Effects of isoflurane on arterial blood pressure, heart rate, and phrenic nerve discharge in the decerebrate rat.

BACKGROUND: The potent inhalational anesthetic isoflurane has widespread use in experimental investigations. Intratracheal administration of the agent attenuates breathing, blood pressure, heart rate, and baroreflex control of heart rate. Concurrent effects of potent inhalational anesthetics on hemodynamic waves and neural respiratory output have yet to be systematically interrogated. OBJECTIVES: We sought to determine the effects of administering isoflurane to unanesthetized decerebrate animals upon breathing, dynamic arterial pressure magnitude, and ventricular depolarization frequency. METHODS AND RESULTS: Experiments were conducted on ten unanesthetized decerebrate Sprague-Dawley adult male rats. Saturation of a hyperoxic gas mixture with 2.0% isoflurane in supracollicularly decerebrate rats having undergone successful weaning from isoflurane anesthesia quantally reduced phrenic nerve bursting frequency and coupling with the ventilator cycle from 1:1 to 1:2 and prolonged phrenic expiratory duration, though failed to modify phrenic inspiratory burst amplitude or duration. Isoflurane also reduced dynamic arterial pressure magnitude and heart rate, increased heart rate variability, and reduced blood pressure variability. CONCLUSIONS: Use of unanesthetized decerebrate preparations eschewing the confounding effects of anesthesia upon neural networks may prudently supplant the use of anesthetized animals when seeking to mechanistically interrogate propriobulbar interneuronal microcircuit oscillators constituting the respiratory rhythm and pattern generator, sympathetic oscillators, and cardiovagal premotoneurons.

Dynamic changes in arterial pressure following high cervical transection in the decerebrate rat.

Objective: Spinal transection has variable effects on arterial pressure, with some investigators demonstrating a precipitous decline and others reporting only a minimal decrease below normal. Recovery of arterial pressure following spinalization occurs with varying time courses - in some cases over days and in others over weeks to months. Given these findings, we sought to systematically test the hypothesis that in the unanesthetized decerebrate rat, arterial pressure would recover to pre-transection values over an acute time course.Design: Experiments were performed on a total of six Sprague-Dawley unanesthetized decerebrate adult male rats. In four rats, we determined dynamic changes in arterial pressure and heart rate in response to C1 transection.Results: Immediately following spinal cord injury, there were significant decreases in systolic blood (SBP) and mean arterial pressure (MAP), but not diastolic blood pressure (DBP). SBP, DBP, and MAP were significantly greater 170 min post-transection compared to immediate and 5 min-post transection values and were not statistically significantly different from pre-transection control. Heart rate decreased significantly following transection, but not immediately following the spinal cord injury. Lung inflation elicited depressor responses in all animals tested (n = 4 animals) and in three animals resulted in bradycardia. Hypercapnia tests effected a decrease in arterial pressure and heart rate (n = 3 animals).Conclusions: We demonstrate that in the unanesthetized decerebrate spinalized animal, arterial pressure is reduced by spinal transection and recovers over an acute time course to pre-transection values.

Sphenoid dural arteriovenous fistulas.

Sphenoid wing dural AVFs represent a rare clinical entity. These lesions may be asymptomatic or present with focal neurologic deficits, intracranial venous hypertension, or intracranial hemorrhage. Diagnosis is based on clinical findings and diagnostic imaging. They are alternatively classified as lesions of either the greater or lesser wings of the sphenoid bone. We performed a search of the PubMed database of studies evaluating the clinical behavior and surgical and endovascular therapies of these lesions. Dural AVFs draining into the superficial middle cerebral vein and/or laterocavernous sinus, or rather, lesions of the greater wing of the sphenoid, exhibit a greater likelihood of developing an aggressive clinical course, with higher probability of cortical venous reflux and consequent intracranial venous hypertension, intracranial hemorrhage, and symptomatic presentation. Dural AVFs of the sphenoparietal sinus, that is, lesions of the lesser wing of the sphenoid, typically exhibit a more benign clinical course, as there is a prominent epidural venous drainage into the cavernous sinus, reducing the risk of cortical venous reflux, and consequently, the probability of intracranial venous hypertension, hemorrhage, and floridly symptomatic presentation. These lesions may be treated via surgical clipping of the fistulous point, transarterial or transvenous embolization, and/or stereotactic radiosurgery. Though surgical intervention was the principal therapy due to facility of craniotomy access to the fistulous point, embolization has become standard of care permitted by innovation in endovascular technology. The natural history, clinical presentation, angioarchitecture, diagnosis, and management of these lesions are reviewed and discussed.

RETRACTED ARTICLE: Two dimensional speckle tracking echocardiography detects cardiac allograft stage III vasculopathy in recipients of heart transplants with preserved systolic function.

We, the Editors and Publisher of Acta Cardiologica, have retracted the following article:Michael George Zaki Ghali, Rebecca Stewart, George Zaki Ghali & Wolf Blitzer (2020) Two dimensional speckle tracking echocardiography detects cardiac allograft stage III vasculopathy in recipients of heart transplants with preserved systolic function, Acta Cardiologica, DOI: 10.1080/00015385.2020.1800963Since publication, we have received confirmation from the Karolinska Institutet that the corresponding author is not and has not been affiliated with their institution. The Karolinska Institutet is listed in the above article as having provided funding and ethical approval for the reported study. We have also reached out to the listed co-authors but have not been able to verify their authorship of the article. We have contacted the corresponding author for an explanation, but we have not received a response. As accurately representing authorship, affiliated institution, ethics approval and the source of funding is core to the integrity of published work, we are therefore retracting the article. The corresponding author listed in this publication has been informed.We have been informed in our decision-making by our policy on publishing ethics and integrity and the COPE guidelines on retractions.The retracted article will remain online to maintain the scholarly record, but it will be digitally watermarked on each page as 'Retracted'.

Trimethoprim-sulfamethoxazole-induced hyponatremia in an elderly lady with Achromobacter xylosoxidans pneumonia: Case report and insights into mechanism.

RATIONALE: Hyponatremia occurs frequently in the hospital setting and may be attributable to a host of etiologies. Drugs are frequently implicated. Trimethoprim-sulfamethoxazole (TMP/SMX) represents a well-recognized pharmacologic precipitant of drug-induced hyponatremia, with several reports extant in the retrievable literature. Nephrologists thus debate the mechanisms giving rise to TMP/SMX-induced hyponatremia and the precise mechanism by which treatment with TMP/SMX generates reductions of serum sodium concentration remain controversial. The agent has a well-known effect of antagonizing the effects of aldosterone upon the distal nephron. Renal salt wasting and the syndrome of inappropriate antidiuretic hormone secretion represent implicated mechanistic intermediaries in TMP/SMX-induced hyponatremia. PATIENT CONCERNS: The patient endorsed no explicit concerns. DIAGNOSES: We describe the case of an 83-year-old female clinically diagnosed with pneumonia found to have an initial serum sodium in the range of 130 to 134 mEq/L consistent with mild hyponatremia upon admission. Sputum cultures grew Achromobacter xylosoxidans susceptible to TMP/SMX. The patient's serum sodium concentration precipitously decline following institution of treatment with TMP/SMX to 112 to 114 mEq/L during the course of 5 days. INTERVENTIONS: Severe hyponatremia proved recalcitrant to initial therapy with supplemental salt tabs and standard doses of the vasopressin receptor antagonist tolvaptan. OUTCOMES: Escalating doses of tolvaptan increased the patient's sodium to 120 to 124 mEq/L. The patient was transferred to another hospital for further management. During her stay, the patient did not exhibit frank or obvious clinical features consistent with hyponatremia nor readily appreciable evidence of volume depletion. LESSONS: TMP/SMX represents a frequent, though underreported cause of hyponatremia in the hospital setting several authors believe natriuresis may represent the most common mechanism underlying TMP/SMX-induced hyponatremia. Evidence implicating natriuresis to be mechanistic in TMP/SMX-induced hyponatremia include clinically appreciable hypovolemia and resolution of hyponatremia with oral or intravenous salt repletion. Salt repletion failed to monotherapeutically enhance our patient's hyponatremiadisfavoring renal salt wasting as originately mechanistic. Contemporaneous refractoriness of serum sodium to fluid restriction nor standard doses of tolvaptan confounded our initial attempts to mechanistically attribute the patient's hyponatremia to a specific cause. Clinical euvolemia and rapid response of hyponatremia to exceptionally high doses of tolvaptan strongly favors syndrome of inappropriate antidiuretic hormone to represent the chief mechanism by which TMP/SMX exacerbates hyponatremia.

The Ethical Dilemma in the Surgical Management of Low Grade Gliomas According to the Variable Availability of Resources and Surgeon Experience.

Low grade gliomas (LGGs) affect young individuals in the prime of life. Management may alternatively include biopsy and observation or surgical resection. Recent evidence strongly favors maximal and supramaximal resection of LGGs in optimizing survival metrics. Awake craniotomy with cortical mapping and electrical stimulation along with other preoperative and intraoperative surgical adjuncts, including intraoperative magnetic resonance and diffusion tensor imaging, facilitates maximization of resection and eschews precipitating neurological deficits. Intraoperative imaging permits additional resection of identified residual to be completed within the same surgical session, improving extent of resection and consequently progression free and overall survival. These resources are available in only a few centers throughout the United States, raising an ethical dilemma as to where patients harboring LGGs should most appropriately be treated.

Structure and function of the perivascular fluid compartment and vertebral venous plexus: Illumining a novel theory on mechanisms underlying the pathogenesis of Alzheimer's, cerebral small vessel, and neurodegenerative diseases.

Blood dynamically and richly supplies the cerebral tissue via microvessels invested in pia matter perforating the cerebral substance. Arteries penetrating the cerebral substance derive an investment from one or two successive layers of pia mater, luminally apposed to the pial-glial basal lamina of the microvasculature and abluminally apposed to a series of aquaporin IV-studded astrocytic end feet constituting the soi-disant glia limitans. The full investment of successive layers forms the variably continuous walls of the periarteriolar, pericapillary, and perivenular divisions of the perivascular fluid compartment. The pia matter disappears at the distal periarteriolar division of the perivascular fluid compartment. Plasma from arteriolar blood sequentially transudates into the periarteriolar division of the perivascular fluid compartment and subarachnoid cisterns in precession to trickling into the neural interstitium. Fluid from the neural interstitium successively propagates into the venules through the subarachnoid cisterns and perivenular division of the perivascular fluid compartment. Fluid fluent within the perivascular fluid compartment flows gegen the net direction of arteriovenular flow. Microvessel oscillations at the central tendency of the cerebral vasomotion generate corresponding oscillations of within the surrounding perivascular fluid compartment, interposed betwixt the abluminal surface of the vessels and internal surface of the pia mater. The precise microanatomy of this most fascinating among designable spaces has eluded the efforts of various investigators to interrogate its structure, though most authors non-consensusly concur the investing layers effectively and functionally segregate the perivascular and subarachnoid fluid compartments. Enlargement of the perivascular fluid compartment in a variety of neurological disorders, including senile dementia of the Alzheimer's type and cerebral small vessel disease, may alternately or coordinately constitute a correlative marker of disease severity and a possible cause implicated in the mechanistic pathogenesis of these conditions. Venular pressures modulating oscillatory dynamic flow within the perivascular fluid compartment may similarly contribute to the development of a variety among neurological disorders. An intimate understanding of subtle features typifying microanatomy and microphysiology of the investing structures and spaces of the cerebral microvasculature may powerfully inform mechanistic pathophysiology mediating a variety of neurovascular ischemic, neuroinfectious, neuroautoimmune, and neurodegenerative diseases.

Galenic Pial Arteriovenous Fistulas in Adults.

BACKGROUND: Vein of Galen aneurysmal malformations (VOGMs) are pial arteriovenous fistulas possessing Galenic venous drainage most commonly presenting during the neonatal period and infancy, with initial discovery during adulthood quite rare. OBJECTIVES AND METHODS: We conducted a literature survey of the PubMed database in order to identify Galenic pial arteriovenous fistulas (GPAVFs) with major manifestation or initial presentation during adulthood. Inclusionary criteria included pial AVFs with Galenic drainage with major manifestation or initial presentation at, or older than, 18 years. Exclusionary criteria included exclusive pediatric onset of symptomatology attributable to GPAVFs without a new onset major presentation during adulthood, exclusive or major dural arterial supply, arteriovenous malformations with Galenic drainage, developmental venous anomalies with Galenic drainage, isolated varices or anomalies of the vein of Galen, and any lesions with uncertainty regarding true GPAVF nature. RESULTS: Our search generated 1589 articles. Excluding duplicates, 26 cases met criteria for evaluation. Mean age was 34.1 +/- 2.53 years. Clinical presentations of GPAVFs among adults included headache, intracranial hemorrhage, seizures, and focal neurologic deficits. Management strategies included observation (n = 5), emergent ventriculostomy or Torkildsen shunt (n = 3), cerebrospinal fluid diversion via ventriculoperitoneal shunting (n = 4), microsurgical obliteration or thrombectomy (n = 4), transarterial and/or transvenous embolotherapeutic obliteration (n = 7), and concurrent embolotherapy and radiosurgical irradiation (n = 1). CONCLUSIONS: GPAVFs in adults often present with symptomatology of mild severity and may be effectively managed conservatively, though occasionally present catastrophically or may be treated via cerebrospinal fluid diversion, microsurgical obliteration, or endovascular embolization. Severity sufficient to require emergent intervention portended a poor outcome.

Nafamostat mesylate attenuates the pathophysiologic sequelae of neurovascular ischemia.

Nafamostat mesylate, an apparent soi-disant panacea of sorts, is widely used to anticoagulate patients undergoing hemodialysis or cardiopulmonary bypass, mitigate the inflammatory response in patients diagnosed with acute pancreatitis, and reverse the coagulopathy of patients experiencing the commonly preterminal disseminated intravascular coagulation in the Far East. The serine protease inhibitor nafamostat mesylate exhibits significant neuroprotective effects in the setting of neurovascular ischemia. Nafamostat mesylate generates neuroprotective effects by attenuating the enzymatic activity of serine proteases, neuroinflammatory signaling cascades, and the endoplasmic reticulum stress responses, downregulating excitotoxic transient receptor membrane channel subfamily 7 cationic currents, modulating the activity of intracellular signal transduction pathways, and supporting neuronal survival (brain-derived neurotrophic factor/TrkB/ERK1/2/CREB, nuclear factor kappa B. The effects collectively reduce neuronal necrosis and apoptosis and prevent ischemia mediated disruption of blood-brain barrier microarchitecture. Investigational clinical applications of these compounds may mitigate ischemic reperfusion injury in patients undergoing cardiac, hepatic, renal, or intestinal transplant, preventing allograft rejection, and treating solid organ malignancies. Neuroprotective effects mediated by nafamostat mesylate support the wise conduct of randomized prospective controlled trials in Western countries to evaluate the clinical utility of this compound.

Retracted: Control of hypoglossal pre-inspiratory discharge.

NEW FINDINGS: What is the topic of this review? This review explores the modulatory role of lung vagal afferents and intra-neuraxial and carotid body chemoreceptors upon hypoglossal pre-inspiratory activity. What advances does it highlight? Pre-inspiratory activity manifesting in hypoglossal neural efferent discharge may be potentiated by mechanical interruption of vagal continuity and challenge with administration of a hypoxic and/or hypercapnic gas mixture and attenuated by static and/or dynamic pulmonary stretch. Differential excitability of, or premotoneuronal volleys exhibiting distinct spatiotemporal patterns of discharge arriving at, motoneurons residing within the hypoglossal motor nucleus may emergently generate phase-spanning pre-inspiratory inspiratory activity of hypoglossal neural efferent discharge manifest at the population level. ABSTRACT: The hypoglossal nerve (XII) innervates muscles mediating excursive movements of the tongue. The population discharge of hypoglossalmotoneuronal axons constituting the hypoglossal nerve precedes and extends through the inspiratory epoch. The epoch subtended between the onsets of hypoglossal and phrenic neural discharge constitutes so-called pre-inspiration. Hypoglossal pre-inspiratory neural discharge serendipitously displaces the tongue along a tensor reducing upper airway resistance anticipative of succeeding inspiratory efforts. Hypoglossal motoneurons exhibiting discharge onset during pre-inspiration experience successive hyperpolarization of membrane voltage and attenuation of unitary spiking frequency, although a subset may, paradoxically and state-dependently, exhibit depolarization of membrane voltage and augmentation of neuronal spiking frequency, by dynamic stretch placed upon the alveolar walls and interstitium. Marked static elevation of positive-end expiratory pressure may induce hypoglossal bursting decoupled from phasic rhythmic phrenic discharge. Augmentation of the amplitude and/or duration of hypoglossal inspiratory discharge during successive pre-inspiratory and inspiratory epochs by inhalation of a hypoxic and/or hypercapnic gas mixture remains restrained in the presence of intact vagal inputs and is potentiated by interruptions of vagal continuity. Unravelling the mechanisms underlying the genesis of pre-inspiratory activity will inform our understanding of respiratory rhythm generation and pattern shaping. In the present work, I seek to explore the mechanisms underlying modulation of hypoglossal pre-inspiratory discharge by hypercapnia, hypoxia and static and dynamic lung stretch placed upon hypoglossal pre-inspiratory activity, the mechanisms underlying the generation of hypoglossal pre-inspiratory activity, and the extent of microanatomical and functional overlap between propriobulbar interneuronal microcircuits generating hypoglossal pre-inspiratory activity and propriobulbar interneuronal microcircuit oscillators generating pre-inspiratory activity inaugurally inducing respiratory rhythmic activity and thus use experimental data from previous work and that developed by other investigators to explore the modulatory role of lung vagal afferents and intra-neuraxial and carotid body chemoreceptors upon hypoglossal pre-inspiratory activity.

ß adrenergic receptor modulated signaling in glioma models: promoting ß adrenergic receptor-ß arrestin scaffold-mediated activation of extracellular-regulated kinase 1/2 may prove to be a panacea in the treatment of intracranial and spinal malignancy and extra-neuraxial carcinoma.

Neoplastically transformed astrocytes express functionally active cell surface ß adrenergic receptors (ßARs). Treatment of glioma models in vitro and in vivo with ß adrenergic agonists variably amplifies or attenuates cellular proliferation. In the majority of in vivo models, ß adrenergic agonists generally reduce cellular proliferation. However, treatment with ß adrenergic agonists consistently reduces tumor cell invasive potential, angiogenesis, and metastasis. ß adrenergic agonists induced decreases of invasive potential are chiefly mediated through reductions in the expression of matrix metalloproteinases types 2 and 9. Treatment with ß adrenergic agonists also clearly reduce tumoral neoangiogenesis, which may represent a putatively useful mechanism to adjuvantly amplify the effects of bevacizumab. Bevacizumab is a monoclonal antibody targeting the vascular endothelial growth factor receptor. We may accordingly designate ßagonists to represent an enhancer of bevacizumab. The antiangiogenic effects of ß adrenergic agonists may thus effectively render an otherwise borderline effective therapy to generate significant enhancement in clinical outcomes. ß adrenergic agonists upregulate expression of the major histocompatibility class II DR alpha gene, effectively potentiating the immunogenicity of tumor cells to tumor surveillance mechanisms. Authors have also demonstrated crossmodal modulation of signaling events downstream from the ß adrenergic cell surface receptor and microtubular polymerization and depolymerization. Complex effects and desensitization mechanisms of the ß adrenergic signaling may putatively represent promising therapeutic targets. Constant stimulation of the ß adrenergic receptor induces its phosphorylation by ß adrenergic receptor kinase (ßARK), rendering it a suitable substrate for alternate binding by ß arrestins 1 or 2. The binding of a ß arrestin to ßARK phosphorylated ßAR promotes receptor mediated internalization and downregulation of cell surface receptor and contemporaneously generates a cell surface scaffold at the ßAR. The scaffold mediated activation of extracellular regulated kinase 1/2, compared with protein kinase A mediated activation, preferentially favors cytosolic retention of ERK1/2 and blunting of nuclear translocation and ensuant pro-transcriptional activity. Thus, ßAR desensitization and consequent scaffold assembly effectively retains the cytosolic homeostatic functions of ERK1/2 while inhibiting its pro-proliferative effects. We suggest these mechanisms specifically will prove quite promising in developing primary and adjuvant therapies mitigating glioma growth, angiogenesis, invasive potential, and angiogenesis. We suggest generating compounds and targeted mutations of the ß adrenergic receptor favoring ß arrestin binding and scaffold facilitated activation of ERK1/2 may hold potential promise and therapeutic benefit in adjuvantly treating most or all cancers. We hope our discussion will generate fruitful research endeavors seeking to exploit these mechanisms.

Microneurosurgical techniques and perioperative strategies utilized to optimize experimental supracollicular decerebration in rats.

Decerebration permits neurophysiological experimentation absent the confounding effects of anesthesia. Use of the unanesthetized decerebrate preparation in vivo offers several advantages compared with recordings performed in reduced slice preparations, providing the capacity to perform extracellular and intracellular neuronal recordings in the presence of an intact brainstem network. The decerebration procedure typically generates variable degrees of blood loss, which often compromises the hemodynamic stability of the preparation. We describe our microsurgical techniques and discuss microsurgical pearls utilized in order to consistently generate normotensive supracollicularly decerebrate preparations of the rat, exhibiting an augmenting pattern of phrenic nerve discharge. In brief, we perform bilateral ligation of the internal carotid arteries, biparietal craniectomies, securing of the superior sagittal sinus to the overlying strip of bone, removal of the median strip of bone overlying the superior sagittal sinus, supracollicular decerebrative encephalotomy, removal of the cerebral hemispheres, and packing of the anterior and middle cranial fossae with thrombin soaked gelfoam sponges. Hypothermia and potent inhalational anesthesia ensure neuroprotection during postdecerebrative neurogenic shock. Advantages of our approach include a bloodless and fast operation with a nil percent rate of operative mortality. We allow animal arterial pressure to recover gradually in parallel with gentle weaning of anesthesia following decerebration, performed contemporaneously with the provision of the neuromuscular antagonist vecuronium. Anesthetic weaning and institution of vecuronium should be contemporaneous, coordinate, gentle, gradual, and guided by the spontaneous recovery of the arterial blood pressure. We describe our microsurgical techniques and perioperative management strategy designed to achieve decerebration and accordingly survey the literature on techniques used across several studies in achieving these goals.

Preservation of the Lenticulostriate Arteries During Insular Glioma Resection.

Insular gliomas represent 25% and 10% of low- and high-grade gliomas, respectively. Their resection proves challenging due to the intimate involvement of eloquent parenchyma and the lenticulostriate arteries (LSAs), limiting facility of achieving maximal safe resection. The majority of postoperative deficits following insular glioma resection is attributed to compromise of the LSAs. It is contemporaneously critical and challenging to preserve these vessels, given they are numerous and small, with an intraparenchymal course hidden from direct visualization during the operative intervention. A lesser degree of medially directed displacement of the LSAs predicts tumoral encasement of these vessels, which portends a decreased likelihood for achieving a gross total resection and increased probability of postoperative morbidity. Preservation of these vessels thus requires knowledge of their location during the entirety of the insular glioma resection and is facilitated by pre- and intra-operative imaging. Intraoperative real-time tracking, however, may prove rather challenging, especially with transcortical access. Conventional catheter digital subtraction angiography, computed tomographic angiography, magnetic resonance imaging and angiography, and three-dimensional ultrasound powered Doppler have proven effective modalities in assessing lenticulostriate position, and their use facilitates a greater extent of resection while minimizing the attendant morbidity consequent to LSA injury.

Role of fast inhibitory synaptic transmission in neonatal respiratory rhythmogenesis and pattern formation.

Several studies have investigated the general role of chloride-based neurotransmission (GABAA and glycinergic signaling) in respiratory rhythmogenesis and pattern formation. In several brain regions, developmental alterations in these signaling pathways have been shown to be mediated by changes in cation-chloride cotransporter (CC) expression. For instance, CC expression changes during the course of neonatal development in medullary respiratory nuclei and other brain/spinal cord regions in a manner which decreases the cellular import, and increases the export, of chloride ions, shifting reversal potentials for chloride to progressively more negative values with maturation. In slice preparations of the same, this is related to an excitatory-to-inhibitory shift of GABAA- and glycinergic signaling. In medullary slices, GABAA-/glycinergic signaling in the early neonatal period is excitatory, becoming inhibitory over time. Additionally, blockade of the Na+/K+/2Cl- cotransporter, which imports these ions via secondary active transport, converts excitatory response to inhibitory ones. These effects have not yet been demonstrated at the individual respiratory-related neuron level to occur in intact (in vivo or in situ) animal preparations, which in contrast to slices, possess normal network connectivity and natural sources of tonic drive. Developmental changes in respiratory rhythm generating and pattern forming pontomedullary respiratory circuitry may contribute to critical periods, during which there exist increased risk for perinatal respiratory disturbances of central, obstructive, or hypoxia/hypercapnia-induced origin, including the sudden infant death syndrome. Thus, better characterizing the neurochemical maturation of the central respiratory network will enhance our understanding of these conditions, which will facilitate development of targeted therapies for respiratory disturbances in neonates and infants.

Rubral modulation of breathing.

NEW FINDINGS: What is the topic of this review? Rubral modulation of pontomedullary respiratory rhythm and pattern generating circuitry powerfully contributes to regulation of breathing. What advances does it highlight? Studies have demonstrated extensive rubromedullary and rubrospinal projections to zones generating and organizing the respiratory rhythm and pattern. Rubral modulation of respiratory output effects inspiratory expiratory phase transitions with stimulation generating inhibitory or excitatory responses of medullary inspiratory and expiratory units. The red nucleus mediates hypoxic ventilatory depression, integrates respiratory output with oromotor and locomotor activity, and modulates respiratory output during noxious stimulation. ABSTRACT: Although normal triphasic eupnoea can be produced by the pontomedullary respiratory network after pontomesencephalic transection, the midbrain provides important modulation of respiration. Specifically, stimulation of the red nucleus elicits inspiratory inhibition, as manifest in the phrenic neurogram, in addition to excitation and inhibition of individual medullary respiratory-related units, with the majority of premotor units that receive rubral modulation being inhibited. Stimulation of the red nucleus also induces respiratory phase transitions, which appear to be pontine independent. These effects might be mediated by rubrobulbar and/or rubrospinal tracts. Although lesioning of the red nucleus does not alter respiration in normoxic conditions, it eliminates hypoxic ventilatory depression, which is the second phase of the biphasic ventilatory response to low oxygen tension. The finding that the red nucleus also plays a role in anti-nociception suggests that it might coordinate respiratory responses during noxious stimulation and, given that the red nucleus regulates upper limb flexors, it might represent one region in a distributed bulbar network contributing to respiratory-locomotor integration. Modulation of jaw opening by the red nucleus would support a model whereby it coordinates oromotor activity with breathing. Thus, the multiplicity of roles played by the red nucleus aptly position it to coordinate respiration in a variety of behavioural states. In this review, we seek to highlight the different features and regional specializations of the rubral contribution to respiratory control and underscore its vital importance to breathing in the freely behaving mammal.

Flow Diversion for the Treatment of Petrous Internal Carotid Artery Aneurysms.

Petrous internal carotid artery (ICA) aneurysms are rare and pose a unique management dilemma. They are most commonly fusiform. They are difficult to treat surgically and typically not amenable to selective aneurysmal obliteration. The advent of flow diverters, such as the Pipeline endovascular device, has offered a new approach to these historically challenging lesions. The unique utility of flow diversion in treatment of petrous ICA aneurysms is reviewed and discussed.

Posteroinferior Cerebellar Artery Aneurysms: Influence of Angioanatomy on the Safety of Flow Diversion Treatment.

Several anatomical variables critically influence therapeutic strategies for posteroinferior cerebellar artery (PICA) aneurysms and, specifically, the safety of flow diversion for these lesions. We review the microsurgical anatomy of the PICA, discussing and detailing these considerations in the treatment of aneurysms of this vessel from a theoretical perspective and in light of our previously published clinical results.

Respiratory rhythm generation and pattern formation: oscillators and network mechanisms.

The respiratory rhythm is generated by the interaction of oscillators disparately distributed throughout the pons, medulla, and spinal cord. According to the classic model, the interaction amongst preBötzinger complex (preBötzC) spontaneously bursting preinspiratory units and Bötzinger complex (BötzC) expiratory cells generates the principal respiratory rhythm, thence relayed caudally to the pattern generating elements and premotoneurons of the rostral and caudal divisions of the ventral respiratory group and bulbospinal units of the dorsal respiratory group. Rhythm and pattern generating elements in the ventrolateral medulla receive powerful phasic and tonic modulatory inputs from diencephalic structures, midbrain, Kölliker-Fuse, and parabrachial nuclei, retrotrapezoid nucleus, parafacial respiratory group, ventrolateral metencephalon, nucleus tractus solitarius, and brainstem reticular formation, collectively shaping the normal eupneic discharge. Empirical and computational studies have generated models of respiratory rhythmogenesis and pattern formation variously predicated upon pacemaker, network, or hybrid pacemaker network mechanisms to explain oscillatory behavior and regularity. Network mechanisms critically require the integrity and functionality of inhibitory synaptic neurotransmission. The operation and contribution of inhibitory elements in respiratory rhythm generation and pattern formation are well demonstrated empirically and incorporated in computational network and hybrid models of breathing. Fast inhibitory synaptic neurotransmission utilizes GABAAergic and glycinergic mediated activation of receptor linked chloride conductances, generating an inwardly directed flux of chloride ions mediating membrane voltage hyperpolarization and is required to generate eupneic respiratory patterns in vivo and situ. Persistence of rhythmicity in the presence of synaptic antagonism of GABAA and glycine receptor mediated fast inhibitory neurotransmission indicates pacemaker generating mechanisms sufficiently capable of independently generating this behavior in vivo and transected intact preparations maintaining the preBötzC as the most rostrally preserved structure. The role of GABAB receptor mediated neuromodulation in respiratory rhythm generation and pattern formation is comparatively significantly less investigated. GABABergic activation of postsynaptic and presynaptic membrane receptors variably upregulates potassium conductances and downregulates calcium conductances. Respiratory rhythm and pattern are powerfully modulated in vivo, in situ, and in vitro by superfusion or localized microinjections of GABABergic agonists and antagonists, though are typically not abolished by these experimental interventions. Directionality and magnitude of these effects exhibit maturational changes. The relative depolarization of chloride reversal potentials during the early neonatal period, with gradual shifts towards normal hyperpolarizing values during development, suggests GABABergic signaling may mediate the inhibitory neurotransmission necessary to generate triphasic eupnea. We review and discuss the role of spontaneously bursting oscillators and network mechanisms predicating upon fast inhibitory synaptic neurotransmission in contributing to respiratory rhythmogenesis and pattern formation.