvement of the neurovascular unit in the presence of persistent symptoms in pediatric SRC patients.

  14. 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

  15. 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. © The Author 2014. Published by Oxford University Press on behalf of The Gerontological Society of America. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.

  16. Computed tomographic evaluation of dynamic alteration of the canine lumbosacral intervertebral neurovascular foramina.

    PubMed

    Worth, Andrew J; Hartman, Angela; Bridges, Janis P; Jones, Boyd R; Mayhew, Joe I G

    2017-02-01

    To develop a computed tomographic (CT) method to measure the volume of the lumbosacral intervertebral neurovascular foramina (IVF) in dogs, and determine the effect of the range of motion of the lumbosacral (LS) junction on this measurement in German shepherd dogs (GSDs) with degenerative lumbosacral stenosis (DLSS) compared to unaffected controls. In vivo analysis and retrospective case series. Twenty-four working Police GSDs, 12 diagnosed with DLSS and 12 unaffected by DLSS were compared to 10 Greyhounds without DLSS. Three-dimensional renderings of CT data were used to measure the lumbosacral foraminal volume of dogs positioned in dorsal recumbency with the LS junction alternately positioned in extension, neutral position, and flexion. Volumetric analysis of the IVF was found repeatable for the extended and neutral positions (interclass correlation coefficient of 0.89 and 0.8, respectively). The mean lumbosacral IVF volume was decreased by 74% between LS flexion and extension in Greyhounds, compared to 79 and 85% reductions in GSDs unaffected and affected by DLSS, respectively. The lumbosacral IVF volume was decreased by 23% when comparing extended to neutral LS positions in Greyhounds, 29% in unaffected GSDs, and 31% in affected GSDs. IVF volumes were smaller in affected GSDs compared to unaffected GSDs (P < .05) and Greyhounds (P < .01). Positioning the LS junction in full extension decreases the volume of the lumbosacral IVF. This dynamic narrowing was more pronounced in GSDs with signs of DLSS than in GSDs not overtly affected by DLSS. © 2017 The American College of Veterinary Surgeons.

  17. Erythropoietin promotes neurovascular remodeling and long-term functional recovery in rats following traumatic brain injury.

    PubMed

    Ning, Ruizhuo; Xiong, Ye; Mahmood, Asim; Zhang, Yanlu; Meng, Yuling; Qu, Changsheng; Chopp, Michael

    2011-04-12

    Erythropoietin (EPO) improves functional recovery after traumatic brain injury (TBI). This study was designed to investigate long-term (3 months) effects of EPO on brain remodeling and functional recovery in rats after TBI. Young male Wistar rats were subjected to unilateral controlled cortical impact injury. TBI rats were divided into the following groups: (1) saline group (n=7); (2) EPO-6h group (n=8); and (3) EPO-24h group (n=8). EPO (5000 U/kg in saline) was administered intraperitoneally at 6h, and 1 and 2 days (EPO-6h group) or at 1, 2, and 3 days (EPO-24h group) postinjury. Neurological function was assessed using a modified neurological severity score, footfault and Morris water maze tests. Animals were sacrificed at 3 months after injury and brain sections were stained for immunohistochemical analyses. Compared to the saline, EPO-6h treatment significantly reduced cortical lesion volume, while EPO-24h therapy did not affect the lesion volume (P<0.05). Both the EPO-6h and EPO-24h treatments significantly reduced hippocampal cell loss (P<0.05), promoted angiogenesis (P<0.05) and increased endogenous cellular proliferation (BrdU-positive cells) in the injury boundary zone and hippocampus (P<0.05) compared to saline controls. Significantly enhanced neurogenesis (BrdU/NeuN-positive cells) was seen in the dentate gyrus of both EPO groups compared to the saline group. Both EPO treatments significantly improved long-term sensorimotor and cognitive functional recovery after TBI. In conclusion, the beneficial effects of posttraumatic EPO treatment on injured brain persisted for at least 3 months. The long-term improvement in functional outcome may in part be related to the neurovascular remodeling induced by EPO.

  18. Design of catheter radio frequency coils using coaxial transmission line resonators for interventional neurovascular MR imaging.

    PubMed

    Zhang, Xiaoliang; Martin, Alastair; Jordan, Caroline; Lillaney, Prasheel; Losey, Aaron; Pang, Yong; Hu, Jeffrey; Wilson, Mark; Cooke, Daniel; Hetts, Steven W

    2017-04-01

    It is technically challenging to design compact yet sensitive miniature catheter radio frequency (RF) coils for endovascular interventional MR imaging. In this work, a new design method for catheter RF coils is proposed based on the coaxial transmission line resonator (TLR) technique. Due to its distributed circuit, the TLR catheter coil does not need any lumped capacitors to support its resonance, which simplifies the practical design and construction and provides a straightforward technique for designing miniature catheter-mounted imaging coils that are appropriate for interventional neurovascular procedures. The outer conductor of the TLR serves as an RF shield, which prevents electromagnetic energy loss, and improves coil Q factors. It also minimizes interaction with surrounding tissues and signal losses along the catheter coil. To investigate the technique, a prototype catheter coil was built using the proposed coaxial TLR technique and evaluated with standard RF testing and measurement methods and MR imaging experiments. Numerical simulation was carried out to assess the RF electromagnetic field behavior of the proposed TLR catheter coil and the conventional lumped-element catheter coil. The proposed TLR catheter coil was successfully tuned to 64 MHz for proton imaging at 1.5 T. B1 fields were numerically calculated, showing improved magnetic field intensity of the TLR catheter coil over the conventional lumped-element catheter coil. MR images were acquired from a dedicated vascular phantom using the TLR catheter coil and also the system body coil. The TLR catheter coil is able to provide a significant signal-to-noise ratio (SNR) increase (a factor of 200 to 300) over its imaging volume relative to the body coil. Catheter imaging RF coil design using the proposed coaxial TLR technique is feasible and advantageous in endovascular interventional MR imaging applications.

  19. Remission of neurovascular conflicts in the cerebellopontine angle in interventional neuroradiology.

    PubMed

    Li, Chuanhui; Li, Youxiang; Jiang, Chuhan; Wu, Zhongxue; Wang, Yang; Yang, Xinjian

    2016-01-01

    To investigate the efficacy of endovascular treatment (EVT) for neurovascular conflicts (NVCs) in the cerebellopontine angle (CPA) caused by intracranial aneurysms (IAs) and intracranial arteriovenous malformations (AVMs), including trigeminal neuralgia, hemifacial spasm, and glossopharyngeal neuralgia. From January 2010 to January 2014, 14 consecutive patients presenting with three NVCs caused by IAs or intracranial AVMs were admitted to our department. The clinical outcomes of these NVCs after EVT were retrospectively analyzed. For four patients with IAs, angiographic follow-up confirmed total occlusion of the lesion in all, and the clinical outcomes of NVC were as follows: gradual relief in two (50%), transient partial relief but recurrence in one (25%), and no palliative effect in one (25%). For the 10 patients with intracranial AVMs, one (10%) experienced transient relief of NVC after angiogram examination (no EVT was performed). Of the other nine patients who received EVT, angiographic follow-up was obtained in seven (70%), demonstrating total obliteration of the lesion in three (30%), subtotal obliteration in two (20%), and partial obliteration in two (20%). Clinical outcomes included immediate relief of NVCs after single EVT in two cases (20%), gradual relief after single EVT in five (50%, one of them experienced transient aggravation), and complete relief after two sessions of EVT in two (20%). Complications of transient cranial nerve paresis related to EVT occurred in two cases (20%) with intracranial AVMs. In all, complete lasting relief of the NVCs was obtained finally in 11 cases (78.6%). EVT is a feasible and less invasive approach for relief of NVCs in the CPA caused by IA or intracranial AVM and could be considered as a therapeutic option in these situations. Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://www.bmj.com/company/products-services/rights-and-licensing/

  20. 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

  1. Diet in inflammatory bowel disease.

    PubMed

    Issa, Mazen; Saeian, Kia

    2011-04-01

    The past few years have seen a great expansion of our understanding of the pathophysiology of inflammatory bowel disease (IBD). Much of the progress has been on the genetic basis of disease as well as the role of microbiota. These findings have magnified the role of the environmental component of this rather complex process. Recent advances have emanated from more in-depth, comprehensive, and at times nontraditional inquiry into the potential role of diet through its anti-inflammatory properties and modulation of microbiota. This concise review focuses on the novel aspects of research related to the potential role of diet in IBD.

  2. Moderate dietary restriction reduces p53-mediated neurovascular damage and microglia activation after hypoxic ischemia in neonatal brain.

    PubMed

    Tu, Yi-Fang; Lu, Pei-Jung; Huang, Chao-Ching; Ho, Chien-Jung; Chou, Ya-Ping

    2012-02-01

    Neurovascular damage, including neuronal apoptosis and blood-brain barrier (BBB) damage, and microglia activation account for the hypoxic-ischemia (HI) susceptibility in neonatal brain. The p53 upregulation is involved in apoptosis, endothelial cell damage, and microglia activation. We hypothesized that underweight induced by dietary restriction (DR) protects against HI in rat pups by attenuating p53-mediated neurovascular damage. Male rat pups were grouped as normal litter (NL) size (12 pups/dam), DR (18 pups/dam), and extreme DR (24 pups/dam) from postnatal day 1 and subjected to HI on postnatal day 7. Immunohistochemistry and immunoblotting were used to determine p53, phospho-murine double minute-2, caspases, BBB damage and microglia activation, and immunofluorescence to determine the cellular distribution of p53. Pharmacological approaches were used to regulate p53. The NL, DR, and extreme DR pups had similar TUNEL-positive cells and caspases on postnatal day 7 and comparable learning performance at adulthood. After HI, the DR-HI, but not extreme DR-HI, pups had significantly lower p53, higher phospho-murine double minute-2, lower cleaved caspases, less BBB damage and microglia activation, and less brain volume loss than NL-HI pups. In NL-HI pups, p53 expression was located mainly in the neurons, endothelial cells, and microglia. The p53 blockage by pifithrin-α in NL-HI pups decreased apoptosis, BBB damage, and microglia activation, and was neuroprotective. In contrast, upregulating p53 by nutlin-3 in DR-HI pups increased apoptosis, BBB damage, and microglia activation, and worsened brain damage. Moderate DR, but not extreme DR, reduces p53-mediated neurovascular damage after HI and confers long-term protection in neonatal brain.

  3. System for the measurement of blood flow and oxygenation in tissue applied to neurovascular coupling in brain

    NASA Astrophysics Data System (ADS)

    Kohl-Bareis, Matthias; Leithner, Christoph; Sellien, Heike; Guertler, Roland; Geraskin, Dmitri; Rohrer, Benjamin; Royl, Georg; Dirnagl, Ulrich; Lindauer, Ute

    2005-08-01

    We designed a system incorporating the independent measurement of blood flow and oxygenation of haemoglobin. This is based on laser-Doppler spectroscopy with NIR wavelengths which gives a measure for changes in blood flow or tissue perfusion as well as reflectance spectroscopy in the VIS wavelength range for the calculation of the oxygenated and deoxygenated haemoglobin components. The co-registration of these parameters allows the neurovascular coupling of brain to be investigated. This is demonstrated by recording functional activity of the rat brain during electrical forepaw stimulation.

  4. Neurovascular sparing vas clipping: last option for recurrent epididymo-orchitis in urethrovasal reflux due to urethral injury.

    PubMed

    Khorramirouz, Reza; Mozafarpour, Sarah; Mohseni, Mohammad Javad; Kajbafzadeh, Abdol-Mohammad

    2014-05-01

    Acute scrotum is a critical clinical entity in children. This report presents a 12-year-old boy presented with recurrent epididymo-orchitis (EO) with a history of pelvic trauma and urethral disruption 10 years ago. Antegrade and retrograde studies confirmed urethrovasal reflux. The patient did not respond to prophylactic antibiotics, clean intermittent catheterization and endoscopic injection of bulking agent at the junction of the ejaculatory duct and posterior urethra. As the last option, neurovascular sparing vas clipping was performed and the patient made a full recovery. This is the first report of this technique in the treatment for recurrent EO caused by traumatic injury.

  5. Preoperative detection of the neurovascular relationship in trigeminal neuralgia using three-dimensional fast imaging employing steady-state acquisition (FIESTA) and magnetic resonance angiography (MRA).

    PubMed

    Zeng, QingShi; Zhou, Qin; Liu, ZhiLing; Li, ChuanFu; Ni, ShiLei; Xue, Feng

    2013-01-01

    Microvascular decompression is an accepted treatment for trigeminal neuralgia (TN). Preoperative identification of neurovascular compression, therefore, could aid determination of the appropriate treatment for TN. To preoperatively visualize the neurovascular relationship, three-dimensional fast imaging employing steady-state acquisition (3D FIESTA) and magnetic resonance angiography (MRA) were performed on 37 patients with TN in our study. 3D FIESTA in combination with MRA identified surgically verified neurovascular contact in 35 of 36 symptomatic nerves. The offending vessel (artery or vein) was correctly identified in 94.4% of patients, and agreement between preoperative MRI visualization and surgical findings was excellent (k=0.92; 95% confidence interval, 0.67-1.00). Thus, 3D FIESTA in combination with MRA is useful in the detection of vascular contact with the trigeminal nerve in patients with TN.

  6. Predictive value of magnetic resonance for identifying neurovascular compressions in trigeminal neuralgia.

    PubMed

    Ruiz-Juretschke, F; Guzmán-de-Villoria, J G; García-Leal, R; Sañudo, J R

    2017-05-23

    Microvascular decompression (MVD) is accepted as the only aetiological surgical treatment for refractory classic trigeminal neuralgia (TN). There is therefore increasing interest in establishing the diagnostic and prognostic value of identifying neurovascular compressions (NVC) using preoperative high-resolution three-dimensional magnetic resonance (MRI) in patients with classic TN who are candidates for surgery. This observational study includes a series of 74 consecutive patients with classic TN treated with MVD. All patients underwent a preoperative three-dimensional high-resolution MRI with DRIVE sequences to diagnose presence of NVC, as well as the degree, cause, and location of compressions. MRI results were analysed by doctors blinded to surgical findings and subsequently compared to those findings. After a minimum follow-up time of six months, we assessed the surgical outcome and graded it on the Barrow Neurological Institute pain intensity score (BNI score). The prognostic value of the preoperative MRI was estimated using binary logistic regression. Preoperative DRIVE MRI sequences showed a sensitivity of 95% and a specificity of 87%, with a 98% positive predictive value and a 70% negative predictive value. Moreover, Cohen's kappa (CK) indicated a good level of agreement between radiological and surgical findings regarding presence of NVC (CK 0.75), type of compression (CK 0.74) and the site of compression (CK 0.72), with only moderate agreement as to the degree of compression (CK 0.48). After a mean follow-up of 29 months (range 6-100 months), 81% of the patients reported pain control with or without medication (BNI score i-iiiI). Patients with an excellent surgical outcome, i.e. without pain and off medication (BNI score i), made up 66% of the total at the end of follow-up. Univariate analysis using binary logistic regression showed that a diagnosis of NVC on the preoperative MRI was a favorable prognostic factor that significantly increased the odds of

  7. Neurovascular congruence results from a shared patterning mechanism that utilizes Semaphorin3A and Neuropilin-1.

    PubMed

    Bates, Damien; Taylor, G Ian; Minichiello, Joe; Farlie, Peter; Cichowitz, Adam; Watson, Nadine; Klagsbrun, Michael; Mamluk, Roni; Newgreen, Donald F

    2003-03-01

    hemorrhage as well as altered nerve trajectories and peripheral nerve defasciculation at E5-E6. These results suggest that neurovascular congruency does not arise from interdependence between peripheral nerves and blood vessels, but supports the hypothesis that it arises by a shared patterning mechanism that utilizes semaphorin3A.

  8. The tissue-type plasminogen activator-plasminogen activator inhibitor 1 complex promotes neurovascular injury in brain trauma: evidence from mice and humans.

    PubMed

    Sashindranath, Maithili; Sales, Eunice; Daglas, Maria; Freeman, Roxann; Samson, Andre L; Cops, Elisa J; Beckham, Simone; Galle, Adam; McLean, Catriona; Morganti-Kossmann, Cristina; Rosenfeld, Jeffrey V; Madani, Rime; Vassalli, Jean-Dominique; Su, Enming J; Lawrence, Daniel A; Medcalf, Robert L

    2012-11-01

    The neurovascular unit provides a dynamic interface between the circulation and central nervous system. Disruption of neurovascular integrity occurs in numerous brain pathologies including neurotrauma and ischaemic stroke. Tissue plasminogen activator is a serine protease that converts plasminogen to plasmin, a protease that dissolves blood clots. Besides its role in fibrinolysis, tissue plasminogen activator is abundantly expressed in the brain where it mediates extracellular proteolysis. However, proteolytically active tissue plasminogen activator also promotes neurovascular disruption after ischaemic stroke; the molecular mechanisms of this process are still unclear. Tissue plasminogen activator is naturally inhibited by serine protease inhibitors (serpins): plasminogen activator inhibitor-1, neuroserpin or protease nexin-1 that results in the formation of serpin:protease complexes. Proteases and serpin:protease complexes are cleared through high-affinity binding to low-density lipoprotein receptors, but their binding to these receptors can also transmit extracellular signals across the plasma membrane. The matrix metalloproteinases are the second major proteolytic system in the mammalian brain, and like tissue plasminogen activators are pivotal to neurological function but can also degrade structures of the neurovascular unit after injury. Herein, we show that tissue plasminogen activator potentiates neurovascular damage in a dose-dependent manner in a mouse model of neurotrauma. Surprisingly, inhibition of activity following administration of plasminogen activator inhibitor-1 significantly increased cerebrovascular permeability. This led to our finding that formation of complexes between tissue plasminogen activator and plasminogen activator inhibitor-1 in the brain parenchyma facilitates post-traumatic cerebrovascular damage. We demonstrate that following trauma, the complex binds to low-density lipoprotein receptors, triggering the induction of matrix

  9. Transplanted bone marrow stromal cells protect neurovascular units and ameliorate brain damage in stroke-prone spontaneously hypertensive rats.

    PubMed

    Ito, Masaki; Kuroda, Satoshi; Sugiyama, Taku; Maruichi, Katsuhiko; Kawabori, Masahito; Nakayama, Naoki; Houkin, Kiyohiro; Iwasaki, Yoshinobu

    2012-10-01

    This study was aimed to assess whether bone marrow stromal cells (BMSC) could ameliorate brain damage when transplanted into the brain of stroke-prone spontaneously hypertensive rats (SHR-SP). The BMSC or vehicle was stereotactically engrafted into the striatum of male SHR-SP at 8 weeks of age. Daily loading with 0.5% NaCl-containing water was started from 9 weeks. MRIs and histological analysis were performed at 11 and 12 weeks, respectively. Wistar-Kyoto rats were employed as the control. As a result, T2-weighted images demonstrated neither cerebral infarct nor intracerebral hemorrhage, but identified abnormal dilatation of the lateral ventricles in SHR-SP. HE staining demonstrated selective neuronal injury in their neocortices. Double fluorescence immunohistochemistry revealed that they had a decreased density of the collagen IV-positive microvessels and a decreased number of the microvessels with normal integrity between basement membrane and astrocyte end-feet. BMSC transplantation significantly ameliorated the ventricular dilatation and the breakdown of neurovascular integrity. These findings strongly suggest that long-lasting hypertension may primarily damage neurovascular integrity and neurons, leading to tissue atrophy and ventricular dilatation prior to the occurrence of cerebral stroke. The BMSC may ameliorate these damaging processes when directly transplanted into the brain, opening the possibility of prophylactic medicine to prevent microvascular and parenchymal-damaging processes in hypertensive patients at higher risk for cerebral stroke.

  10. Cognitive impairment and neurovascular function in patients with severe steno-occlusive disease of a main cerebral artery.

    PubMed

    Ishikawa, Mami; Saito, Haruna; Yamaguro, Tomotaka; Ikoda, Masashi; Ebihara, Akira; Kusaka, Gen; Tanaka, Yuichi

    2016-02-15

    Patients with severe steno-occlusive disease of a main cerebral artery may demonstrate cognitive impairment without identification of causative lesions on magnetic resonance imaging. We investigated whether cognitive impairment in these patients is associated with regional cerebral blood flow (rCBF), leukoaraiosis, risk factors of atherosclerosis and cerebrovascular reserve (CVR), which shows so-called clinical neurovascular function. In 65 patients with severe steno-occlusive disease of an internal carotid artery or a middle cerebral artery (MCA) and no cerebral infarction (CI), we examined cognitive function with COGNISTAT, grades of leukoaraiosis, and CBF and CVR as calculated by iodine-123-N-isopropyl-p-iodoamphetamine single photon emission computed tomography and blood data. We compared such values of the left and right sided diseases. rCBF and CVR on the affected side were compared to other side. Logistic regression analysis revealed that CVR correlated with cognitive impairment. There was no significant difference in rCBF, CVR, or COGNISTAT score when comparing the left and right sided diseases. There were good correlations between CBF or CVR of the ipsilateral MCA area and ipsilateral and contralateral other areas. Cognitive impairment is associated with CVR in the whole brain. Nonselective widespread neurovascular mild dysfunction can be a reason for cognitive impairment in patients with severe steno-occlusive disease of a main cerebral artery and no CI. Copyright © 2015 Elsevier B.V. All rights reserved.

  11. Neurovascular anatomy of the penis and pelvis in Thai males: applications to male-to-female and pelvic surgeries.

    PubMed

    Tansatit, Tanvaa; Jindarak, Sirachai; Sampatanukul, Pichet; Wannaprasert, Thanakul

    2007-01-01

    To determine the neurovascular profiles in the pelvis and penis for applying to sex reassignment surgery. Dissection of the pelvis and penile shaft was performed in 12 soft-preserved and 32 fresh adult male cadavers respectively. The neurovascular structures were located and documented, and the distances between anatomical landmarks were measured. Thirty-two specimens from the glans penis were obtained for immunohistochemical analysis to analyze its innervation and blood supply. Several anatomical variations of penile arterial supply were found. They are the presence of the accessory pudendal artery, multiple cavernous and bulbourethral arteries. The unilateral dorsal artery was observed in 10 of 32 cadavers, predominantly on the left. From the root to the neck of the penis, the dorsal nerves were divided into two groups. The first group of fibers innervating the glans coursed along the dorsolateral surface of the shaft and pierced the entire area of the corona. The other group diverged to distribute throughout the lateral surface to innervate the lateral and ventral portions. The mean distance between the left and right medial main branches that terminated in the glans was 1.18 cm. Immunohistochemical analysis revealed that the main nerves, after entering the glans, divided into terminal branches that concentrated around urethra. A mean distance from the main nerves to the epithelium was 0.71 cm. This detailed anatomy in the pelvis and along the penis should provide a valuable guide for sex reassignment surgery and intrapelvic operations.

  12. Blood-Brain Barrier Disruption and Neurovascular Unit Dysfunction in Diabetic Mice: Protection with the Mitochondrial Carbonic Anhydrase Inhibitor Topiramate.

    PubMed

    Salameh, Therese S; Shah, Gul N; Price, Tulin O; Hayden, Melvin R; Banks, William A

    2016-12-01

    All forms of diabetes mellitus are characterized by chronic hyperglycemia, resulting in the development of a number of microvascular and macrovascular pathologies. Diabetes is also associated with changes in brain microvasculature, leading to dysfunction and ultimately disruption of the blood-brain barrier (BBB). These changes are correlated with a decline in cognitive function. In diabetes, BBB damage is associated with increased oxidative stress and reactive oxygen species. This occurs because of the increased oxidative metabolism of glucose caused by hyperglycemia. Decreasing the production of bicarbonate with the use of a mitochondrial carbonic anhydrase inhibitor (mCAi) limits oxidative metabolism and the production of reactive oxygen species. In this study, we have demonstrated that 1) streptozotocin-induced diabetes resulted in BBB disruption, 2) ultrastructural studies showed a breakdown of the BBB and changes to the neurovascular unit (NVU), including a loss of brain pericytes and retraction of astrocytes, the two cell types that maintain the BBB, and 3) treatment with topiramate, a mCAi, attenuated the effects of diabetes on BBB disruption and ultrastructural changes in the neurovascular unit.

  13. In vivo 3D morphology of astrocyte–vasculature interactions in the somatosensory cortex: implications for neurovascular coupling

    PubMed Central

    McCaslin, Addason F H; Chen, Brenda R; Radosevich, Andrew J; Cauli, Bruno; Hillman, Elizabeth M C

    2011-01-01

    Astrocytes are increasingly believed to play an important role in neurovascular coupling. Recent in vivo studies have shown that intracellular calcium levels in astrocytes correlate with reactivity in adjacent diving arterioles. However, the hemodynamic response to stimulation involves a complex orchestration of vessel dilations and constrictions that spread rapidly over wide distances. In this work, we study the three-dimensional cytoarchitecture of astrocytes and their interrelations with blood vessels down through layer IV of the mouse somatosensory cortex using in vivo two-photon microscopy. Vessels and astrocytes were visualized through intravenous dextran-conjugated fluorescein and cortically applied sulforhodamine 101 (SR101), respectively. In addition to exploring astrocyte density, vascular proximity, and microvascular density, we found that sheathing of subpial vessels by astrocyte processes was continuous along all capillaries, arterioles, and veins, comprising a highly interconnected pathway through which signals could feasibly be relayed over long distances via gap junctions. An inner SR101-positive sheath noted along pial and diving arterioles was determined to be nonastrocytic, and appears to represent selective SR101 staining of arterial endothelial cells. Our findings underscore the intimate relationship between astrocytes and all cortical blood vessels, and suggest that astrocytes could influence neurovascular regulation at a range of sites, including the capillary bed and pial arterioles. PMID:21139630

  14. Characteristics of neurovascular compression in facial neuralgia patients by 3D high-resolution MRI and fusion technology.

    PubMed

    Guo, Zi-Yi; Chen, Jing; Yang, Guang; Tang, Qian-Yu; Chen, Cai-Xiang; Fu, Shui-Xi; Yu, Dan

    2012-12-01

    To evaluate the anatomical characteristics and patterns of neurovascular compression in patients suffering trigeminal neuralgia, using 3D high-resolution magnetic resonance imaging methods and fusion technologies. The analysis of the anatomy of the facial nerve, brain stem and the vascular structures related to this nerve was made in 100 consecutive patients for TN. 3D high resolution MRI studies (3D SPGR, T1 enhanced 3D MP-RAGE and T2/T1 3D FIESTA) simultaneous visualization were used to assessed using the software 3D DOCTOR. In 93 patients (93%), there were one or several locals of neurovascular compression (NVC). The superior cerebellar artery was involved in 71 cases (76%), the other vessels including the antero-inferior cerebellar artery, the basilar artery, the vertebral artery, and some venous structures. The mean distance between NVC and nerve origin site in the brainstem was (3.76 ± 2.90) mm). In 39 patients (42%), the vascular compression was located proximally and in 42 (45%) the compression was located distally. Nerve dislocation or distortion by the vessel was observed in 30 cases (32%). This 3D high resolution MRI and image fusion technology could be useful for diagnostic and therapeutic decisions in TN. Copyright © 2012 Hainan Medical College. Published by Elsevier B.V. All rights reserved.

  15. Inflammatory Bowel Disease

    PubMed Central

    Nasseri-Moghaddam, Siavosh

    2012-01-01

    Inflammatory bowel disease (IBD) is the term used for a group of diseases with yet unknown etiology, prevalence of which is increasing almost everywhere in the world. The disease was almost non-existent four decades ago in the east, including the middle-east, while now a days it is seen more and more. In addition to the increasing prevalence, our knowledge about its pathogenesis, clinical course, diagnosis, and treatment has changed dramatically over the past couple of decades. This has changed our concept of this group of diseases, their diagnosis, treatment, and treatment goals. Considering the vast literature on the subject, it is timely to review major topics in IBD with a look on the regional progress and knowledge as well. This essay is aimed to cover this task. PMID:24829639

  16. The forkhead transcription factor FOXO3a controls microglial inflammatory activation and eventual apoptotic injury through caspase 3.

    PubMed

    Shang, Yan Chen; Chong, Zhao Zhong; Hou, Jinling; Maiese, Kenneth

    2009-02-01

    Memory loss and cognitive failure are increasingly being identified as potential risks with the recognized increase in life expectancy of the general population. As a result, the development of novel therapeutic strategies for disorders such as Alzheimer's disease have garnered increased attention. The etiologies that can lead to Alzheimer's disease are extremely varied, but a number of therapeutic options are directed against amyloid-beta peptide and inflammatory cell regulation to prevent or halt progressive cognitive loss. In particular, inflammatory microglial cells may have disparate functions that in some scenarios lead to disability through the removal of functional neurovascular cells and in other circumstances foster tissue repair. Given the significance microglial cells hold for neurodegenerative disorders, we therefore examined the function that amyloid (Abeta(1-42)) has upon the microglial cell line EOC 2 and identified a novel role for the forkhead transcription factor FoxO3a and caspase 3. Here we show that Abeta(1-42) leads to progressive injury and apoptotic cell loss in microglial cells that involves both early phosphatidylserine (PS) externalization and late genomic DNA fragmentation over a 24 hour course. Prior to these injury programs, Abeta(1-42) results in the activation and proliferation of microglia as demonstrated by increased proliferating cell nuclear antigen (PCNA) expression and bromodeoxyuridine (BrdU) uptake. Both apoptotic injury as well as the prior activation and proliferation of microglial cells relies upon the presence of FoxO3a, since specific gene silencing of FoxO3a promotes microglial cell protection and prevents the early activation and proliferation of these cells. Furthermore, Abeta(1-42) exposure maintained FoxO3a in an unphosphorylated "active" state and facilitated the cellular trafficking of FoxO3a from the cytoplasm to the cell nucleus to potentially lead to "pro-apoptotic" programs by this transcription factor. One

  17. Long-term efficacy and safety of internal neurolysis for trigeminal neuralgia without neurovascular compression.

    PubMed

    Ko, Andrew L; Ozpinar, Alp; Lee, Albert; Raslan, Ahmed M; McCartney, Shirley; Burchiel, Kim J

    2015-05-01

    OBJECT Trigeminal neuralgia (TN) occurs and recurs in the absence of neurovascular compression (NVC). While microvascular decompression (MVD) is the most effective treatment for TN, it is not possible when NVC is not present. Therefore, the authors sought to evaluate the safety, efficacy, and durability of internal neurolysis (IN), or "nerve combing," as a treatment for TN without NVC. METHODS This was a retrospective review of all cases of Type 1 TN involving all patients 18 years of age or older who underwent evaluation (and surgery when appropriate) at Oregon Health & Science University between July 2006 and February 2013. Chart reviews and telephone interviews were conducted to assess patient outcomes. Pain intensity was evaluated with the Barrow Neurological Institute (BNI) Pain Intensity scale, and the Brief Pain Inventory-Facial (BPI-Facial) was used to assess general and face-specific activity. Pain-free survival and durability of successful pain relief (BNI pain scores of 1 or 2) were statistically evaluated with Kaplan-Meier analysis. Prognostic factors were identified and analyzed using Cox proportional hazards regression. RESULTS A total of 177 patients with Type 1 TN were identified. A subgroup of 27 was found to have no NVC on high-resolution MRI/MR angiography or at surgery. These patients were significantly younger than patients with classic Type 1 TN. Long-term follow-up was available for 26 of 27 patients, and 23 responded to the telephone survey. The median follow-up duration was 43.4 months. Immediate postoperative results were comparable to MVD, with 85% of patients pain free and 96% of patients with successful pain relief. At 1 year and 5 years, the rate of pain-free survival was 58% and 47%, respectively. Successful pain relief at those intervals was maintained in 77% and 72% of patients. Almost all patients experienced some degree of numbness or hypesthesia (96%), but in patients with successful pain relief, this numbness did not

  18. 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

  19. Peroxynitrite decomposition catalyst prevents matrix metalloproteinase-9 activation and neurovascular injury after hemoglobin injection into the caudate nucleus of rats.

    PubMed

    Ding, R; Feng, L; He, L; Chen, Y; Wen, P; Fu, Z; Lin, C; Yang, S; Deng, X; Zeng, J; Sun, G

    2015-06-25

    Hemoglobin (Hb) is a major constituent of blood and a potent mediator of oxidative or nitrative stress after intracerebral hemorrhage (ICH). Our previous study demonstrated that Hb could induce abundant peroxynitrite (ONOO(-)) formation in vivo, which may be involved in the blood-brain barrier (BBB) disruption, however, the drug intervention is absent and also the underlying mechanism. Using an experimental stroke model by injecting Hb into the caudate nucleus of male Sprague-Dawley rats, we assessed the role of ONOO(-) decomposition catalyst, 5,10,15,20-tetrakis (4-sulfonatophenyl) porphyrinato iron(III) [FeTPPS] in the activation of MMP-9 and Hb-induced neurovascular injuries. 3-Nitrotyrosine (3-NT, as an index of ONOO(-) formation) and NF-κB expression was measured by western blot (WB) and immunohistochemistry (IHC)/immunofluorescence (IF). Activity of MMP was evaluated by in situ zymography. Neurovascular injury was assessed using zonula occludens-1 (ZO-1) by WB and IF, fibronectin (FN) and neuron-specific nuclear protein (NeuN) IHC. Perihematomal cell death was determined by TUNEL assay. Behavioral outcome was measured by modified neurological severity score (mNSS) test. At the injured striata, profuse 3-NT was produced and mainly expressed in neutrophils and microglia/macrophages. 3-NT formation significantly colocalized with nuclear factor-κB (NF-κB) expression. In situ zymography showed that gelatinase activity was mostly co-localized with neurons and blood vessel walls and partly with neutrophils and microglia/macrophages. Enhanced 3-NT production, NF-κB induction and MMP-9 activation were obviously reduced after FeTPPS treatment. Hb-induced injury to tight junction protein (ZO-1), basal lamina of FN-immunopositive microvasculature and neural cells was evidently ameliorated by FeTPPS. In addition, apoptotic cell numbers as well as behavioral deficits were also improved. The present study shows that the administration of the ONOO(-) decomposition

  20. Prostate tissue ablation with MRI guided transurethral therapeutic ultrasound and intraoperative assessment of the integrity of the neurovascular bundle

    NASA Astrophysics Data System (ADS)

    Sammet, Steffen; Partanen, Ari; Yousuf, Ambereen; Wardrip, Craig; Niekrasz, Marek; Antic, Tatjana; Razmaria, Aria; Sokka, Sham; Karczmar, Gregory; Oto, Aytekin

    2017-03-01

    OBJECTIVES: Evaluation of the precision of prostate tissue ablation with MRI guided therapeuticultrasound by intraoperative objective assessment of the neurovascular bundle in canines in-vivo. METHODS: In this ongoing IACUC approved study, eight male canines were scanned in a clinical 3T Achieva MRI scanner (Philips) before, during, and after ultrasound therapy with a prototype MR-guided ultrasound therapy system (Philips). The system includes a therapy console to plan treatment, to calculate real-time temperature maps, and to control ultrasound exposures with temperature feedback. Atransurethral ultrasound applicator with eight transducer elements was used to ablate canine prostate tissue in-vivo. Ablated prostate tissue volumes were compared to the prescribed target volumes to evaluate technical effectiveness. The ablated volumes determined by MRI (T1, T2, diffusion, dynamic contrast enhanced and 240 CEM43 thermal dose maps) were compared to H&E stained histological slides afterprostatectomy. Potential nerve damage of the neurovascular bundle was objectively assessed intraoperativelyduring prostatectomy with a CaverMap Surgical Aid nerve stimulator (Blue Torch Medical Technologies). RESULTS: Transurethral MRI -guided ultrasound therapy can effectively ablate canine prostate tissue invivo. Coronal MR-imaging confirmed the correct placement of the HIFU transducer. MRI temperature maps were acquired during HIFU treatment, and subsequently used for calculating thermal dose. Prescribed target volumes corresponded to the 240 CEM43 thermal dose maps during HIFU treatment in all canines. Ablated volumes on high resolution anatomical, diffusion weighted, and contrast enhanced MR images matched corresponding histological slides after prostatectomy. MRI guidance with realtime temperature monitoring showed no damage to surrounding tissues, especially to the neurovascular bundle (assessed intra-operatively with a nerve stimulator) or to the rectum wall. CONCLUSIONS: Our study

  1. 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

  2. Melatonin decreases neurovascular oxidative/nitrosative damage and protects against early increases in the blood-brain barrier permeability after transient focal cerebral ischemia in mice.

    PubMed

    Chen, Hung-Yi; Chen, Tsung-Ying; Lee, Ming-Yang; Chen, Shur-Tzu; Hsu, Yun-Shang; Kuo, Yen-Liang; Chang, Guan-Liang; Wu, Tian-Shung; Lee, E-Jian

    2006-09-01

    We have recently shown that melatonin decreases the late (24 hr) increase in blood-brain barrier (BBB) permeability and the risk of tissue plasminogen activator-induced hemorrhagic transformation following ischemic stroke in mice. In the study, we further explored whether melatonin would reduce postischemic neurovascular oxidative/nitrosative damage and, therefore, improve preservation of the early increase in the BBB permeability at 4 hr after transient focal cerebral ischemia for 60 min in mice. Melatonin (5 mg/kg) or vehicle was given intraperitoneally at the beginning of reperfusion. Hydroethidine (HEt) in situ detection and immunohistochemistry for nitrotyrosine were used to evaluate postischemic accumulation in reactive oxygen and nitrogen species, respectively, in the ischemic neurovascular unit. BBB permeability was evaluated by spectrophotometric and microscopic quantitation of Evans Blue leakage. Relative to controls, melatonin-treated animals not only had a significantly reduced superoxide accumulation in neurovascular units in boundary zones of infarction, by reducing 35% and 54% cytosolic oxidized HEt in intensity and cell-expressing percentage, respectively (P < 0.001), but also exhibited a reduction in nitrotyrosine by 52% (P < 0.01). Additionally, melatonin-treated animals had significantly reduced early postischemic disruption in the BBB permeability by 53% (P < 0.001). Thus, melatonin reduced postischemic oxidative/nitrosative damage to the ischemic neurovascular units and improved the preservation of BBB permeability at an early phase following transient focal cerebral ischemia in mice. The findings further highlight the ability of melatonin in anatomical and functional preservation for the ischemic neurovascular units and its relevant potential in the treatment of ischemic stroke.

  3. Oxidative stress and inflammatory bowel disease.

    PubMed

    Almenier, Hazem A; Al Menshawy, Hazem H; Maher, Maha M; Al Gamal, Salah

    2012-01-01

    Inflammatory Bowel Disease (IBD) is a chronic relapsing and remitting inflammatory condition of the gastrointestinal tract. The exact cause of IBD remains undetermined, the condition appears to be related to a combination of genetic and environmental factors. While many gaps in our knowledge still exist, the last two decades have witnessed an unprecedented progress not only in the etiology ; but mainly in the mechanisms underlying the chronic inflammatory response, immunologic and genetic aspects. We review some recent points of research in pathogenesis with special stress on oxidative stress and its correlations with disease activity.

  4. [A subacute dementia: Inflammatory cerebral amyloid angiopathy].

    PubMed

    Charef, S; Leblanc, A; Guibourg, B; Quintin-Roue, I; Ben Salem, D; Zagnoli, F

    2015-12-01

    We report a case of inflammatory cerebral amyloid angiopathy (CAA) that led to rapid cognitive decline, seizures, visual hallucinations, hyperproteinorrachia and right hemispheric leukopathy. Brain biopsy gave the diagnosis of CAA. Although no inflammatory infiltrate was found in the biopsy sample, corticosteroids led to a regression of the radiological lesions without significant clinical improvement. CAA is a rare disease, defined by lesions of classical cerebral amyloid angiopathy and perivascular infiltrates in contact with the affected vessels. In cases of rapidly progressive dementia associated with leukopathy, inflammatory amyloid angiopathy should be considered as cognitive disorders may improve after immunosuppressive therapy. Copyright © 2015 Elsevier Masson SAS. All rights reserved.

  5. Monocyte and macrophage differentiation: circulation inflammatory monocyte as biomarker for inflammatory diseases.

    PubMed

    Yang, Jiyeon; Zhang, Lixiao; Yu, Caijia; Yang, Xiao-Feng; Wang, Hong

    2014-01-07

    Monocytes express various receptors, which monitor and sense environmental changes. Monocytes are highly plastic and heterogeneous, and change their functional phenotype in response to environmental stimulation. Evidence from murine and human studies has suggested that monocytosis can be an indicator of various inflammatory diseases. Monocytes can differentiate into inflammatory or anti-inflammatory subsets. Upon tissue damage or infection, monocytes are rapidly recruited to the tissue, where they can differentiate into tissue macrophages or dendritic cells. Given the rapid progress in monocyte research from broad spectrum of inflammatory diseases, there is a need to summarize our knowledge in monocyte heterogeneity and its impact in human disease. In this review, we describe the current understanding of heterogeneity of human and murine monocytes, the function of distinct subsets of monocytes, and a potential mechanism for monocyte differentiation. We emphasize that inflammatory monocyte subsets are valuable biomarkers for inflammatory diseases, including cardiovascular diseases.

  6. 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

  7. Exploiting neurovascular coupling: a Bayesian sequential Monte Carlo approach applied to simulated EEG fNIRS data

    NASA Astrophysics Data System (ADS)

    Croce, Pierpaolo; Zappasodi, Filippo; Merla, Arcangelo; Chiarelli, Antonio Maria

    2017-08-01

    Objective. Electrical and hemodynamic brain activity are linked through the neurovascular coupling process and they can be simultaneously measured through integration of electroencephalography (EEG) and functional near-infrared spectroscopy (fNIRS). Thanks to the lack of electro-optical interference, the two procedures can be easily combined and, whereas EEG provides electrophysiological information, fNIRS can provide measurements of two hemodynamic variables, such as oxygenated and deoxygenated hemoglobin. A Bayesian sequential Monte Carlo approach (particle filter, PF) was applied to simulated recordings of electrical and neurovascular mediated hemodynamic activity, and the advantages of a unified framework were shown. Approach. Multiple neural activities and hemodynamic responses were simulated in the primary motor cortex of a subject brain. EEG and fNIRS recordings were obtained by means of forward models of volume conduction and light propagation through the head. A state space model of combined EEG and fNIRS data was built and its dynamic evolution was estimated through a Bayesian sequential Monte Carlo approach (PF). Main results. We showed the feasibility of the procedure and the improvements in both electrical and hemodynamic brain activity reconstruction when using the PF on combined EEG and fNIRS measurements. Significance. The investigated procedure allows one to combine the information provided by the two methodologies, and, by taking advantage of a physical model of the coupling between electrical and hemodynamic response, to obtain a better estimate of brain activity evolution. Despite the high computational demand, application of such an approach to in vivo recordings could fully exploit the advantages of this combined brain imaging technology.

  8. Functional MRI during Hyperbaric Oxygen: Effects of Oxygen on Neurovascular Coupling and BOLD fMRI signals

    PubMed Central

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

    2015-01-01

    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) was 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

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

    PubMed Central

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

    2015-01-01

    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 35 days 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 to not only protect against ischemic injury for the long term but also to actively promote neurovascular restorative dynamics and brain repair. PMID:25771800

  10. EEG-NIRS based assessment of neurovascular coupling during anodal transcranial direct current stimulation--a stroke case series.

    PubMed

    Dutta, Anirban; Jacob, Athira; Chowdhury, Shubhajit Roy; Das, Abhijit; Nitsche, Michael A

    2015-04-01

    A method for electroencephalography (EEG) - near-infrared spectroscopy (NIRS) based assessment of neurovascular coupling (NVC) during anodal transcranial direct current stimulation (tDCS). Anodal tDCS modulates cortical neural activity leading to a hemodynamic response, which was used to identify impaired NVC functionality. In this study, the hemodynamic response was estimated with NIRS. NIRS recorded changes in oxy-hemoglobin (HbO2) and deoxy-hemoglobin (Hb) concentrations during anodal tDCS-induced activation of the cortical region located under the electrode and in-between the light sources and detectors. Anodal tDCS-induced alterations in the underlying neuronal current generators were also captured with EEG. Then, a method for the assessment of NVC underlying the site of anodal tDCS was proposed that leverages the Hilbert-Huang Transform. The case series including four chronic (>6 months) ischemic stroke survivors (3 males, 1 female from age 31 to 76) showed non-stationary effects of anodal tDCS on EEG that correlated with the HbO2 response. Here, the initial dip in HbO2 at the beginning of anodal tDCS corresponded with an increase in the log-transformed mean-power of EEG within 0.5Hz-11.25Hz frequency band. The cross-correlation coefficient changed signs but was comparable across subjects during and after anodal tDCS. The log-transformed mean-power of EEG lagged HbO2 response during tDCS but then led post-tDCS. This case series demonstrated changes in the degree of neurovascular coupling to a 0.526 A/m(2) square-pulse (0-30 s) of anodal tDCS. The initial dip in HbO2 needs to be carefully investigated in a larger cohort, for example in patients with small vessel disease.

  11. Intranasal delivery of bone marrow mesenchymal stem cells improved neurovascular regeneration and rescued neuropsychiatric deficits after neonatal stroke in rats.

    PubMed

    Wei, Zheng Zachory; Gu, Xiaohuan; Ferdinand, Anwar; Lee, Jin Hwan; Ji, Xiaoya; Ji, Xun Ming; Yu, Shan Ping; Wei, Ling

    2015-01-01

    Neonatal stroke is a major cause of mortality and long-term morbidity in infants and children. Currently, very limited therapeutic strategies are available to protect the developing brain against ischemic damage and promote brain repairs for pediatric patients. Moreover, children who experienced neonatal stroke often have developmental social behavior problems. Cellular therapy using bone marrow mesenchymal stem cells (BMSCs) has emerged as a regenerative therapy after stroke. In the present investigation, neonatal stroke of postnatal day 7 (P7) rat pups was treated with noninvasive and brain-specific intranasal delivery of BMSCs at 6 h and 3 days after stroke (1 × 10(6)cells/animal). Prior to transplantation, BMSCs were subjected to hypoxic preconditioning to enhance their tolerance and regenerative properties. The effects on regenerative activities and stroke-induced sensorimotor and social behavioral deficits were specifically examined at P24 of juvenile age. The BMSC treatment significantly reduced infarct size and blood-brain barrier disruption, promoted angiogenesis, neurogenesis, neurovascular repair, and improved local cerebral blood flow in the ischemic cortex. BMSC-treated rats showed better sensorimotor and olfactory functional recovery than saline-treated animals, measured by the adhesive removal test and buried food finding test. In social behavioral tests, we observed functional and social behavioral deficits in P24 rats subjected to stroke at P7, while the BMSC treatment significantly improved the performance of stroke animals. Overall, intranasal BMSC transplantation after neonatal stroke shows neuroprotection and great potential as a regenerative therapy to enhance neurovascular regeneration and improve functional recovery observed at the juvenile stage of development.

  12. Protective Effects of Calpain Inhibition on Neurovascular Unit Injury through Downregulating Nuclear Factor-κB-related Inflammation during Traumatic Brain Injury in Mice

    PubMed Central

    Tao, Xiao-Gang; Shi, Jing-Hua; Hao, Shu-Yu; Chen, Xue-Tao; Liu, Bai-Yun

    2017-01-01

    Background: In addition to neurons, all components of the neurovascular unit (NVU), such as glial, endothelial, and basal membranes, are destroyed during traumatic brain injury (TBI). Previous studies have shown that excessive stimulation of calpain is crucial for cerebral injury after traumatic insult. The objective of this study was to investigate whether calpain activation participated in NVU disruption and edema formation in a mouse model of controlled cortical impact (CCI). Methods: One hundred and eight mice were divided into three groups: the sham group, the control group, and the MDL28170 group. MDL28170 (20 mg/kg), an efficient calpain inhibitor, was administered intraperitoneally at 5 min, 3 h, and 6 h after experimental CCI. We then measured neurobehavioral deficits, calpain activity, inflammatory mediator levels, blood–brain barrier (BBB) disruption, and NVU deficits using electron microscopy and histopathological analysis at 6 h and 24 h after CCI. Results: The MDL28170 treatment significantly reduced the extent of both cerebral contusion (MDL28170 vs. vehicle group, 16.90 ± 1.01 mm3 and 17.20 ± 1.17 mm3 vs. 9.30 ± 1.05 mm3 and 9.90 ± 1.17 mm3, both P < 0.001) and edema (MDL28170 vs. vehicle group, 80.76 ± 1.25% and 82.00 ± 1.84% vs. 82.55 ± 1.32% and 83.64 ± 1.25%, both P < 0.05), improved neurological scores (MDL28170 vs. vehicle group, 7.50 ± 0.45 and 6.33 ± 0.38 vs. 12.33 ± 0.48 and 11.67 ± 0.48, both P < 0.001), and attenuated NVU damage resulting (including tight junction (TJ), basement membrane, BBB, and neuron) from CCI at 6 h and 24 h. Moreover, MDL28170 markedly downregulated nuclear factor-κB-related inflammation (tumor necrosis factor-α [TNF-α]: MDL28170 vs. vehicle group, 1.15 ± 0.07 and 1.62 ± 0.08 vs. 1.59 ± 0.10 and 2.18 ± 0.10, both P < 0.001; inducible nitric oxide synthase: MDL28170 vs. vehicle group, 4.51 ± 0.23 vs. 6.23 ± 0.12, P < 0.001 at 24 h; intracellular adhesion molecule-1: MDL28170 vs. vehicle group

  13. Methyl salicylate 2-O-β-d-lactoside alleviates the pathological progression of pristane-induced systemic lupus erythematosus-like disease in mice via suppression of inflammatory response and signal transduction

    PubMed Central

    He, Yang-Yang; Yan, Yu; Zhang, Hui-Fang; Lin, Yi-Huang; Chen, Yu-Cai; Yan, Yi; Wu, Ping; Fang, Jian-Song; Yang, Shu-Hui; Du, Guan-Hua

    2016-01-01

    Systemic lupus erythematosus (SLE), with a high incidence rate and insufficient therapy worldwide, is a complex disease involving multiple organs characterized primarily by inflammation due to deposition of immunocomplexes formed by production of autoantibodies. The mechanism of SLE remains unclear, and the disease still cannot be cured. We used pristane to induce SLE in female BALB/c mice. Methyl salicylate 2-O-β-d-lactoside (MSL; 200, 400, and 800 mg/kg) was orally administered 45 days after pristane injection for 4.5 months. The results showed that MSL antagonized the increasing levels of multiple types of antibodies and cytokines in lupus mice. MSL was found to suppress joint swelling and have potent inhibitory effect on arthritis-like symptoms. MSL also significantly decreased the spleen index and expression of inflammatory markers in the lupus mice. MSL protected the kidneys of lupus mice from injury through inhibiting the expression of inflammatory cytokines and reducing the IgG and C3 immunocomplex deposits. Further Western blot assays revealed that the downregulation of the intracellular inflammatory signals of NFκB and JAK/STAT3 might be the potential molecular mechanisms of the pharmacological activity of MSL against SLE in vivo. These findings may demonstrate that MSL has the potential to be a useful and highly effective treatment for SLE. PMID:27729775

  14. A double-blind, randomized controlled trial to compare the effect of biannual peripheral magnetic resonance imaging, radiography and standard of care disease progression monitoring on pharmacotherapeutic escalation in rheumatoid and undifferentiated inflammatory arthritis: study protocol for a randomized controlled trial.

    PubMed

    Tavares, Ruben; Beattie, Karen Anne; Bensen, William George; Bobba, Raja S; Cividino, Alfred A; Finlay, Karen; Goeree, Ron; Hart, Lawrence Errol; Jurriaans, Erik; Larche, Maggie J; Parasu, Naveen; Tarride, Jean-Eric; Webber, Colin E; Adachi, Jonathan D

    2014-07-05

    Permanent joint damage is a major consequence of rheumatoid arthritis (RA), the most common and destructive form of inflammatory arthritis. In aggressive disease, joint damage can occur within 6 months from symptom onset. Early, intensive treatment with conventional and biologic disease-modifying anti-rheumatic drugs (DMARDs) can delay the onset and progression of joint damage. The primary objective of the study is to investigate the value of magnetic resonance imaging (MRI) or radiography (X-ray) over standard of care as tools to guide DMARD treatment decision-making by rheumatologists for the care of RA. A double-blind, randomized controlled trial has been designed. Rheumatoid and undifferentiated inflammatory arthritis patients will undergo an MRI and X-ray assessment every 6 months. Baseline adaptive randomization will be used to allocate participants to MRI, X-ray, or sham-intervention groups on a background of standard of care. Prognostic markers, treating physician, and baseline DMARD therapy will be used as intervention allocation parameters. The outcome measures in rheumatology RA MRI score and the van der Heijde-modified Sharp score will be used to evaluate the MRI and X-ray images, respectively. Radiologists will score anonymized images for all patients regardless of intervention allocation. Disease progression will be determined based on the study-specific, inter-rater smallest detectable difference. Allocation-dependent, intervention-concealed reports of positive or negative disease progression will be reported to the treating rheumatologist. Negative reports will be delivered for the sham-intervention group. Study-based radiology clinical reports will be provided to the treating rheumatologists for extra-study X-ray requisitions to limit patient radiation exposure as part of diagnostic imaging standard of care. DMARD treatment dose escalation and therapy changes will be measured to evaluate the primary objective. A sample size of 186 (62 per group

  15. Chronic inflammatory demyelinating polyneuropathy.

    PubMed

    Vanasse, Michel; Rossignol, Elsa; Hadad, Elie

    2013-01-01

    Chronic inflammatory demyelinating polyneuropathy (CIDP) is characterized clinically by a progressive symmetrical weakness evolving over a period of at least 2 months. There is increased CSF protein and conduction block, reduced nerve conduction velocities, increased distal latencies, and/or absent F wave or prolonged F wave latency in two or more nerves. Incidence is lower in children (10 times less) than in adults, and the condition presents in an acute or subacute manner with frequent relapses. It is not associated with other systemic diseases such as neoplasia, diabetes mellitus, or monoclonal gammopathies. It appears to be immune-related as a variety of humoral and cellular autoimmune mechanisms have been implicated. Treatment is based on results obtained in randomized clinical trials (RCTs) conducted in adults as such studies are lacking in the pediatric population. The evolution of CIDP is more favorable in children than in adults, with 80-100% response rates to standard treatments (steroids, intravenous immunoglobulins, and/or plasmapheresis) and excellent outcome with complete functional recovery in most patients. Cases refractory to standard therapies do exist in children, for which azathioprine, methotrexate, and mycophenolate mofetil alone or more often in association with other treatments have been used. However, safety and efficacy data are still insufficient to give specific recommendations regarding the optimal choice.

  16. Progressive multiple sclerosis

    PubMed Central

    Ontaneda, Daniel; Fox, Robert J.

    2015-01-01

    Purpose to Review To highlight the pathological features and clinical aspects of progressive multiple sclerosis (PMS). To highlight results of clinical trial experience to date and review ongoing clinical trials and perspective new treatment options. Explain the challenges of clinical trial design in PMS. Recent Findings MS has been identified as a chronic immune mediated disease, and the progressive phase of the disease appears to have significant neurodegenerative mechanisms. The classification of the course of PMS has been re-organized into categories of active vs. inactive inflammatory disease and the presence vs. absence of gradual disease progression. This differentiation allows clearer conceptualization of PMS and possibly even more efficient recruitment of PMS subjects into clinical trials. Clinical trial experience to date in PMS has been negative with anti-inflammatory medications used in relapsing MS. Simvastatin was recently tested in a phase II trial and showed a 43% reduction on annualized atrophy progression in secondary progressive MS. Ongoing PMS trials are currently being conducted with the phosphodiesterase inhibitor ibudilast, S1P modulator siponimod, and anti-B-cell therapy ocrelizumab. Several efforts for development of outcome measures in PMS are ongoing. Summary PMS represents a significant challenge, as the pathogenesis of the disease is not well understood, no validated outcome metrics have been established, and clinical trial experience to date has been disappointing. Advances in the understanding of the disease and lessons learned in previous clinical trials are paving the way for successful development of disease modifying agents for this disease. PMID:25887766

  17. 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

  18. Delayed puberty associated with inflammatory bowel disease.

    PubMed

    Ballinger, Anne B; Savage, Martin O; Sanderson, Ian R

    2003-02-01

    Delayed puberty frequently complicates the clinical course of young patients with inflammatory bowel disease, more often in Crohn's disease than ulcerative colitis. Undernutrition has been thought to be the main reason for delayed puberty in these patients. However, puberty may be delayed despite a normal nutritional status. Observations in patients with inflammatory bowel disease and in rats with experimental colitis suggest that inflammatory mediators may have a direct adverse influence, independent of undernutrition, on the onset and progression of puberty. Serum androgens are consistently reported to be reduced in patients with delayed puberty and inflammatory bowel disease. This reduction is not necessarily secondary to a reduction in gonadotrophins as serum concentrations of gonadotrophins have been reported to be normal or even increased in some studies. Management of delayed puberty involves calorie supplements to correct undernutrition and treatment of inflammation. Observations in boys with delayed puberty and controlled studies in experimental models of intestinal inflammation suggest that testosterone therapy can accelerate puberty.

  19. Distribution of temperature changes and neurovascular coupling in rat brain following 3,4-methylenedioxymethamphetamine (MDMA, "ecstasy") exposure.

    PubMed

    Coman, Daniel; Sanganahalli, Basavaraju G; Jiang, Lihong; Hyder, Fahmeed; Behar, Kevin L

    2015-10-01

    (+/-)3,4-methylenedioxymethamphetamine (MDMA, "ecstasy") is an abused psychostimulant that produces strong monoaminergic stimulation and whole-body hyperthermia. MDMA-induced thermogenesis involves activation of uncoupling proteins (UCPs), primarily a type specific to skeletal muscle (UCP-3) and absent from the brain, although other UCP types are expressed in the brain (e.g. thalamus) and might contribute to thermogenesis. Since neuroimaging of brain temperature could provide insights into MDMA action, we measured spatial distributions of systemically administered MDMA-induced temperature changes and dynamics in rat cortex and subcortex using a novel magnetic resonance method, Biosensor Imaging of Redundant Deviation in Shifts (BIRDS), with an exogenous temperature-sensitive probe (thulium ion and macrocyclic chelate 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetramethyl-1,4,7,10-tetraacetate (DOTMA(4-))). The MDMA-induced temperature rise was greater in the cortex than in the subcortex (1.6 ± 0.4 °C versus 1.3 ± 0.4 °C) and occurred more rapidly (2.0 ± 0.2 °C/h versus 1.5 ± 0.2 °C/h). MDMA-induced temperature changes and dynamics in the cortex and body were correlated, although the body temperature exceeded the cortex temperature before and after MDMA. Temperature, neuronal activity, and blood flow (CBF) were measured simultaneously in the cortex and subcortex (i.e. thalamus) to investigate possible differences of MDMA-induced warming across brain regions. MDMA-induced warming correlated with increases in neuronal activity and blood flow in the cortex, suggesting that the normal neurovascular response to increased neural activity was maintained. In contrast to the cortex, a biphasic relationship was seen in the subcortex (i.e. thalamus), with a decline in CBF as temperature and neural activity rose, transitioning to a rise in CBF for temperature above 37 °C, suggesting that MDMA affected CBF and neurovascular coupling differently in subcortical regions

  20. Distribution of temperature changes and neurovascular coupling in rat brain following 3,4-methylenedioxymethamphetamine (MDMA,‘ecstasy’) exposure

    PubMed Central

    Coman, Daniel; Sanganahalli, Basavaraju G.; Jiang, Lihong; Hyder, Fahmeed; Behar, Kevin L.

    2015-01-01

    (+/−)3,4-methylenedioxymethamphetamine (MDMA, ‘ecstasy’) is an abused psychostimulant producing strong monoaminergic stimulation and whole-body hyperthermia. MDMA-induced thermogenesis involves activation of uncoupling proteins (UCP), primarily a type specific to skeletal muscle (UCP-3) and which is absent in brain, although other UCP types are expressed in brain (e.g., thalamus) and might contribute to thermogenesis. Since neuroimaging of brain temperature could provide insights of MDMA action, we measured spatial distributions of systemically-administered MDMA-induced temperature changes and dynamics in rat cortex and subcortex using a novel magnetic resonance method, Biosensor Imaging of Redundant Deviation of Shifts (BIRDS), with an exogenous temperature-sensitive probe (thulium ion and macrocyclic chelate 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetramethyl-1,4,7,10-tetraacetate (DOTMA4−)). The MDMA-induced temperature rise in cortex was greater than in subcortex (1.6±0.4°C vs. 1.3±0.4°C) and occurred more rapidly (2.0±0.2°C/h vs. 1.5±0.2°C/h). MDMA-induced temperature changes and dynamics in cortex and body were correlated, although body temperature exceeded cortex before and after MDMA. Temperature, neuronal activity, and blood flow (CBF) were measured simultaneously in cortex and subcortex (i.e., thalamus) to investigate possible differences of MDMA-induced warming across brain regions. MDMA-induced warming correlated with increases in neuronal activity and blood flow in cortex, suggesting that the normal neurovascular response to increased neural activity was maintained. In contrast to cortex, a biphasic relationship was seen in subcortex (i.e., thalamus), with a decline in CBF as temperature and neural activity rose, transitioning to a rise in CBF for temperature >37°C, suggesting that MDMA affected CBF and neurovascular coupling differently in subcortical regions. Considering that MDMA effects on CBF and heat dissipation (as well as

  1. Is preoperative high-resolution magnetic resonance imaging accurate in predicting neurovascular compression in patients with trigeminal neuralgia? A single-blind study.

    PubMed

    Benes, Ludwig; Shiratori, Kiyoshi; Gurschi, Mariana; Sure, Ulrich; Tirakotai, Wuttipong; Krischek, Boris; Bertalanffy, Helmut

    2005-04-01

    High-resolution magnetic resonance imaging (HR-MRI) using three-dimensional fast imaging employing steady-state acquisition (3D-FIESTA) and double-dose contrast-enhanced three-dimensional fast spoiled gradient echo (3D-FSPGR) sequences is considered to be a useful tool in detecting neurovascular compression in patients with trigeminal neuralgia. The purpose of this study was to analyze the accuracy and preoperative diagnostic value of these high-resolution imaging techniques in patients with trigeminal neuralgia, in a single-blind study. The preoperative MRI images of 21 consecutive patients were matched to one neuroradiologist, who was blind as to which side exhibited the symptoms. The images and post-processing multiplanar reconstructions were compared with the video-documented operative observations. HR-MRI using only 3D-FSPGR sequences demonstrated neurovascular compression in accordance with the intraoperative finding in 11 patients (52.4%). In the subgroup where, additionally, 3D-FIESTA sequences were available, neurovascular compression was in accordance with the intraoperative finding in 71.4% (n = 7). High-resolution magnetic resonance imaging using double-dose contrast-enhanced 3D-FSPGR and 3D-FIESTA sequences is currently not sufficient enough to make an accurate prediction of neurovascular compression in a single-blind setting. These 3D imaging techniques currently provide only limited information, and one should consider their use carefully when identifying patients with trigeminal neuralgia from operation until image quality is improved by superior image resolution that can accurately discriminate vessels surrounding the trigeminal root entry zone.

  2. 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

  3. Preoperative evaluation of neurovascular relationship by using contrast-enhanced and unenhanced 3D time-of-flight MR angiography in patients with trigeminal neuralgia.

    PubMed

    Zhou, Qin; Liu, Zhiling; Li, Chuanfu; Qu, Chuncheng; Ni, Shilei; Zeng, Qingshi

    2011-10-01

    Microvascular decompression is an etiological strategy for the therapy of trigeminal neuralgia (TN). Preoperative identification of neurovascular compression, therefore, could have an impact on the determination of appropriate treatment for TN. To evaluate the value of contrast-enhanced and unenhanced three-dimensional (3D) time-of-flight (TOF) MR angiography in the visualization of neurovascular relationship in patients with TN. Thirty-seven patients with unilateral TN underwent unenhanced and contrast-enhanced 3D TOF MR angiography with a 3.0-T MR system. Images were reviewed by a radiologist blinded to clinical details. Vascular contact with the trigeminal nerve was identified, and the nature of the involved vessels (artery or vein) was determined. All patients underwent microvascular decompression. In 37 patients with TN, contrast-enhanced 3D TOF MR angiography identified surgically verified neurovascular contact in 35 of 36 symptomatic nerves, and there was no false-positive. Based on surgical findings, the sensitivity of MR imaging was 97.2% and specificity 100%. The nature of the offending vessel was correctly identified in 94.4% of the patients by using the combination of contrast-enhanced and unenhanced MR angiography. Contrast-enhanced 3D TOF MR angiography is useful in the detection of vascular contact with the trigeminal nerve in patients with TN, and this MR imaging in combination with unenhanced MR angiography could help in the identification of the nature of the responsible vessels.

  4. Neurovascular unit dysfunction with blood-brain barrier hyperpermeability contributes to major depressive disorder: a review of clinical and experimental evidence.

    PubMed

    Najjar, Souhel; Pearlman, Daniel M; Devinsky, Orrin; Najjar, Amanda; Zagzag, David

    2013-12-01

    About one-third of people with major depressive disorder (MDD) fail at least two antidepressant drug trials at 1 year. Together with clinical and experimental evidence indicating that the pathophysiology of MDD is multifactorial, this observation underscores the importance of elucidating mechanisms beyond monoaminergic dysregulation that can contribute to the genesis and persistence of MDD. Oxidative stress and neuroinflammation are mechanistically linked to the presence of neurovascular dysfunction with blood-brain barrier (BBB) hyperpermeability in selected neurological disorders, such as stroke, epilepsy, multiple sclerosis, traumatic brain injury, and Alzheimer's disease. In contrast to other major psychiatric disorders, MDD is frequently comorbid with such neurological disorders and constitutes an independent risk factor for morbidity and mortality in disorders characterized by vascular endothelial dysfunction (cardiovascular disease and diabetes mellitus). Oxidative stress and neuroinflammation are implicated in the neurobiology of MDD. More recent evidence links neurovascular dysfunction with BBB hyperpermeability to MDD without neurological comorbidity. We review this emerging literature and present a theoretical integration between these abnormalities to those involving oxidative stress and neuroinflammation in MDD. We discuss our hypothesis that alterations in endothelial nitric oxide levels and endothelial nitric oxide synthase uncoupling are central mechanistic links in this regard. Understanding the contribution of neurovascular dysfunction with BBB hyperpermeability to the pathophysiology of MDD may help to identify novel therapeutic and preventative approaches.

  5. Anatomy of Mandibular Vital Structures. Part II: Mandibular Incisive Canal, Mental Foramen and Associated Neurovascular Bundles in Relation with Dental Implantology

    PubMed Central

    Wang, Hom-Lay; Sabalys, Gintautas

    2010-01-01

    ABSTRACT Objectives The purpose of the present study was to review the literature of how to identify the mental foramen, mandibular incisive canal and associated neurovascular bundles during implant surgery and how to detect and avoid the damage of these vital structures during implant therapy. Material and Methods Literature was selected through a search of PubMed, Embase and Cochrane electronic databases. The keywords used for search were mandibular incisive canal, mental foramen, mental nerve, anterior mental loop. The search was restricted to English language articles, published from 1979 to November 2009. Additionally, a manual search in the major anatomy, dental implant, and periodontal journals and books was performed. Results In total, 47 literature sources were obtained and reviewed. The morphology and variations of the mandibular incisive canal, mental foramen and associated neurovascular bundles were presented as two entities. It suggested that clinicians should carefully assess these vital structures to avoid nerve/artery damage. Conclusions The mandibular incisive canal, mental foramen and associated neurovascular bundles exist in different locations and possess many variations. Individual, gender, age, race, assessing technique used and degree of edentulous alveolar bone atrophy largely influence these variations. It suggests that the clinicians should carefully identify these anatomical landmarks, by analyzing all influencing factors, prior to their implant surgical operation. PMID:24421959

  6. Microstructural alterations in trigeminal neuralgia determined by diffusion tensor imaging are independent of symptom duration, severity, and type of neurovascular conflict.

    PubMed

    Lutz, Juergen; Thon, Niklas; Stahl, Robert; Lummel, Nina; Tonn, Joerg-Christian; Linn, Jennifer; Mehrkens, Jan-Hinnerk

    2016-03-01

    In this prospective study diffusion tensor imaging (DTI) was used to evaluate the influence of clinical and anatomical parameters on structural alterations within the fifth cranial nerve in patients with trigeminal neuralgia (TN) due to neurovascular compression. Overall, 81 patients (40 men and 41 women; mean age 60 ± 5 years) with typical TN were included who underwent microsurgical decompression. Preoperative 3.0-T high-resolution MRI and DTI were analyzed in a blinded fashion. The respective fractional anisotropy (FA) and apparent diffusion coefficient values were compared with the clinical, imaging, and intraoperative data. This study was approved by the institutional review board, and written informed consent was obtained from all patients. DTI analyses revealed significantly lower FA values within the vulnerable zone of the affected trigeminal nerve compared with the contralateral side (p = 0.05). The DTI analyses also included 3 patients without clear evidence of neurovascular conflict on preoperative MRI. No differences were seen between arterial and venous compression. Lower FA values were found 5 months after symptom onset; however, no correlation was found with the duration of symptoms or severity of compression. DTI analysis allows the quantification of structural alterations, even in those patients without any discernible neurovascular contact on MRI. Moreover, our findings support the hypothesis that both the arteries and veins can cause structural alterations that lead to TN. These aspects can be useful for making treatment decisions.

  7. Neurovascular unit dysfunction with blood-brain barrier hyperpermeability contributes to major depressive disorder: a review of clinical and experimental evidence

    PubMed Central

    2013-01-01

    About one-third of people with major depressive disorder (MDD) fail at least two antidepressant drug trials at 1 year. Together with clinical and experimental evidence indicating that the pathophysiology of MDD is multifactorial, this observation underscores the importance of elucidating mechanisms beyond monoaminergic dysregulation that can contribute to the genesis and persistence of MDD. Oxidative stress and neuroinflammation are mechanistically linked to the presence of neurovascular dysfunction with blood-brain barrier (BBB) hyperpermeability in selected neurological disorders, such as stroke, epilepsy, multiple sclerosis, traumatic brain injury, and Alzheimer’s disease. In contrast to other major psychiatric disorders, MDD is frequently comorbid with such neurological disorders and constitutes an independent risk factor for morbidity and mortality in disorders characterized by vascular endothelial dysfunction (cardiovascular disease and diabetes mellitus). Oxidative stress and neuroinflammation are implicated in the neurobiology of MDD. More recent evidence links neurovascular dysfunction with BBB hyperpermeability to MDD without neurological comorbidity. We review this emerging literature and present a theoretical integration between these abnormalities to those involving oxidative stress and neuroinflammation in MDD. We discuss our hypothesis that alterations in endothelial nitric oxide levels and endothelial nitric oxide synthase uncoupling are central mechanistic links in this regard. Understanding the contribution of neurovascular dysfunction with BBB hyperpermeability to the pathophysiology of MDD may help to identify novel therapeutic and preventative approaches. PMID:24289502

  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.

  9. Inflammatory Responses in Brain Ischemia

    PubMed Central

    Kawabori, Masahito; Yenari, Midori A.

    2017-01-01

    Brain infarction causes tissue death by ischemia due to occlusion of the cerebral vessels and recent work has shown that post stroke inflammation contributes significantly to the development of ischemic pathology. Because secondary damage by brain inflammation may have a longer therapeutic time window compared to the rescue of primary damage following arterial occlusion, controlling inflammation would be an obvious therapeutic target. A substantial amount of experimentall progress in this area has been made in recent years. However, it is difficult to elucidate the precise mechanisms of the inflammatory responses following ischemic stroke because inflammation is a complex series of interactions between inflammatory cells and molecules, all of which could be either detrimental or beneficial. We review recent advances in neuroinflammation and the modulation of inflammatory signaling pathways in brain ischemia. Potential targets for treatment of ischemic stroke will also be covered. The roles of the immune system and brain damage versus repair will help to clarify how immune modulation may treat stroke. PMID:25666795

  10. Neurovascular dysfunction in diabetic rats. Potential contribution of autoxidation and free radicals examined using transition metal chelating agents.

    PubMed Central

    Cameron, N E; Cotter, M A

    1995-01-01

    Oxygen free radical activity is elevated in diabetes mellitus and has been implicated in the etiology of vascular complications. Recent studies have shown that impaired perfusion of nerve endoneurium is a major cause of nerve fiber dysfunction in experimental diabetes. Free radical scavenger treatment prevents the development of nerve conduction abnormalities in diabetic rats. In vitro experiments suggest that autoxidation reactions of glucose, catalyzed by free transition metal ions, are a potential source of free radicals in diabetes. We investigated whether chronic treatment with deferoxamine and trientine, transition metal chelating agents which can prevent autoxidation, could correct nerve conduction and blood flow changes in streptozotocin-diabetic rats. A 20% reduction in sciatic nerve motor conduction velocity after 2 mo diabetes was 90% ameliorated by 2 wk of treatment with deferoxamine or trientine. Sciatic endoneurial nutritive blood flow was 45% reduced by diabetes, but was completely corrected by treatment. In contrast, transition metal chelation had no effect on blood flow or conduction velocity in nondiabetic rats. Thus, the data support the hypothesis that increased free radical activity by glucose autoxidation as a result of impaired transition metal handling is a major cause of early neurovascular deficits in diabetes. PMID:7635953

  11. The supraorbital region revisited: An anatomic exploration of the neuro-vascular bundle with regard to frontal migraine headache.

    PubMed

    Berchtold, Valeria; Stofferin, Hannes; Moriggl, Bernhard; Brenner, Erich; Pauzenberger, Reinhard; Konschake, Marko

    2017-09-01

    Recent findings on the pathogenesis of frontal migraine headache support, besides a central vasogenic cause, an alternative peripheral mechanism involving compressed craniofacial nerves. This is further supported by the efficiency of botulinum toxin injections as a new treatment option in frontal migraine headache patients. The supraorbital regions of 22 alcohol-glycerine-embalmed facial halves of both sexes were dissected. Both the supratrochlear and supraorbital nerves (STN and SON, respectively) were identified, and their relationship with the corrugator supercilii muscle (CSM) was investigated by dissection and ultrasound. The course of both nerves was defined, and the interaction between the supraorbital artery (SOA) and SON was determined. We discovered a new possible compression point of the STN passing through the orbital septum and verified previously described compression points of both STN and SON. Osteofibrous channels used by the STN and SON were found constantly. We described the varying topography of the STN and CSM, the SON and CSM, and the SON and SOA. Further, we provide an algorithm for the ultrasound visualization of the supraorbital neurovascular bundle. Our data support the hypothesis of a peripheral mechanism for frontal migraine headache because of following potential irritation points: first, the CSM is constantly perforated by the SON and frequently by the STN; second, the topographic proximity between SOA and SON and the osteofibrous channels is used by the SON and STN; and third, the STN passes through the orbital septum. Copyright © 2017 British Association of Plastic, Reconstructive and Aesthetic Surgeons. Published by Elsevier Ltd. All rights reserved.

  12. Intermittent pneumatic compression enhances neurovascular ingrowth and tissue proliferation during connective tissue healing: a study in the rat.

    PubMed

    Dahl, Johan; Li, Jian; Bring, Daniel K-I; Renström, Per; Ackermann, Paul W

    2007-09-01

    Intermittent pneumatic compression (IPC) is a treatment method to decrease venous stasis and stimulate blood flow. Recently, it was hypothesized that IPC may exert positive effects on tissue healing, a process highly dependent upon adequate circulation. In this study, we investigated the effects of daily 1-h IPC treatment during 2 and 4 weeks post-rat Achilles tendon rupture. The tendons were subjectively and semiquantitatively analyzed for collagen organization, fibroblast density, angiogenesis, and the occurrence of sensory neuropeptides, substance P (SP) and calcitonine gene related peptide (CGRP), as well as for a nerve regeneration marker, growth associated protein 43 (GAP-43). After 2 weeks of treatment, fibroblast density increased by 53% (p = 0.0004), vessel density by 64% (p = 0.022), and the occurrence of SP by 110% (p = 0.047) and CGRP by 47% (p = 0.0163) compared to untreated controls. Following 4 weeks of treatment, both the occurrence of sensory neuropeptides and the vessel density remained significantly higher (p < 0.05), whereas fibroblast density returned to normal. However, at 4 weeks the treated tendons displayed a higher degree of organized parallel collagen fibers, a sign of increased maturation. Daily IPC treatment improves neurovascular ingrowth and fibroblast proliferation in the healing tendon and may accelerate the repair process.

  13. A simple bracing technique to correct kinking of arterial branches to avoid ischemic sequelae during neurovascular surgery

    PubMed Central

    Motoyama, Yasushi; Tanaka, Yoshitaka; Gurung, Pritam; Nakagawa, Ichiro; Park, Young-Soo; Nakase, Hiroyuki

    2016-01-01

    Background: During microscopic procedures for neurovascular disease, we sometimes encounter kinking of arterial branches resulting in ischemic sequelae. A simple and useful technique that involves inserting a small, ball-like prosthesis made of oxidized cellulose or shredded Teflon with fibrin glue that corrects the arterial branch kinking and avoids subsequent compromise is reported. Methods: Between January and December 2014, three patients developed arterial kinking during microscopic procedures, including two in the caudal loop of the posterior inferior cerebellar artery during microvascular decompression for glossopharyngeal neuralgia and one in a branch of the middle cerebral artery (MCA) during clipping for an unruptured MCA aneurysm. Blood flow insufficiency was confirmed by microvascular Doppler ultrasonography (MDU) and indocyanine green (ICG) videoangiography. The prosthesis, which was made of shredded Teflon in two cases and oxidized cellulose in one case, was inserted into the crotch of the kinked arteries to correct the kinking of the arteries and restore the proper vascular shape and normal blood flow. Results: The small, ball-shaped prosthesis corrected the kinked arteries and maintained the proper shape, which was confirmed by ICG videoangiography and MDU during the operation and three-dimensional computerized tomography angiography postoperatively. Postoperatively, the patients did not manifest any ischemic sequelae related to the kinked arteries. Conclusion: The insertion of prostheses with fibrin glue into the crotch of a kinked artery for repair is considered a simple and useful method for correcting a kinked artery that avoids ischemic sequelae. PMID:26862447

  14. Endovascular Treatment of Wide-Necked Visceral Artery Aneurysms Using the Neurovascular Comaneci Neck-Bridging Device: A Technical Report.

    PubMed

    Maingard, Julian; Kok, Hong Kuan; Phelan, Emma; Logan, Caitriona; Ranatunga, Dinesh; Brooks, Duncan Mark; Chandra, Ronil V; Lee, Michael J; Asadi, Hamed

    2017-06-29

    Visceral and renal artery aneurysms (VRAAs) are an uncommon clinical entity but carry a risk of rupture with associated morbidity and mortality. The rupture risk is particularly high when the aneurysms are large, of unfavourable morphology or in the setting of pregnancy and perioperative period. Endovascular approaches are now first line in the treatment of VRAA, but conventional techniques may be ineffective in excluding aneurysms with unfavourable anatomy such as those with wide necks or at arterial bifurcation points. The neurovascular Comaneci neck-bridging device is used to temporarily cover the neck of intracranial aneurysms without occluding forward arterial flow during endovascular coiling. We report the novel use of the Comaneci neck-bridging device for the treatment of complex peripheral VRAAs. We describe the treatment of two patients with renal and splenic artery aneurysms demonstrating unfavourable anatomic morphology for conventional endovascular approaches. In the first patient, the renal artery aneurysm was situated at the intrarenal bifurcation of the main renal artery in the setting of a solitary kidney. In the second patient, the splenic artery aneurysm was situated close to the splenic hilum at the distal splenic arterial bifurcation. The Comaneci neck-bridging device was successfully used in both cases to assist coil embolisation with visceral preservation. The Comaneci neck-bridging device is potentially safe and effective for the treatment of peripheral VRAA with unfavourable anatomic characteristics that would have been deemed unsuitable for treatment using conventional techniques. Level 4, Technical Report.

  15. Virtual Stenting Workflow with Vessel-Specific Initialization and Adaptive Expansion for Neurovascular Stents and Flow Diverters

    PubMed Central

    Xu, Jinhui; Xiang, Jianping; Siddiqui, Adnan; Yang, Xinjian; Li, Haiyun; Meng, Hui

    2016-01-01

    Endovascular intervention using traditional neurovascular stents and densely braided flow diverters (FDs) have become the preferred treatment strategies for traditionally challenging intracranial aneurysms (IAs). Modeling stent and FD deployment in patient-specific aneurysms and its flow modification results prior to the actual intervention can potentially predict the patient outcome and treatment optimization. We present a clinically focused, streamlined virtual stenting workflow that efficiently simulates stent and FD treatment in patient-specific aneurysms based on expanding a simplex mesh structure. The simplex mesh is generated using an innovative vessel-specific initialization technique, which uses the patient’s parent artery diameter to identify the initial position of the simplex mesh inside the artery. A novel adaptive expansion algorithm enables the acceleration of deployment process by adjusting the expansion forces based on the distance of the simplex mesh from the parent vessel. The virtual stenting workflow was tested by modeling the treatment of two patient-specific aneurysms using the Enterprise stent and the Pipeline Embolization Device (commercial FD). Both devices were deployed in the aneurysm models in a few seconds. Computational fluid dynamics analyses of pre- and post-treatment aneurysmal hemodynamics show flow reduction in the aneurysmal sac in treated aneurysms, with the FD diverting more flow than the Enterprise stent. The test results show that this workflow can rapidly simulate clinical deployment of stents and FDs, hence paving the way for its future clinical implementation. PMID:26899135

  16. A connection between neurovascular conflicts within the cerebellopontine angle and vestibular neuritis, a case controlled cohort study.

    PubMed

    Loader, B; Linauer, I; Korkesch, S; Krammer-Effenberger, I; Zielinski, V; Schibany, N; Kaider, A; Vyskocil, E; Tscholakoff, D; Franz, P

    2016-10-01

    This retrospective, observer blinded case-control study aims to compare the prevalence of neurovascular conflicts (NVCs) of the vestibulocochlear nerve and the anterior inferior cerebellar artery (AICA) in patients presenting with clinical signs of acute vestibular neuritis with and without subsequent objective vestibular function loss (VFL). 58 acute cases of clinically suspected acute vestibular neuritis were investigated with same day cranial MRI at a tertiary referral centre and co