Is it really on your hand? Spontaneous sensations are not peripheral sensations - Evidence from able-bodied individuals and a phantom limb syndrome patient.

Among other bodily signals, the perception of sensations arising spontaneously on the skin with no external triggers contributes to body awareness. The topic of spontaneous sensations (SPS) being quite recent in the literature, there is still a debate whether this phenomenon is elicited by peripheral cutaneous units' activity underlying tactile perception or originates directly from central mechanisms. In a first experiment, we figured that, if SPS depended on peripheral afferents, their perception on the glabrous hand should relate to the hand tactile sensitivity. On the contrary, we found no relationship at all, which led us to envisage the scenario of SPS in the absence of cutaneous units. In a second experiment, we present the case of Julie, a right-hand amputee that could perceive and report SPS arising on her phantom limb syndrome. We found that SPS distribution on the phantom limb followed the same gradient as that observed in control participants, unlike SPS perceived on the intact left hand. Those findings are crucial to the understanding of neural factors determining body awareness through SPS perception and provide insights into the existence of a precise neural gradient underlying somesthesis.

Unresolved haemosporidia of the Australian skink, Egernia stokesii.

The Australian skink Egernia stokesii had been recognised as a host of two species of Plasmodium, Plasmodium mackerrasae and P. circularis; nevertheless, molecular data are available for only a single haemosporidian species of this host. Its sequences are labelled as "Plasmodium sp." or "Plasmodium mackerrasae", but morphological characteristics of this isolate are unavailable. Phylogenetic analyses of these sequences placed them into the clade of the genus Haemocystidium. In this study, blood samples of six E. stokesii were analysed by both, molecular and microscopic methods to clarify the haemosporidia of this lizard. Application of these approaches offered discordant results. Whereas sequence analysis clustered our isolates with lizard species of Haemocystidium, morphology of blood stages is more akin to Plasmodium than Haemocystidium. However, limited sampling, indistinguishable nuclei/merozoites and risk of possible hidden presence of mixed infection prevent reliable species identification of detected parasites or their description as new species of Haemocystidium.

Near-peer teaching in a psychomotor skills course: Benefits, challenges and solutions.

INTRODUCTION: This study evaluates the perceptions and experiences of students in the role of near-peer teachers in a psychomotor skills course. MATERIALS AND METHODS: Final year BDS students were invited to participate as near-peer teachers in a 4th-year conventional bridges course. Near-peer teachers attended eight sessions (3 h) of simulation laboratory teaching relating to conventional bridge tooth preparations and provided feedback on near-peer tooth preparations and answered their questions. Interviews were conducted with all near-peer teachers to evaluate their perceptions of this novel teaching and learning experience and a thematic analysis was performed to analyse the data. RESULTS: Near-peer teachers reported this to be a rewarding, enjoyable and challenging experience. They benefited from learning and revising content-related materials as well as gained insights and teaching skills through the peer teaching process. Students felt supported and learned from peers and teaching staff and some used dyad teaching as a strategy to overcome perceived challenges. Students also reported the benefits of social and cognitive congruence in interacting with junior peers. However, students reported the feeling of inadequacy or lack of confidence and suggested the need for a training to prepare them better for the course. CONCLUSION: This paper reports on the benefits as well as challenges perceived by near-peer teachers during simulation laboratory teaching experience. We provide solutions into how to better prepare students for such teaching experience.

Well-being of undergraduate dental students: Questionnaire design, findings and future directions.

INTRODUCTION: The recent pandemic has highlighted the importance of addressing well-being in the overall health of students. There is a need for support systems within dental schools to help students demonstrate resilience, adapt to learning environments and thrive in their professional careers. OBJECTIVES: The main aim of the study was to evaluate Bachelor of Dental Surgery (BDS) students' understanding and experience of well-being. The objectives were to create a suitable survey to assess students' well-being, investigate the factors affecting dental students' well-being and develop a student well-being action plan based on the analysis of the survey. METHODS: A literature review was conducted to identify and critically assess existing measures of well-being in dental students. Four domains of well-being (emotional, physical, social, intellectual) relevant to dental students were identified. Through a comprehensive iterative process, a two-part survey was developed and tested, which measured individual experiences of well-being across the four domains and collected feedback on proposed initiatives to support student well-being. The survey was disseminated to all 452 dental students from Years 1 through 6, of which 71% (321) responded. RESULTS: The survey revealed low levels of overall well-being among the dental student population, which worsened with increasing years of clinical study. Fear of failing exams presented the biggest challenge with regard to emotional well-being, while sleep deprivation and occupational health hazards most affected the physical well-being domain. Intellectual well-being was compromised by insufficient free time to pursue extracurricular interests and concerns about achieving the required skills. Despite a majority experiencing positive relationships with their peers and tutors, less than a fifth agreed that the Faculty of Dentistry 'supported my well-being as a dental student'. CONCLUSION: As the first investigation of the well-being of dental students in Hong Kong, the key stressors identified were examinations, long schedules and the physical burden of dental work, which are consistent with international literature. The findings reveal students' needs and preferences for well-being initiatives which will be optimized in the implementation of student-centred curricular activities.

A synthetic data integration framework to leverage external summary-level information from heterogeneous populations.

There is a growing need for flexible general frameworks that integrate individual-level data with external summary information for improved statistical inference. External information relevant for a risk prediction model may come in multiple forms, through regression coefficient estimates or predicted values of the outcome variable. Different external models may use different sets of predictors and the algorithm they used to predict the outcome Y given these predictors may or may not be known. The underlying populations corresponding to each external model may be different from each other and from the internal study population. Motivated by a prostate cancer risk prediction problem where novel biomarkers are measured only in the internal study, this paper proposes an imputation-based methodology, where the goal is to fit a target regression model with all available predictors in the internal study while utilizing summary information from external models that may have used only a subset of the predictors. The method allows for heterogeneity of covariate effects across the external populations. The proposed approach generates synthetic outcome data in each external population, uses stacked multiple imputation to create a long dataset with complete covariate information. The final analysis of the stacked imputed data is conducted by weighted regression. This flexible and unified approach can improve statistical efficiency of the estimated coefficients in the internal study, improve predictions by utilizing even partial information available from models that use a subset of the full set of covariates used in the internal study, and provide statistical inference for the external population with potentially different covariate effects from the internal population.

Near-peer teaching for learning clinical photography skills: Perceptions of students.

AIM: This paper evaluates the perceptions and experience of students, in the role of both near-peer teacher and learner who participated in the clinical dental photography course, using a mixed-method analysis with focus group interviews of student tutors and a questionnaire of learner perceptions. METHODS: A student-led course on Digital Clinical Photography took place with BDS 5 and 6 students as near-peer teachers (NPTs) and BDS 2 and 3 students as learners. Interviews were conducted with near-peer teachers, and a questionnaire was distributed to learners to evaluate students' perceptions of this novel teaching and learning experience. RESULTS: Near-peer teaching has proven to be a beneficial alternative teaching pedagogy which was well-received by NPTs and student learners. The content creation and teaching experience deepened NPTs' understanding on the subject matter and were motivated given the autonomous nature of the project. NPTs enjoyed and benefited from the collaborative nature of the project and the relevance of the subject matter and improved their clinical skills. The student learners enjoyed the learning experience and benefits of learning from NPTs which is supported by social and cognitive congruence. The positive perception of teaching and learning in pairs were also described. CONCLUSION: This project demonstrates the perceived benefits of near-peer teaching for clinical photography skills for student experiential learning and highlights key elements on how to structure such an activity to engage and support students to participate in such future activities.

An exploration of clinical communication needs among undergraduate dental students.

INTRODUCTION: This study examines undergraduate dental students' perceptions of their self-confidence in communicating with patients and paradental staff. MATERIALS AND METHODS: A survey questionnaire was designed based on a literature review and input from students and academic staff relating to clinical communication skills with 19 questions across 7 domains. Through email, a convenience sampling of undergraduate students were invited to complete the survey questionnaire. Qualitative and quantitative analysis of the responses was performed with a thematic analysis to the open-ended questions. RESULTS: In total, 102 students were surveyed from 4 years of students with a 36.6% response rate. Students reported some areas of low confidence across various communication domains, in particular, building rapport, behavioural change, management of patient expectation and breaking bad news. Students reported insufficient confidence and knowledge in specialist clinical areas, layperson terms and success rates and longevity of treatment items when communicating with patients. Information sheets and visual aids such as models or photos were suggested by students to be helpful in patient communication. Students also reported challenges in communication with nurses when they might challenge or change their clinical decisions in front of their patients. CONCLUSION: Our study reveals areas of low confidence among undergraduate dental students in communication towards patients and paradental staff. Barriers and challenges have been identified with an action plan suggested accordingly. There is a need for additional training in the form of learning content and communications experiences, and channels of communications for undergraduate students.

Eye Direction Detection and Perception as Premises of a Social Brain: A Narrative Review of Behavioral and Neural Data.

The eyes and the gaze are important stimuli for social interaction in humans. Impaired recognition of facial identity, facial emotions, and inference of the intentions of others may result from difficulties in extracting information relevant to the eye region, mainly the direction of gaze. Therefore, a review of these data is of interest. Behavioral data demonstrating the importance of the eye region and how humans respond to gaze direction are reviewed narratively, and several theoretical models on how visual information on gaze is processed are discussed to propose a unified hypothesis. Several issues that have not yet been investigated are identified. The authors tentatively suggest experiments that might help progress research in this area. The neural aspects are subsequently reviewed to best describe the low-level and higher-level visual information processing stages in the targeted subcortical and cortical areas. A specific neural network is proposed on the basis of the literature. Various gray areas, such as the temporality of the processing of visual information, the question of salience priority, and the coordination between the two hemispheres, remain unclear and require further investigations. Finally, disordered gaze direction detection mechanisms and their consequences on social cognition and behavior are discussed as key deficiencies in several conditions, such as autism spectrum disorder, 22q11.2 deletion, schizophrenia, and social anxiety disorder. This narrative review provides significant additional data showing that the detection and perception of someone's gaze is an essential part of the development of our social brain.

Suppression of JAK-STAT Signaling by Epstein-Barr Virus Tegument Protein BGLF2 through Recruitment of SHP1 Phosphatase and Promotion of STAT2 Degradation.

Some lytic proteins encoded by Epstein-Barr virus (EBV) suppress host interferon (IFN) signaling to facilitate viral replication. In this study, we sought to identify and characterize EBV proteins antagonizing IFN signaling. The induction of IFN-stimulated genes (ISGs) by IFN-ß was effectively suppressed by EBV. A functional screen was therefore performed to identify IFN-antagonizing proteins encoded by EBV. EBV tegument protein BGLF2 was identified as a potent suppressor of JAK-STAT signaling. This activity was found to be independent of its stimulatory effect on p38 and JNK pathways. Association of BGLF2 with STAT2 resulted in more pronounced K48-linked polyubiquitination and proteasomal degradation of the latter. Mechanistically, BGLF2 promoted the recruitment of SHP1 phosphatase to STAT1 to inhibit its tyrosine phosphorylation. In addition, BGLF2 associated with cullin 1 E3 ubiquitin ligase to facilitate its recruitment to STAT2. Consequently, BGLF2 suppressed ISG induction by IFN-ß. Furthermore, BGLF2 also suppressed type II and type III IFN signaling, although the suppressive effect on type II IFN response was milder. When pretreated with IFN-ß, host cells became less susceptible to primary infection of EBV. This phenotype was reversed when expression of BGLF2 was enforced. Finally, genetic disruption of BGLF2 in EBV led to more pronounced induction of ISGs. Our study unveils the roles of BGLF2 not only in the subversion of innate IFN response but also in lytic infection and reactivation of EBV. IMPORTANCE Epstein-Barr virus (EBV) is an oncogenic virus associated with the development of lymphoid and epithelial malignancies. EBV has to subvert interferon-mediated host antiviral response to replicate and cause diseases. It is therefore of great interest to identify and characterize interferon-antagonizing proteins produced by EBV. In this study, we perform a screen to search for EBV proteins that suppress the action of interferons. We further show that BGLF2 protein of EBV is particularly strong in this suppression. This is achieved by inhibiting two key proteins STAT1 and STAT2 that mediate the antiviral activity of interferons. BGLF2 recruits a host enzyme to remove the phosphate group from STAT1 thereby inactivating its activity. BGLF2 also redirects STAT2 for degradation. A recombinant virus in which BGLF2 gene has been disrupted can activate host interferon response more robustly. Our findings reveal a novel mechanism by which EBV BGLF2 protein suppresses interferon signaling.

A Multicenter, Randomized, Double-Blind, Placebo-Controlled Trial of Preoperative Antithrombin Supplementation in Patients at Risk for Antithrombin Deficiency After Cardiac Surgery.

BACKGROUND: Antithrombin (AT) activity is reduced during cardiac operations with cardiopulmonary bypass (CPB), which is associated with adverse outcomes. Preoperative AT supplementation, to achieve >58% and <100% AT activity, may potentially reduce postoperative morbidity and mortality in cardiac operations with CPB. This prospective, multicenter, randomized, double-blind, placebo-controlled study was designed to evaluate the safety and efficacy of preoperative treatment with AT supplementation in patients at risk for low AT activity after undergoing cardiac surgery with CPB. METHODS: A total of 425 adult patients were randomized (1:1) to receive either a single dose of AT (n = 213) to achieve an absolute increase of 20% above pretreatment AT activity or placebo (n = 212) before surgery. The study duration was approximately 7 weeks. The primary efficacy end point was the percentage of patients with any component of a major morbidity composite (postoperative mortality, stroke, acute kidney injury [AKI], surgical reexploration, arterial or venous thromboembolic events, prolonged mechanical ventilation, and infection) in the 2 groups. Secondary end points included AT activity, blood loss, transfusion requirements, duration of intensive care unit (ICU), and hospital stays. Safety was also assessed. RESULTS: Overall, 399 patients (men, n = 300, 75.2%) with a mean (standard deviation [SD]) age of 66.1 (11.7) years, with the majority undergoing complex surgical procedures (n = 266, 67.9%), were analyzed. No differences in the percentage of patients experiencing morbidity composite outcomes between groups were observed (AT-treated 68/198 [34.3%] versus placebo 58/194 [29.9%]; P = .332; relative risk, 1.15). After AT infusion, AT activity was significantly higher in the AT group (108% [42-143]) versus placebo group (76% [40-110]), and lasted up to postoperative day 2. At ICU, the frequency of patients with AT activity ≥58% in the AT group (81.5%) was significantly higher ( P < .001) versus placebo group (43.2%). Secondary end point analysis did not show any advantage of AT over placebo group. There were significantly more patients with AKI ( P < .001) in the AT group (23/198; 11.6%) than in the placebo group (5/194, 2.6%). Safety results showed no differences in treatment-emergent adverse events nor bleeding events between groups. CONCLUSIONS: AT supplementation did not attenuate adverse postoperative outcomes in our cohort of patients undergoing cardiac surgery with CPB.

Compositional profile of mucosal bacteriome of smokers and smokeless tobacco users.

INTRODUCTION: Smoked, and especially smokeless, tobacco are major causes of oral cancer globally. Here, we examine the oral bacteriome of smokers and of smokeless tobacco users, in comparison to healthy controls, using 16S rRNA gene sequencing. METHODS: Oral swab samples were collected from smokers, smokeless tobacco users, and healthy controls (n = 44). Microbial DNA was extracted and the 16S rRNA gene profiled using the Illumina MiSeq platform. Sequencing reads were processed using DADA2, and taxonomical classification was performed using the phylogenetic placement method. Differentially abundant taxa were identified using DESeq2, while functional metagenomes based on KEGG orthology abundance were inferred using LIMMA. RESULTS: A significantly higher microbial diversity was observed in smokeless tobacco users and smokers relative to controls (P < 0.05). Compositional differences in microbial communities were observed in all comparisons with healthy controls (PERMANOVA P < 0.05) but not between smokers and smokeless tobacco users. Levels of Fusobacterium spp., Saccharibacterium spp., and members of Shuttleworthia were elevated in smokers when compared to controls (BH adj P < 0.01). In addition, the relative abundance of three bacterial taxa belonging to genera Fusobacterium spp., Catonella, and Fretibacterium spp. was significantly increased in smokeless tobacco users relative to controls (BH adj P < 0.01). Major functional pathways significantly increased in smokeless tobacco users relative to both controls, and smokers were similar and involved amino acid metabolism including glutamate and aspartate biosynthesis and degradation (log FC > 1.5; BH adj P < 0.01). CONCLUSIONS: A distinct taxonomic and functional profile of oral microbiome in smokers and smokeless tobacco users as compared to healthy controls implicates a significant role of microbes and their metabolites in diseases associated with tobacco use including oral cancer. CLINICAL RELEVANCE: Future efforts in preventive, diagnostic, curative, and prognostic strategies for diseases associated with tobacco use in smokers and smokeless tobacco users could incorporate the oral microbiome.

Clinical Outcomes in Surgical and Transcatheter Aortic Valve Replacement: An ANZSCTS Database Review 2001-2019.

BACKGROUND: Since the last formal publication reporting on the findings of the Australian and New Zealand Society of Cardiac and Thoracic Surgeons (ANZSCTS) database on surgical aortic valve replacement (SAVR) and transcatheter aortic valve replacement (TAVR) in 2016, transcatheter approaches have become common practice. There has been an increase in use of TAVR following large, randomised control trials that only report on short-term outcomes in a selective cohort. This study aims to report on primary outcome measures and identify complications associated with SAVR and TAVR from a large national database. METHODS: From the ANZSCTS database (2001-19), 14,097 SAVR and 1,194 TAVR patients were identified with clinical details and 30-day follow-up available. The primary endpoint was the composite of all-cause mortality and/or permanent stroke at 30 days. Secondary endpoints were post-procedure complications requiring treatment. Logistical regression followed by propensity score matching was performed. RESULTS: Using logistical regression when all patient factors considered for all patients who had SAVR and TAVR, the only preoperative factors that had an impact on 30-day mortality was cerebrovascular disease, respiratory disease, preoperative dialysis, angina, and hypertension. Primary outcome 30-day mortality rate was 1.83% in the SAVR group, and 1.68% in patients in the TAVR group, p=0.7001, and permanent stroke was seen in 1.07% patients in the SAVR group, and 1.26% patients in the TAVR group. Acute limb ischaemia, aortic dissection, ventricular tachycardia, bradyarrhythmia and heart block were more common following TAVR (p<0.001), while reintubation and atrial arrhythmia were more common following SAVR (p<0.001). CONCLUSIONS: In the real world SAVR and TAVR have been used in very different patient groups and it is difficult to compare as different baseline characteristics and complications. The two patient groups maintain similarities in primary and secondary endpoints, but differences in life threatening and life altering morbidity remains significant. Collection of SAVR and TAVR data in a combined database may help to better capture and compare these complications and institute strategies to prevent them.

Visuospatial working memory abilities and spontaneous sensations perception.

Aim: Body awareness arises when attending to and maintaining awareness of visuospatial body representations. By the same token, focussing on representations transfers them to working memory. Body awareness and working memory seemingly rely on similar processes and recruit common parietal areas involved in perception. Therefore, we asked whether visuospatial working memory abilities would define individual differences in the perception of spontaneous sensations (SPS), i.e., bodily sensations perceived in the absence of triggers (e.g., tactile stimulation or movement), when attending to the body.Method: Participants completed two visuospatial working memory tasks to assess various mechanisms: (i) the decay of representations was assessed through a Brown-Peterson task in which the delay between the memorandum presentation and its recall was manipulated, and (ii) the impact of distractors' interference and cognitive load (i.e., complexity) on recall performances were assessed through a complex span task that required the processing of distractors while maintaining a memorandum. A standard SPS task involving localization and characterization of SPS perceived on the hands was completed afterwards.Results: Low performance due to decay, distractors' interference and cognitive load in visuospatial working memory was associated with a decrease in the frequency of SPS. Additionally, low performance due to distractors' cognitive load predicted a decrease in the perception of surface-type sensations, and high performance despite distractors' interference led to a better perception of SPS on less sensitive areas of the hand.Conclusion: We discuss how visuospatial working memory processes might contribute to body awareness and perceptual distortions of the body.

Positive and negative urgency as a single coherent construct: Evidence from a large-scale network analysis in clinical and non-clinical samples.

AIMS: Negative and positive urgency are emotion-related impulsivity traits that are thought to be transdiagnostic factors in psychopathology. However, it has recently been claimed that these two traits are closely related to each other and that considering them separately might have limited conceptual and methodological value. The present study aimed to examine whether positive and negative urgency constructs constitute separate impulsivity traits. METHODS: In contrast to previous studies that have used latent variable approaches, this study employed an item-based network analysis conducted in two different samples: a large sample of non-clinical participants (N = 18,568) and a sample of clinical participants with psychiatric disorders (N = 385). RESULTS: The network analysis demonstrated that items denoting both positive and negative urgency cohere as a single cluster of items termed "general urgency" in both clinical and non-clinical samples, thereby suggesting that differentiating positive and negative urgency as separate constructs is not necessary. CONCLUSION: These findings have important implications for the conceptualization and assessment of urgency and, more broadly, for future research on impulsivity, personality, and psychopathology.

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.

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.

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.

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.

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.