Developmental Venous Anomalies and Arteriovenous Malformations Coordinately Drained by the Internal Cerebral Vein: Clues to Pathogenesis.

An intimate understanding of dynamic angioarchitectural development of vascular malformations involving the intracranium may provide mechanistic insight into the incipient pathogenesis of these lesions. The authors report two patients harboring cerebral developmental venous anomaly (DVA) and three patients harboring sporadically developing cerebral arteriovenous malformations (AVM) in whom the internal cerebral vein (ICV) represented the chief venous egress route. Onyx embolization successfully achieved complete obliteration in all patients harboring cerebral AVMs. Two female patients presenting with a chief complaint of chronic headaches was found to harbor deeply situated DVA draining via the lateral group of direct lateral vein (DLV) egress via the ICV. Three female patients presenting with chronic headaches or intraparenchymal hemorrhage were found to possess cerebral AVMs deriving arterial feeders from the anterior cerebral arteries, with major venous drainage into the ICV via the direct lateral veins or terminal vein. Common drainage of DVAs and AVMs may indicate a common originate genesis. This pattern of venous drainage in the context of seeking to develop a cohesive and coherent model illumining our understanding of the mechanistic incipient pathogenesis of AVMs.

Retraction: Ghali MGZ, et al. Mechanisms underlying the generation of autonomorespiratory coupling amongst the respiratory central pattern generator, sympathetic oscillators, and cardiovagal premotoneurons. Journal of Integrative Neuroscience. 2020; 19: 521-560.

No abstract present.

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.

Telovelar surgical approach.

Surgical access to lesions in the fourth ventricle may be achieved utilizing transvermian or transtelovelar trajectories. We performed a search of the PubMed database for studies describing the microsurgical details and evaluating the clinical utility of the telovelar surgical approach. The telovelar approach has proven to be a safe, effective, and versatile alternative to the transvermian approach. The operative strategy utilizes midline suboccipital craniotomy without or with C1 laminectomy, followed by cerebellar hemispheric and tonsillar retraction, and wide durotomy. Access is generously provided to the fourth ventricle from calamus scriptorius to Sylvian aqueduct and foramen Luschkae bilaterally. Anatomic dissection studies evaluating and comparing the relative benefits of the operative exposure offered by these approaches have demonstrated improved access to the lateral recess gained by the telovelar trajectory and facilitated exposure of rostral reaches of the fourth ventricle by the vermian trajectory. In general, operative exposure may be significantly improved with tonsillar retraction or resection, bilateral telovelar opening, and performing C1 laminectomy in order to improve access to the rostral fourth ventricle, which may be variably combined depending on location of pathology. Cerebellar mutism, a high incidence of which occurs with vermian approaches, is not commonly observed with use of the telovelar trajectory, though injury to the dentate nuclei may precipitate this syndrome. Deficits incurred with the vermian approach may include cerebellar mutism, dysequilibrium, truncal ataxia, posterior fossa syndrome, cranial nucleopathies and nerve palsies, and vascular injury to the posterior inferior cerebellar artery. The telovelar surgical approach has proven a safe and useful alternative to the transvermian trajectory. A significantly lower incidence of cerebellar mutism and cerebellogenic deficits represents the principal advantage of the telovelar approach. Further studies are necessary in order to prospectively evaluate and compare extents of resection, morbidity, and mortality utilizing the telovelar versus vermian approaches for microsurgically resecting fourth ventricular tumors.

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'.

Mechanisms underlying the generation of autonomorespiratory coupling amongst the respiratory central pattern generator, sympathetic oscillators, and cardiovagal premotoneurons.

The respiratory rhythm and pattern and sympathetic and parasympathetic outflows are generated by distinct, though overlapping, propriobulbar arrays of neuronal microcircuit oscillators constituting networks utilizing mutual excitatory and inhibitory neuronal interactions, residing principally within the metencephalon and myelencephalon, and modulated by synaptic influences from the cerebrum, thalamus, hypothalamus, cerebellum, and mesencephalon and ascending influences deriving from peripheral stimuli relayed by cranial nerve afferent axons. Though the respiratory and cardiovascular regulatory effector mechanisms utilize distinct generators, there exists significant overlap and interconnectivity amongst and between these oscillators and pathways, evidenced reciprocally by breathing modulation of sympathetic oscillations and sympathetic modulation of neural breathing. These coupling mechanisms are well-demonstrated coordinately in sympathetic- and respiratory-related central neuronal and efferent neurogram recordings and quantified by the findings of cross-correlation, spectra, and coherence analyses, combined with empirical interventions including lesioning and pharmacological agonist and antagonist microinjection studies, baroloading, barounloading, and hypoxic and/or hypercapnic peripheral and/or central chemoreceptor stimulation. Sympathetic and parasympathetic central neuronal and efferent neural discharge recordings evidence classic fast rhythms produced by propriobulbar neuronal networks located within the medullary division of the lateral tegmental field, coherent with cardiac sympathetic nerve discharge. These neural efferent nerve discharges coordinately evidence slow synchronous oscillations, constituted by Traube Hering (i.e., high frequency), Mayer wave (i.e., medium or low frequency), and vasogenic autorhythmicity (i.e., very low frequency) wave spectral bands. These oscillations contribute to coupling neural breathing, sympathetic oscillations, and parasympathetic cardiovagal premotoneuronal activity. The mechanisms underlying the origins of and coupling amongst, these waves remains to be unresolved.

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.

Mechanisms Contributing to the Generation of Mayer Waves.

Mayer waves may synchronize overlapping propriobulbar interneuronal microcircuits constituting the respiratory rhythm and pattern generator, sympathetic oscillators, and cardiac vagal preganglionic neurons. Initially described by Sir Sigmund Mayer in the year 1876 in the arterial pressure waveform of anesthetized rabbits, authors have since extensively observed these oscillations in recordings of hemodynamic variables, including arterial pressure waveform, peripheral resistance, and blood flow. Authors would later reveal the presence of these oscillations in sympathetic neural efferent discharge and brainstem and spinal zones corresponding with sympathetic oscillators. Mayer wave central tendency proves highly consistent within, though the specific frequency band varies extensively across, species. Striking resemblance of the Mayer wave central tendency to the species-specific baroreflex resonant frequency has led the majority of investigators to comfortably presume, and generate computational models premised upon, a baroreflex origin of these oscillations. Empirical interrogation of this conjecture has generated variable results and derivative interpretations. Sinoaortic denervation and effector sympathectomy variably reduces or abolishes spectral power contained within the Mayer wave frequency band. Refractorines of Mayer wave generation to barodeafferentation lends credence to the hypothesis these waves are chiefly generated by brainstem propriobulbar and spinal cord propriospinal interneuronal microcircuit oscillators and likely modulated by the baroreflex. The presence of these waves in unitary discharge of medullary lateral tegmental field and rostral ventrolateral medullary neurons (contemporaneously exhibiting fast sympathetic rhythms [2-6 and 10 Hz bands]) in spectral variability in vagotomized pentobarbital-anesthetized and unanesthetized midcollicular (i.e., intercollicular) decerebrate cats supports genesis of Mayer waves by supraspinal sympathetic microcircuit oscillators. Persistence of these waves following high cervical transection in vagotomized unanesthetized midcollicular decerebrate cats would seem to suggest spinal sympathetic microcircuit oscillators generate these waves. The widespread presence of Mayer waves in brainstem sympathetic-related and non-sympathetic-related cells would seem to betray a general tendency of neurons to oscillate at this frequency. We have thus presented an extensive and, hopefully cohesive, discourse evaluating, and evolving the interpretive consideration of, evidence seeking to illumine our understanding of origins of, and insight into mechanisms contributing to, the genesis of Mayer waves. We have predicated our arguments and conjectures in the substance and matter of empirical data, though we have occasionally waxed philosophical beyond these traditional confines in suggesting interpretations exceeding these limits. We believe our synthesis and interpretation of the relevant literature will fruitfully inspire future studies from the perspective of a more intimate appreciation and conceptualization of network mechanisms generating oscillatory variability in neuronal and neural outputs. Our evaluation of Mayer waves informs a novel set of disciplines we term quantum neurophysics extendable to describing subatomic reality. Beyond informing our appreciation of mechanisms generating sympathetic oscillations, Mayer waves may constitute an intrinsic property of neurons extant throughout the cerebrum, brainstem, and spinal cord or reflect an emergent property of interactions between arteriogenic and neuronal oscillations.

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 structure and function: molecular insights guiding the development of novel therapeutic strategies to treat malignancy.

ß adrenergic receptors mediate effects via activation of G proteins, transactivation of membrane growth factor receptors, or ß adrenergic receptor-ß arrestin-facilitated scaffold-mediated signaling. Agonist occupancy of the ß adrenergic receptor induces desensitization by promoting ß adrenergic receptor kinase phosphorylation of the carboxyl terminal domain, facilitating binding of the amino terminal of the ß arrestin, which sterically inhibits interactions between ß adrenergic receptors and G proteins and induces clathrin-coated pit-mediated receptor endocytosis. Scaffold formation promoted by ß arrestin binding to the ß adrenergic receptor activates extracellular regulated kinase 1/2 in a manner which elicits cytosolic retention of, and prevents promotion of nuclear transcriptional activity by, mitogen-activated protein kinase. The ß adrenergic receptor kinase also interacts with a yet to be determined microsomal membrane protein via high-affinity electrostatic interactions. We evaluate ß adrenergic receptor structure, function, and downstream signaling and ß arrestin-mediated desensitization, receptor endocytosis, and scaffold-facilitated signal transduction in order to illumine therapeutic strategies designed to modulate these pathways. We trust these approaches may arm us with the capacity to selectively modulate signal transduction pathways regulating cellular proliferation, immunogenicity, angiogenesis, and invasive and metastatic potential implicated in cancer initiation, promotion, and progression.

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.

Microsurgical techniques for achieving gross total resection of ependymomas of the fourth ventricle.

Ependymomas arising from the ventricular surface present a major challenge to achieving a complete operative extirpation when located in the fourth ventricle given the presence of significant adherence to the floor of the same. Overzealous dissection and removal of a tumor from this zone may precipitate potentially catastrophic neurological deficits attributable to cranial nucleopathies and cranial neuropathies. Consequently, the classic neurosurgical teaching has advised attempted gross total resection, leaving adherent residual in the floor of the fourth ventricle, in order to prevent the development of major cranial nucleopathies and cranial neuropathies. Following surgical tumoral extirpation, residual tumor is adjuvantly stereotactically irradiated. Authors have consequently developed novel neurophysiologically guided microsurgical techniques designed to remove adherent tumor from the fourth ventricular floor. These strategies have successfully and consistently facilitated gross total resection and improved clinical outcomes in patients harboring ependymomas of the fourth ventricle. We discuss and evaluate the innovation in microsurgical strategies developed to achieve complete operative extirpation of tumoral adherence to the floor of the fourth ventricle.

Midbrain control of breathing and blood pressure: The role of periaqueductal gray matter and mesencephalic collicular neuronal microcircuit oscillators.

Neural circuitry residing within the medullary ventral respiratory column nuclei and dorsal respiratory group interact with the Kölliker-Fuse and medial parabrachial nuclei to generate the core breathing rhythm and pattern during resting conditions. Triphasic eupnea consists of inspiratory [I], post-inspiratory [post-I], and late-expiratory [E2] phases. Mesencephalic zones exert modulatory influences upon respiratory rhythm-generating circuitry, sympathetic oscillators, and parasympathetic nuclei. The earliest evidence supporting the existence of midbrain control of breathing derives from studies conducted by Martin and Booker in 1878. These authors demonstrated electrical stimulation of the deep layers of the mesencephalic colliculi in the rabbit augmented ventilation and sequentially elicited chest wall tremors and tetany. Investigations performed during the past several decades would demonstrate stimlation of distributed zones within the midbrain reticular formation elicits starkly disparate effects upon respiratory phase switching. Schmid, Böhmer, and Fallert demonstrated electrical stimulation of the nucleus rubre and emanating axon bundles alternately elicits or inhibits the activity of medullary expiratory- or inspiratory-related units and phrenic nerve discharge with differential latency. A series of studies would later indicate the red nucleus mediates hypoxic ventilatory depression. Periaqueductal gray matter neurons exhibit extensive afferent and efferent interconnectivity with suprabulbar, brainstem, and spinal cord zones aptly positioning these units to modulate breathing, autonomic outflow, nociception locomotion, micturtion, and sexual behavior. Experimental stimulatory activation of the tectal colliculi and periaqueductal gray matter via electrical current or glutamate, D,L-homocysteinic acid, or bicuculline microinjections coordinately modulates neuromotor inspiratory bursting frequency and amplitude and discharge of pre-Bötzinger complex, ventrolateral medullary late-I and post-I, and ventrolateral nucleus tractus solitarius decrementing early-I and augmenting and decrementing late-I neurons, elicits expiratory outflow and vocalization, and blunt the Hering-Breuer reflex in unanesthetzed decerebrate and anesthetized preprations of the cat and rat. Stimulation of the mesencephalic colliuli or dorsal divisions of the PAG potently amplifes renal sympathetic neural efferent activity, dynamic arterial pressure magnitude, and myocardial contraction frequency and elicits various behavioral defense responses. Elicited physiological effects exhibit extensive locoregional heterogeneity and variably enlist requisite contributions from the dorsomedial hypothalamus and/or lateral parabrachial nuclei. Stimulation of the dorsal mesencephalon occasionally elicits dynamic increases of arterial pressure magnitude exhibiting prominent oscillatory variability coherent with phrenic nerve discharge, perhaps by generating intra-neuraxial hysteresis, serving to intermittently deliver blood to organ vascular beds under high pressure in order to prevent organ edema, microcirculatory dysfunction, and downregulation of vascular smooth muscle alpha adrenergic receptors. Chemosensitive mesencephalic caudal raphé units and projections of hypoxia-sensitive units in the caudal hypothalamus to the periaqueductal gray matter may imply the existence of a diencephalo-smesencephalic chemosensitive network modulating breathing and sympathetic discharge.