Punctuated episodes of spreading depolarizations erupt in the brain, encumbering tissue structure and function, and raising fascinating unanswered questions concerning their initiation and ...propagation. Linked to migraine aura and headache, cortical spreading depression contributes to the morbidity in the world's migraine with aura population. Even more ominously, erupting spreading depolarizations accelerate tissue damage during brain injury. The once-held view that spreading depolarizations may not exist in the human brain has changed, largely because of the discovery of migraine genes that confer cortical spreading depression susceptibility, the application of sophisticated imaging tools and efforts to interrogate their impact in the acutely injured human brain.
Celotno besedilo
Dostopno za:
DOBA, IJS, IZUM, KILJ, NUK, PILJ, PNG, SAZU, UILJ, UKNU, UL, UM, UPUK
2.
Pathophysiology of migraine Pietrobon, Daniela; Moskowitz, Michael A
Annual review of physiology,
01/2013, Letnik:
75
Journal Article
Recenzirano
Migraine is a collection of perplexing neurological conditions in which the brain and its associated tissues have been implicated as major players during an attack. Once considered exclusively a ...disorder of blood vessels, compelling evidence has led to the realization that migraine represents a highly choreographed interaction between major inputs from both the peripheral and central nervous systems, with the trigeminovascular system and the cerebral cortex among the main players. Advances in in vivo and in vitro technologies have informed us about the significance to migraine of events such as cortical spreading depression and activation of the trigeminovascular system and its constituent neuropeptides, as well as about the importance of neuronal and glial ion channels and transporters that contribute to the putative cortical excitatory/inhibitory imbalance that renders migraineurs susceptible to an attack. This review focuses on emerging concepts that drive the science of migraine in both a mechanistic direction and a therapeutic direction.
The underlying causes of migraine headache remained enigmatic for most of the 20th century. In 1979, The Lancet published a novel hypothesis proposing an integral role for the neuropeptide-containing ...trigeminal nerve. This hypothesis led to a transformation in the migraine field and understanding of key concepts surrounding migraine, including the role of neuropeptides and their release from meningeal trigeminal nerve endings in the mechanism of migraine, blockade of neuropeptide release by anti-migraine drugs, and activation and sensitisation of trigeminal afferents by meningeal inflammatory stimuli and upstream role of intense brain activity. The study of neuropeptides provided the first evidence that antisera directed against calcitonin gene-related peptide (CGRP) and substance P could neutralise their actions. Successful therapeutic strategies using humanised monoclonal antibodies directed against CGRP and its receptor followed from these findings. Nowadays, 40 years after the initial proposal, the trigeminovascular system is widely accepted as having a fundamental role in this highly complex neurological disorder and provides a road map for future migraine therapies.
This review focuses on mechanisms and emerging concepts that drive the science of stroke in a therapeutic direction. Once considered exclusively a disorder of blood vessels, growing evidence has led ...to the realization that the biological processes underlying stroke are driven by the interaction of neurons, glia, vascular cells, and matrix components, which actively participate in mechanisms of tissue injury and repair. As new targets are identified, new opportunities emerge that build on an appreciation of acute cellular events acting in a broader context of ongoing destructive, protective, and reparative processes. The burden of disease is great, and its magnitude widens as a role for blood vessels and stroke in vascular and nonvascular dementias becomes more clearly established. This review then poses a number of fundamental questions, the answers to which may generate new directions for research and possibly new treatments that could reduce the impact of this enormous economic and societal burden.
Peri-infarct depolarizations (PIDs) are seemingly spontaneous spreading depression-like waves that negatively impact tissue outcome in both experimental and human stroke. Factors triggering PIDs are ...unknown. Here, we show that somatosensory activation of peri-infarct cortex triggers PIDs when the activated cortex is within a critical range of ischemia. We show that the mechanism involves increased oxygen utilization within the activated cortex, worsening the supply-demand mismatch. We support the concept by clinical data showing that mismatch predisposes stroke patients to PIDs as well. Conversely, transient worsening of mismatch by episodic hypoxemia or hypotension also reproducibly triggers PIDs. Therefore, PIDs are triggered upon supply-demand mismatch transients in metastable peri-infarct hot zones due to increased demand or reduced supply. Based on the data, we propose that minimizing sensory stimulation and hypoxic or hypotensive transients in stroke and brain injury would reduce PID incidence and their adverse impact on outcome.
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•Sensory stimuli, episodic hypoxia, or hypotension trigger peri-infarct depolarizations•Mechanism involves transient worsening in O2 supply-demand mismatch in penumbra•In light of the data, clinical management of brain injury may need to be revisited
Peri-infarct depolarizations (PIDs) worsen tissue outcome in stroke. Von Bornstädt et al. show that somatosensory activation, and episodic hypoxemia or hypotension all trigger PIDs by worsening the oxygen supply-demand mismatch. Therefore, minimizing sensory stimulation and hypoxic or hypotensive transients may be beneficial in acute brain injury.
Migraine is a complex neurovascular pain disorder linked to the meninges, a border tissue innervated by neuropeptide-containing primary afferent fibers chiefly from the trigeminal nerve. Electrical ...or mechanical stimulation of this nerve surrounding large blood vessels evokes headache patterns as in migraine, and the brain, blood, and meninges are likely sources of headache triggers. Cerebrospinal fluid may play a significant role in migraine by transferring signals released from the brain to overlying pain-sensitive meningeal tissues, including dura mater. Interactions between trigeminal afferents, neuropeptides, and adjacent meningeal cells and tissues cause neurogenic inflammation, a critical target for current prophylactic and abortive migraine therapies. Here we review the importance of the cranial meninges to migraine headaches, explore the properties of trigeminal meningeal afferents, and briefly review emerging concepts, such as meningeal neuroimmune interactions, that may one day prove therapeutically relevant.
Innate immune cells recruited to inflammatory sites have short life spans and originate from the marrow, which is distributed throughout the long and flat bones. While bone marrow production and ...release of leukocyte increases after stroke, it is currently unknown whether its activity rises homogeneously throughout the entire hematopoietic system. To address this question, we employed spectrally resolved in vivo cell labeling in the murine skull and tibia. We show that in murine models of stroke and aseptic meningitis, skull bone marrow-derived neutrophils are more likely to migrate to the adjacent brain tissue than cells that reside in the tibia. Confocal microscopy of the skull-dura interface revealed myeloid cell migration through microscopic vascular channels crossing the inner skull cortex. These observations point to a direct local interaction between the brain and the skull bone marrow through the meninges.
Among patients with severe ischemic mitral regurgitation who were assigned to mitral-valve repair or replacement, there were no significant between-group differences in left ventricular remodeling or ...mortality at 2 years. Mitral regurgitation recurred more frequently in the repair group.
Ischemic mitral regurgitation is a serious consequence of coronary artery disease that carries a substantial risk of death from cardiovascular causes in proportion to its severity.
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Ischemic mitral regurgitation is anatomically characterized by remodeling or distortion of left ventricular geometry that ultimately results in papillary-muscle displacement, leaflet tethering, and impaired coaptation. For the subgroup of patients with severe ischemic mitral regurgitation, the prognosis is grave, with rates of death ranging from 15 to 40% at 1 year.
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For patients with severe ischemic mitral regurgitation, the benefit of surgical revascularization is undisputed, provided that the patient has suitable coronary . . .
Metabolically dormant bacteria present a critical challenge to effective antimicrobial therapy because these bacteria are genetically susceptible to antibiotic treatment but phenotypically tolerant. ...Such tolerance has been attributed to impaired drug uptake, which can be reversed by metabolic stimulation. Here, we evaluate the effects of central carbon metabolite stimulations on aminoglycoside sensitivity in the pathogen Pseudomonas aeruginosa. We identify fumarate as a tobramycin potentiator that activates cellular respiration and generates a proton motive force by stimulating the tricarboxylic acid (TCA) cycle. In contrast, we find that glyoxylate induces phenotypic tolerance by inhibiting cellular respiration with acetyl-coenzyme A diversion through the glyoxylate shunt, despite drug import. Collectively, this work demonstrates that TCA cycle activity is important for both aminoglycoside uptake and downstream lethality and identifies a potential strategy for potentiating aminoglycoside treatment of P. aeruginosa infections.
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•Central carbon perturbations alter aminoglycoside susceptibility in P. aeruginosa•TCA cycle activation of respiration and PMF overcomes aminoglycoside tolerance•Shunting of the TCA cycle biochemically protects against aminoglycoside lethality•Aminoglycoside lethality requires both drug uptake and downstream TCA cycle activity
Meylan et al. investigate mechanisms underlying antibiotic susceptibility in the cystic fibrosis pathogen Pseudomonas aeruginosa. Taking a systems approach, they find TCA cycle and respiratory activity to be important for both the uptake and the downstream lethality of aminoglycoside antibiotics.
After 2 years of follow-up in a randomized trial involving 301 patients with moderate ischemic mitral regurgitation undergoing CABG, the addition of mitral-valve repair did not improve left ...ventricular function or remodeling.
Ischemic mitral regurgitation of moderate severity develops in approximately 10% of patients after myocardial infarction.
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Mitral regurgitation is caused by the displacement of papillary muscle, leaflet tethering, reduced closing forces, and annular dilatation. Over time, the condition has an adverse effect on the rate of survival free of heart failure.
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Because most patients with ischemic mitral regurgitation have multivessel coronary artery disease requiring revascularization, surgeons have to consider whether to add mitral-valve repair to coronary-artery bypass grafting (CABG).
The appropriate surgical management of moderate ischemic mitral regurgitation at the time of CABG remains controversial. Some experts advocate revascularization alone . . .
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