Modulation of spinal circuits following phase-dependent electrical stimulation of afferent pathways.

Objective.Peripheral electrical stimulation (PES) of afferent pathways is a tool commonly used to induce neural adaptations in some neural disorders such as pathological tremor or stroke. However, the neuromodulatory effects of stimulation interventions synchronized with physiological activity (closed-loop strategies) have been scarcely researched in the upper-limb. Here, the short-term spinal effects of a 20-minute stimulation protocol where afferent pathways were stimulated with a closed-loop strategy named selective and adaptive timely stimulation (SATS) were explored in 11 healthy subjects.Approach. SATS was applied to the radial nerve in-phase (INP) or out-of-phase (OOP) with respect to the muscle activity of the extensor carpi radialis (ECR). The neural adaptations at the spinal cord level were assessed for the flexor carpi radialis (FCR) by measuring disynaptic Group I inhibition, Ia presynaptic inhibition, Ib facilitation from the H-reflex and estimation of the neural drive before, immediately after, and 30 minutes after the intervention.Main results.SATS strategy delivered electrical stimulation synchronized with the real-time muscle activity measured, with an average delay of 17 ± 8 ms. SATS-INP induced increased disynaptic Group I inhibition (77 ± 23% of baseline conditioned FCR H-reflex), while SATS-OOP elicited the opposite effect (125 ± 46% of baseline conditioned FCR H-reflex). Some of the subjects maintained the changes after 30 minutes. No other significant changes were found for the rest of measurements.Significance.These results suggest that the short-term modulatory effects of phase-dependent PES occur at specific targeted spinal pathways for the wrist muscles in healthy individuals. Importantly, timely recruitment of afferent pathways synchronized with specific muscle activity is a fundamental principle that shall be considered when tailoring PES protocols to modulate specific neural circuits. (NCT number 04501133).

Effects of NMES-elicited versus voluntary low-level conditioning contractions on explosive knee extensions.

OBJECTIVES: Electrically-induced or voluntary conditioning-contractions (CC) can be used to affect contractile properties of a subsequent explosive contraction (EC). Here, we aimed at comparing the effect of neuromuscular-electrical-stimulation (NMES) vs voluntary CC performed prior to explosive contractions of the knee extensors. METHODS: A 10 sec NMES CC (100Hz, 1000µs, 10% MVC), or a voluntary contraction (VOL CC) mimicking the NMES CC, preceded an isometric EC of the knee extensors. Explosive contraction was performed with the goal to reach the target (70% MVC) as quickly as possible. RESULTS: All the parameters related with the explosive contractions' muscle-output were similar between protocols (difference ranging from 0.23%, Mean Torque; to 5.8%, Time to Target), except for the Time to Peak Torque, which was lower when preceded by NMES (11.1%, p=0.019). Interestingly, the RTD 0-50 ms_EC was 37.3% higher after the NMES compared with the VOL CC protocol. CONCLUSION: Explosive contraction was potentiated by an NMES CC as compared with a voluntary CC. This may be due to a reduction in descending drive following VOL CC, which has been shown to occur even with low-level voluntary efforts. These findings could be used to improve rehabilitation or training protocols that include conditioning contractions.

Non-invasive electrical stimulation of peripheral nerves for the management of tremor.

Pathological tremor in patients with essential tremor and Parkinsons disease is typically treated using medication or neurosurgical interventions. There is a widely recognized need for new treatments that avoid the side effects of current medications and do not carry the risks of surgical interventions. Building on decades of research and engineering development, non-invasive electrical stimulation of peripheral nerves has emerged as a safe and effective strategy for reducing pathologic tremor in essential tremor. This review surveys the peripheral electrical stimulation (PES) literature and summarizes effectiveness, safety, clinical translatability, and hypothesized tremor-reduction mechanisms of various PES approaches. The review also proposes guidelines for assessing tremor in the context of evaluating new therapies that combine the strengths of clinician assessments, patient evaluations, and novel motion sensing technology. The review concludes with a summary of future directions for PES, including expanding clinical access for patients with Parkinson's disease and leveraging large, at-home datasets to learn more about tremor physiology and treatment effect that will better characterize the state of tremor management and accelerate discovery of new therapies. Growing evidence suggests that non-invasive electrical stimulation of afferent neural pathways provides a viable new option for management of pathological tremor, with one specific PES therapy cleared for prescription and home use, suggesting that PES be considered along with medication and neurosurgical interventions for treatment of tremor. This article is part of the Special Issue "Tremor" edited by Daniel D. Truong, Mark Hallett, and Aasef Shaikh.

Oropharyngeal Dysphagia in Older People is Associated with Reduced Pharyngeal Sensitivity and Low Substance P and CGRP Concentration in Saliva.

Substance P (SP) and Calcitonine gene-related peptide (CGRP) are released by sensory nerve fibers in the oropharynx. Patients with oropharyngeal dysphagia (OD) present reduced oropharyngeal sensitivity and low SP concentration in saliva. We aimed to assess the concentration of salivary SP and CGRP in healthy volunteers, and older people without and with OD, and the relationship with pharyngeal sensory threshold. We included 15 healthy volunteers, 14 healthy elderly and 14 elderly with OD. Swallow function was assessed by videofluoroscopy (VFS). Pharyngeal sensory threshold was assessed by intrapharyngeal electrical stimulation. Hydration and phase angle were assessed by bioimpedance. Saliva samples were collected with a Salivette® to determine SP and CGRP concentration by ELISA. Elderly patients with OD presented impaired safety of swallow (PAS 4.38 ± 0.77 p < 0.0001 vs. healthy volunteers = 1 and healthy elderly = 1.43 ± 0.51). Healthy elderly and elderly with OD presented a reduction in intracellular water and saliva volume (healthy elderly, 592.86 ± 327.79 µl, p = 0.0004; elderly with OD, 422.00 ± 343.01 µl, p = 0.0001 vs healthy volunteers, 1333.33 ± 615.91 µl, r = 0.6621, p < 0.0001). Elderly patients with OD presented an impairment in pharyngeal sensory threshold (10.80 ± 3.92 mA vs. healthy volunteers, 5.74 ± 2.57 mA; p = 0.007) and a reduction in salivary SP (129.34 pg/ml vs. healthy volunteers: 173.89 pg/ml; p = 0.2346) and CGRP levels (24.17 pg/ml vs. healthy volunteers: 508.18 pg/ml; p = 0.0058). There was a negative correlation between both SP and CGRP concentrations and pharyngeal sensory threshold (r = - 0.450, p = 0.024; r = - 0.4597, p = 0.036, respectively), but only SP identified elderly patients with OD with higher pharyngeal sensory threshold. Elderly patients with OD presented hydropenia and sarcopenia, reduced salivary SP and CGRP and impaired pharyngeal sensitivity. Our study suggests SP levels in saliva as a potential biomarker to monitor pharyngeal sensitivity in elderly patients with OD.

Origin, branching pattern, foraminal and intraspinal distribution of the human lumbar sinuvertebral nerves.

BACKGROUND CONTEXT: The lumbar sinuvertebral nerve (SVN) innervates the outer posterior intervertebral disc (IVD); it is thought to mediate discogenic low-back pain (LBP). Controversy, however, exists on its origins at higher (L1-L2) versus lower (L3-L5) lumbar levels. Additionally, lack of knowledge regarding its foraminal and intraspinal branching patterns and extensions may lead to iatrogenic damage. PURPOSE: To systematically describe the origins of the L2 and L5 SVNs, their morphological variation in the intervertebral foramen (IVF) and intraspinal distribution. STUDY DESIGN: Dissection-based study of 20 SVNs with histological confirmation in five embalmed human cadavers. METHODS: The origin, branching pattern and distribution of the L2 and L5 SVNs was investigated bilaterally in five human cadavers using dorsal and anterolateral dissection approaches. Parameters studied included somatic and/or autonomic SVN root contributions, foraminal SVN morphology and course, diameter, branching point, intraspinal distribution and IVD innervation pattern. Nerve tissue was confirmed by immunostaining for neurofilament and S100 proteins. RESULTS: The SVN and its origins was identified in all except one IVF at L2 and in all foramina at L5. At L2, the SVN arose in nearly 90% of sides from both somatic and autonomic roots and at L5 in 40% of sides. The remaining SVNs were formed by purely autonomic roots. The SVN arose from significantly more roots at L2 than L5 (3.1 ± 0.3 vs. 1.9 ± 0.3, respectively; p=.022). Four different SVN morphologies could be discerned in the L2 IVF: single filament (22%), multiple (parallel or diverging) filament (33%), immediate splitting (22%) and plexiform (22%) types, whereas the L5 SVN consisted of single (90%) and multiple (10%) filament types. SVN filaments were significantly thicker at L2 than L5 (0.48 ± 0.06 mm vs. 0.33 ± 0.02 mm, respectively; p=.043). Ascending SVN filaments coursed roughly parallel to the exiting spinal nerve root trajectory at L2 and L5. Branching of the SVN into ascending and descending branches occurred mostly intraspinal both at L2 and L5. Spinal canal distribution was also similar for L2 and L5 SVNs. Lumbar posterior IVDs were innervated by the descending branch of the parent SVN and ascending branch of the subjacent SVN. CONCLUSIONS: The SVN at L2 originates from both somatic and autonomic roots in 90% of cases and at L5 in 40% of cases. The remaining SVNs are purely autonomic. In the IVF, the L2 SVN is morphologically heterogeneous, but generally consists of numerous filaments, whereas at L5 90% contains a single SVN filament. The L2 SVN is formed by more roots and is thicker than the L5 SVN. Intraspinal SVN distribution is confined to its level of origin; lumbar posterior IVDs are innervated by corresponding and subjacent SVNs (ie, two spinal levels). CLINICAL SIGNIFICANCE: Our findings indicate that L5 discogenic LBP may be mediated both segmentally and nonsegmentally in 40% of cases and nonsegmentally in 60% of cases. Failure of lower lumbar discogenic pain treatment may be the result of only interrupting the nonsegmental pathway, but not the segmental one as well. Relating SVN anatomy to microsurgical spinal approaches may prevent iatrogenic damage to the SVN and the formation of postsurgical back pain.

Lower urinary tract electrical sensory assessment: a systematic review and meta-analysis.

OBJECTIVES: To summarize the current literature on lower urinary tract electrical sensory assessment (LUTESA), with regard to current perception thresholds (CPTs) and sensory evoked potentials (SEPs), and to discuss the applied methods in terms of technical aspects, confounding factors, and potential for lower urinary tract (LUT) diagnostics. METHODS: The review was performed according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) statement. Medline (PubMed), Embase and Scopus were searched on 13 October 2020. Meta-analyses were performed and methodological qualities of the included studies were defined by assessing risk of bias (RoB) as well as confounding. RESULTS: After screening 9925 articles, 80 studies (five randomized controlled trials [RCTs] and 75 non-RCTs) were included, comprising a total of 3732 patients and 692 healthy subjects (HS). Of these studies, 61 investigated CPTs exclusively and 19 reported on SEPs, with or without corresponding CPTs. The recording of LUTCPTs and SEPs was shown to represent a safe and reliable assessment of LUT afferent nerve function in HS and patients. LUTESA demonstrated significant differences in LUT sensitivity between HS and neurological patients, as well as after interventions such as pelvic surgery or drug treatments. Pooled analyses showed that several stimulation variables (e.g. stimulation frequency, location) as well as patient characteristics might affect the main outcome measures of LUTESA (CPTs, SEP latencies, peak-to-peak amplitudes, responder rate). RoB and confounding was high in most studies. CONCLUSIONS: Preliminary data show that CPT and SEP recordings are valuable tools to more objectively assess LUT afferent nerve function. LUTESA complements already established diagnostics such as urodynamics, allowing a more comprehensive patient evaluation. The high RoB and confounding rate was related to inconsistency and inaccuracy in reporting rather than the technique itself. LUTESA standardization and well-designed RCTs are crucial to implement LUTESA as a clinical assessment tool.

The Cortical Response Evoked by Robotic Wrist Perturbations Reflects Level of Proprioceptive Impairment After Stroke.

Background: Proprioception is important for regaining motor function in the paretic upper extremity after stroke. However, clinical assessments of proprioception are subjective and require verbal responses from the patient to applied proprioceptive stimuli. Cortical responses evoked by robotic wrist perturbations and measured by electroencephalography (EEG) may be an objective method to support current clinical assessments of proprioception. Objective: To establish whether evoked cortical responses reflect proprioceptive deficits as assessed by clinical scales and whether they predict upper extremity motor function at 26 weeks after stroke. Methods: Thirty-one patients with stroke were included. In week 1, 3, 5, 12, and 26 after stroke, the upper extremity sections of the Erasmus modified Nottingham Sensory Assessment (EmNSA-UE) and the Fugl-Meyer Motor Assessment (FM-UE) and the EEG responses (64 channels) to robotic wrist perturbations were measured. The extent to which proprioceptive input was conveyed to the affected hemisphere was estimated by the signal-to-noise ratio (SNR) of the evoked response. The relationships between SNR and EmNSA-UE as well as SNR and time after stroke were investigated using linear regression. Receiver-operating-characteristic curves were used to compare the predictive values of SNR and EmNSA-UE for predicting whether patients regained some selective motor control (FM-UE > 22) or whether they could only move their paretic upper extremity within basic limb synergies (FM-UE ≤ 22) at 26 weeks after stroke. Results: Patients (N = 7) with impaired proprioception (EmNSA-UE proprioception score < 8) had significantly smaller SNR than patients with unimpaired proprioception (N = 24) [EmNSA-UE proprioception score = 8, t(29) = 2.36, p = 0.03]. No significant effect of time after stroke on SNR was observed. Furthermore, there was no significant difference in the predictive value between EmNSA-UE and SNR for predicting motor function at 26 weeks after stroke. Conclusion: The SNR of the evoked cortical response does not significantly change as a function of time after stroke and differs between patients with clinically assessed impaired and unimpaired proprioception, suggesting that SNR reflects persistent damage to proprioceptive pathways. A similar predictive value with respect to EmNSA-UE suggests that SNR may be used as an objective predictor next to clinical sensory assessments for predicting motor function at 26 weeks after stroke.

Trigone as a diagnostic and therapeutic target for bladder-centric interstitial cystitis/bladder pain syndrome.

The pathophysiology of interstitial cystitis/bladder pain syndrome (IC/BPS) may be bladder-centric, with afferent nerve hyperexcitability and/or due to neural central sensitization. In bladder-centric disease, the trigone's unmyelinated nociceptive C-fibers are thought to be upregulated, suggesting this as a potential target for diagnostic modalities and for treatment with local anesthetics and chemodenervation. We propose that the transvaginal trigone treatment (T3) route of administration of such treatments should be considered in women with IC/BPS, as this approach is easier and less invasive than cystoscopy. For T3, or other bladder-centric treatments to be successful, patient selection should attempt to exclude patients with predominantly neural central sensitization.

Scalp Topography of Lower Urinary Tract Sensory Evoked Potentials.

Impaired lower urinary tract (LUT) afferents often cause LUT symptoms. Assessment of LUT afferent pathways is possible using bipolar cortical sensory evoked potential (SEP) recordings with the active electrode at the vertex during electrical stimulation in the LUT. This study aimed to investigate the topographical distribution and microstates of lower urinary tract sensory evoked potentials (LUTSEPs) using different stimulation frequencies. Ninety healthy subjects (18-36 years old, 40 women) were randomly assigned to one of five stimulation locations [bladder dome; trigone; proximal, membranous (men only) or distal urethra]. Cycles of 0.5 Hz/1.1 Hz/1.6 Hz electrical stimulation were applied using a custom-made catheter. Cortical activity was recorded from 64 surface electrodes. Marker setting was performed manually on an individual subject-level for the P1, N1, and P2 components of vertex recordings. N1 and P2 topographies presented with central negativities and positivities around the vertex. Regarding topographical distribution, Randomization Graphical User interface (RAGU) analyses revealed consistent frequency effects and microstates for N1/P2. Higher stimulation frequencies resulted in decreasing map strength for P1, N1, and P2. LUTSEP topographies suggest central generators in the somatosensory cortex, which are not detectable in a bipolar set-up. The observed frequency effect indicates fiber refractoriness at higher frequencies. The multichannel approach allows more comprehensive assessment of LUTSEPs and might therefore be sensitive to pathological changes. Examinations in patients with LUT symptoms are needed to further investigate this biomarker.

Position-Cortical Coherence as a Marker of Afferent Pathway Integrity Early Poststroke: A Prospective Cohort Study.

Background. Addressing the role of somatosensory impairment, that is, afferent pathway integrity, in poststroke motor recovery may require neurophysiological assessment. Objective. We investigated the longitudinal construct validity of position-cortical coherence (PCC), that is, the agreement between mechanically evoked wrist perturbations and electroencephalography (EEG), as a measure of afferent pathway integrity. Methods. PCC was measured serially in 48 patients after a first-ever ischemic stroke in addition to Fugl-Meyer motor assessment of the upper extremity (FM-UE) and Nottingham Sensory Assessment hand-finger subscores (EmNSA-HF, within 3 and at 5, 12, and 26 weeks poststroke. Changes in PCC over time, represented by percentage presence of PCC (%PCC), mean amplitude of PCC over the affected (Amp-A) and nonaffected hemisphere (Amp-N) and a lateralization index (L-index), were analyzed, as well as their association with FM-UE and EmNSA-HF. Patients were retrospectively categorized based on FM-UE score at baseline and 26 weeks poststroke into high- and low-baseline recoverers and non-recoverers. Results. %PCC increased from baseline to 12 weeks poststroke (ß = 1.6%, CI = 0.32% to 2.86%, P = .01), which was no longer significant after adjusting for EmNSA-HF and FM-UE. A significant positive association was found between %PCC, Amp-A, and EmNSA-HF. Low-baseline recoverers (n = 8) showed longitudinally significantly higher %PCC than high-baseline recoverers (n = 23). Conclusions. We demonstrated the longitudinal construct validity of %PCC and Amp-A as a measure of afferent pathway integrity. A high %PCC in low-baseline recoverers suggests that this measure also contains information on cortical excitability. Use of PCC as an EEG-based measure to address the role of somatosensory integrity to motor recovery poststroke requires further attention.

Internal Subdivisions of the Marmoset Claustrum Complex: Identification by Myeloarchitectural Features and High Field Strength Imaging.

There has been a surge of interest in the structure and function of the mammalian claustrum in recent years. However, most anatomical and physiological studies treat the claustrum as a relatively homogenous structure. Relatively little attention has been directed toward possible compartmentalization of the claustrum complex into anatomical subdivisions, and how this compartmentalization is reflected in claustrum connections with other brain structures. In this study, we examined the cyto- and myelo-architecture of the claustrum of the common marmoset (Callithrix jacchus), to determine whether the claustrum contains internal anatomical structures or compartments, which could facilitate studies focused on understanding its role in brain function. NeuN, Nissl, calbindin, parvalbumin, and myelin-stained sections from eight adult marmosets were studied using light microscopy and serial reconstruction to identify potential internal compartments. Ultra high resolution (9.4T) post-mortem magnetic resonance imaging was employed to identify tractographic differences between identified claustrum subcompartments by diffusion-weighted tractography. Our results indicate that the classically defined marmoset claustrum includes at least two major subdivisions, which correspond to the dorsal endopiriform and insular claustrum nuclei, as described in other species, and that the dorsal endopiriform nucleus (DEnD) contains architecturally distinct compartments. Furthermore, the dorsal subdivision of the DEnD is tractographically distinguishable from the insular claustrum with respect to cortical connections.

Vagus nerve stimulation for primary headache disorders: An anatomical review to explain a clinical phenomenon.

BACKGROUND: Non-invasive stimulation of the vagus nerve has been proposed as a new neuromodulation therapy to treat primary headache disorders, as the vagus nerve is hypothesized to modulate the headache pain pathways in the brain. Vagus nerve stimulation can be performed by placing an electrode on the ear to stimulate the tragus nerve, which contains about 1% of the vagus fibers. Non-invasive vagus nerve stimulation (nVNS) conventionally refers to stimulation of the cervical branch of the vagus nerve, which is made up entirely of vagal nerve fibers. While used interchangeably, most of the research to date has been performed with nVNS or an implanted vagus nerve stimulation device. However, the exact mechanism of action of nVNS remains hypothetical and no clear overview of the effectiveness of nVNS in primary headache disorders is available. METHODS: In the present study, the clinical trials that investigated the effectiveness, tolerability and safety of nVNS in primary headache disorders were systematically reviewed. The second part of this study reviewed the central connections of the vagus nerve. Papers on the clinical use of nVNS and the anatomical investigations were included based on predefined criteria, evaluated, and results were reported in a narrative way. RESULTS: The first part of this review shows that nVNS in primary headache disorders is moderately effective, safe and well-tolerated. Regarding the anatomical review, it was reported that fibers from the vagus nerve intertwine with fibers from the trigeminal, facial, glossopharyngeal and hypoglossal nerves, mostly in the trigeminal spinal tract. Second, the four nuclei of the vagus nerve (nuclei of the solitary tract, nucleus ambiguus, spinal nucleus of the trigeminal nerve and dorsal motor nucleus (DMX)) show extensive interconnections. Third, the efferents from the vagal nuclei that receive sensory and visceral input (i.e. nuclei of the solitary tract and spinal nucleus of the trigeminal nerve) mainly course towards the main parts of the neural pain matrix directly or indirectly via other vagal nuclei. CONCLUSION: The moderate effectiveness of nVNS in treating primary headache disorders can possibly be linked to the connections between the trigeminal and vagal systems as described in animals.

[See the ocular motor pathways disorders in neuro-ophthalmology from the view of major of strabismus].

Neuro-ophthalmology is an interdisciplinary that covers neurology and ophthalmology. Neuro-ophthalmology involves not only visual afferent system disorders but also visual efferent system disorders. We have recognized that any disturbance in afferent system may result in vision decrease or loss. However, our understanding of visual efferent system disorders including strabismus, diplopia, ocular motility and abnormal head posture is incomplete. More attentions should be paid to ocular motor pathways disorders in neuro-ophthalmology including clinical characteristics, localization of potential lesion, nystagmus and pupillary abnormalities, in order to improve diagnosis and treatment of neuro-ophthalmology. (Chin J Ophthalmol, 2019, 55:3-6).

Innervation of the Nose and Nasal Region of the Rat: Implications for Initiating the Mammalian Diving Response.

Most terrestrial animals demonstrate an autonomic reflex that facilitates survival during prolonged submersion under water. This diving response is characterized by bradycardia, apnea and selective increases in peripheral vascular resistance. Stimulation of the nose and nasal passages is thought to be primarily responsible for providing the sensory afferent signals initiating this protective reflex. Consequently, the primary objective of this research was to determine the central terminal projections of nerves innervating the external nose, nasal vestibule and nasal passages of rats. We injected wheat germ agglutinin (WGA) into specific external nasal locations, into the internal nasal passages of rats both with and without intact anterior ethmoidal nerves (AENs), and directly into trigeminal nerves innervating the nose and nasal region. The central terminations of these projections within the medulla were then precisely mapped. Results indicate that the internal nasal branch of the AEN and the nasopalatine nerve, but not the infraorbital nerve (ION), provide primary innervation of the internal nasal passages. The results also suggest afferent fibers from the internal nasal passages, but not external nasal region, project to the medullary dorsal horn (MDH) in an appropriate anatomical way to cause the activation of secondary neurons within the ventral MDH that express Fos protein during diving. We conclude that innervation of the anterior nasal passages by the AEN and nasopalatine nerve is likely to provide the afferent information responsible for the activation of secondary neurons within MDH during voluntary diving in rats.

Inhibitory effects of silodosin on the bladder mechanosensitive afferent activities and their relation with bladder myogenic contractions in male rats with bladder outlet obstruction.

AIMS: We investigated the effects of silodosin, an α1A-adrenoceptor (AR) antagonist, on bladder function, especially on non-voiding contractions (NVCs), in a male rat model of bladder outlet obstruction (BOO) by evaluating cystometry (CMG) findings and bladder mechanosensitive single-unit afferent activities (SAAs), related with microcontractions, which may be similar with NVCs and to be of myogenic origin, in the rat model. METHODS: BOO was created by partial ligation of the posterior urethra. At 4 days after surgery for BOO, an osmotic pump filled with silodosin (0.12 mg/kg/day) or its vehicle was subcutaneously implanted. At 10 days after surgery, CMG and SAAs measurements were taken under conscious and urethane-anesthetized conditions, respectively. The SAAs of Aδ- and C-fibers, which were identified by electrical stimulation of the pelvic nerve and by bladder distention, and intravesical pressure were recorded during constant bladder-filling with saline. Microcontractions were divided into three phases: "ascending," "descending," and "stationary." RESULTS: The silodosin-treated group showed a smaller number of NVCs in CMG measurements and lower SAAs of both Aδ- and C-fibers than the vehicle-treated group during bladder-filling. Moreover, in the vehicle-treated groups, the SAAs of both fibers for the ascending phase of microcontractions were significantly higher than those for the other two phases. On the contrary, no significant change was found between any of these three phases in the silodosin-treated group. CONCLUSION: The present results suggest that silodosin inhibits the SAAs of mechanosensitive Aδ- and C-fibers at least partly due to suppressing myogenic bladder contractions in male BOO rats.

Potential role of lncRNAs in contributing to pathogenesis of chronic glomerulonephritis based on microarray data.

BACKGROUND: Chronic glomerulonephritis (CGN) is the most common form of primary glomerular disease with unclear molecular mechanisms, which related to immune-mediated inflammatory diseases. Our study intended to identify potential long non-coding RNAs (lncRNAs) and genes, and to determine the potential molecular mechanisms of CGN pathogenesis. METHODS: The microarray of GSE64265 and GSE46295 were downloaded from the Gene Expression Omnibus database, GSE64265 including 3 rats control kidney tissues and 5 rats model kidney tissues, GSE46295 including 3 rats control kidney tissues and 3 rats model kidney tissues, which was on the basis of GPL1355 platform. Identification of differentially expressed lncRNAs and mRNAs were performed between the 2 groups. Gene ontology (GO) and pathway enrichment analyses were performed to analyze the biological functions and pathways for the differentially expressed mRNAs. LncRNA-mRNA weighted co-expression network was constructed using the WGCNA package to analyses for the genes in the modules. The protein-protein interaction (PPI) network was visualized. RESULTS: A total of 40 significantly up-regulated and 24 down-regulated lncRNAs, 653 up-regulated and 128 down-regulated mRNAs were identified. Additionally, Cdk1, with the highest connectivity degree in PPI network, was noteworthy enriched in cell cycle. Seven lncRNAs: NONRATT026650, LOC102547664, NONRATT77021989, NONRATT012453, LOC102551856, LOC102553536 and NONRATT7047175 were observed in the modules of lncRNA-mRNA weighted co-expression network. CONCLUSIONS: LncRNAs NONRATT026650, LOC102547664, NONRATT77021989, NONRATT012453, LOC102551856, LOC102553536 and NONRATT7047175 were differentially expressed and might play important roles in the development of CGN. Key genes, such as Cd44, Rftn1, Runx1, may be crucial biomarkers for CGN.

BDNF overexpression in the bladder induces neuronal changes to mediate bladder overactivity.

Elevated levels of brain-derived neurotrophic factor (BDNF) in urine of overactive bladder (OAB) patients support the association of BDNF with OAB symptoms, but the causality is not known. Here, we investigated the functionality of BDNF overexpression in rat bladder following bladder wall transfection of either BDNF or luciferase (luciferase) transgenes (10 µg). One week after transfection, BDNF overexpression in bladder tissue and elevation of urine BDNF levels were observed together with increased transcript of BDNF, its cognate receptors (TrkB and p75NTR), and downstream PLCγ isoforms in bladder. BDNF overexpression can induce the bladder overactivity (BO) phenotype which is demonstrated by the increased voiding pressure and reduced intercontractile interval during transurethral open cystometry under urethane anesthesia. A role for BDNF-mediated enhancement of prejunctional cholinergic transmission in BO is supported by the significant increase in the atropine- and neostigmine-sensitive component of nerve-evoked contractions and upregulation of choline acetyltransferase, vesicular acetylcholine transporter, and transporter Oct2 and -α1 receptors. In addition, higher expression of transient receptor channels (TRPV1 and TRPA1) and pannexin-1 channels in conjunction with elevation of ATP and neurotrophins in bladder and also in L6/S1 dorsal root ganglia together support a role for sensitized afferent nerve terminals in BO. Overall, genomic changes in efferent and afferent neurons of bladder induced by the overexpression of BDNF per se establish a mechanistic link between elevated BDNF levels in urine and dysfunctional voiding observed in animal models and in OAB patients.

Electrical Stimulation of Afferent Pathways for the Suppression of Pathological Tremor.

Pathological tremors are involuntary oscillatory movements which cannot be fully attenuated using conventional treatments. For this reason, several studies have investigated the use of neuromuscular electrical stimulation for tremor suppression. In a recent study, however, we found that electrical stimulation below the motor threshold also suppressed tremor, indicating involvement of afferent pathways. In this study, we further explored this possibility by systematically investigating how tremor suppression by afferent stimulation depends on the stimulation settings. In this way, we aimed at identifying the optimal stimulation strategy, as well as to elucidate the underlying physiological mechanisms of tremor suppression. Stimulation strategies varying the stimulation intensity and pulse timing were tested in nine tremor patients using either intramuscular or surface stimulation. Significant tremor suppression was observed in six patients (tremor suppression > 75% was observed in three patients) and the average optimal suppression level observed across all subjects was 52%. The efficiency for each stimulation setting, however, varied substantially across patients and it was not possible to identify a single set of stimulation parameters that yielded positive results in all patients. For example, tremor suppression was achieved both with stimulation delivered in an out-of-phase pattern with respect to the tremor, and with random timing of the stimulation. Overall, these results indicate that low-current stimulation of afferent fibers is a promising approach for tremor suppression, but that further research is required to identify how the effect can be maximized in the individual patient.

Urothelial Barrier Deficits, Suburothelial Inflammation and Altered Sensory Protein Expression in Detrusor Underactivity.

PURPOSE: The pathophysiology of detrusor underactivity remains unclear and impaired bladder afferent function is considered one of the important etiologies. We investigated urothelial barrier deficits, suburothelial inflammation and sensory proteins expressed in the bladder mucosa of patients with detrusor underactivity. MATERIALS AND METHODS: Bladder mucosa biopsies were performed in 34 patients with videourodynamic proven detrusor underactivity as the study group and in 10 women with stress urinary incontinence as controls. The expression of zona occuldens-1, E-cadherin in the urothelium, tryptase and apoptosis levels in the suburothelium, ß3-adrenoceptor, M2 and M3 muscarinic receptors, P2X3 receptor, and inducible and endothelial nitric oxide synthase were compared between study patients and controls. RESULTS: Study patients included 22 women and 12 men with a mean ± SD age of 56.3 ± 19.7 years, of whom 15 had a history of diabetes. Study patients had significantly lower E-cadherin expression, and a higher number of mast cells and apoptotic cells than controls. Additionally, lower expression of M2 and M3 muscarinic receptors, P2X3 receptors and endothelial nitric oxide synthase was detected in study patients but higher expression of ß3-adrenoceptor. In study patients a positive correlation was noted between tryptase and apoptosis levels (r = 0.527) and between the expression of M2 muscarinic receptor and P2X3 receptor (r = 0.403). However, ß3-adrenoceptor expression negatively correlated with E-cadherin expression (r = -0.490, each p <0.05). CONCLUSIONS: Urothelial dysfunction, increased suburothelial inflammation and altered sensory protein expressions in bladder mucosa were prominent in patients with detrusor underactivity. Impaired urothelial signaling and sensory transduction pathways appear to reflect the pathophysiology of detrusor underactivity.

Falha na ativação da equipe de emergência intra-hospitalar: causas e consequências / Failure to activate the in-hospital emergency team: causes and outcomes

RESUMO Objetivo: Determinar a incidência de falha na ativação da via aferente da Equipe de Emergência Médica intra-hospitalar, caraterizando-a e comparando a mortalidade dessa população com a da população em que não se verificou falha na ativação da via aferente. Métodos: Entre janeiro de 2013 e julho de 2015, ocorreram 478 ativações da Equipe de Emergência Médica do Hospital Pedro Hispano. Após a exclusão de registos incompletos e ativações para doentes com menos de 6 horas de internamento hospitalar, obtivemos uma amostra de 285 ativações. A amostra foi dividida em dois grupos: o grupo com falha na ativação da via aferente e o grupo em que não ocorreu falha na ativação da via aferente da Equipe de Emergência Médica. As duas populações foram caracterizadas e comparadas. A significância estatística foi considerada para p ≤ 0,05. Resultado: Em 22,1% das ativações, verificou-se falha na ativação da via aferente. Relativamente ao estudo causal, verificamos existir diferença estatisticamente significativa quanto aos critérios de ativação da Equipe de Emergência Médica (p = 0,003) no grupo com falha na ativação da via aferente, encontrando taxa mais elevada de ativação da Equipe de Emergência Médica por paragem cardiorrespiratória e disfunção cardiovascular. Em relação às consequências, no grupo em que ocorreu falha na ativação da via aferente houve uma maior taxa de mortalidade imediata e à data de alta hospitalar, sem significado estatístico. Não encontramos diferenças significativas com relação aos outros parâmetros. Conclusão: Nos doentes em que houve falha da ativação da via aferente da Equipe de Emergência Médica, a incidência de paragem cardiorrespiratória e a taxa de mortalidade foram maiores. Este estudo reforça a necessidade de as unidades de saúde investirem na formação de todos os profissionais de saúde sobre os critérios de ativação da Equipe de Emergência Médica e o funcionamento do sistema de resposta a emergência médica.

ABSTRACT Objective: To determine the incidence of afferent limb failure of the in-hospital Medical Emergency Team, characterizing it and comparing the mortality between the population experiencing afferent limb failure and the population not experiencing afferent limb failure. Methods: A total of 478 activations of the Medical Emergency Team of Hospital Pedro Hispano occurred from January 2013 to July 2015. A sample of 285 activations was obtained after excluding incomplete records and activations for patients with less than 6 hours of hospitalization. The sample was divided into two groups: the group experiencing afferent limb failure and the group not experiencing afferent limb failure of the Medical Emergency Team. Both populations were characterized and compared. Statistical significance was set at p ≤ 0.05. Result: Afferent limb failure was observed in 22.1% of activations. The causal analysis revealed significant differences in Medical Emergency Team activation criteria (p = 0.003) in the group experiencing afferent limb failure, with higher rates of Medical Emergency Team activation for cardiac arrest and cardiovascular dysfunction. Regarding patient outcomes, the group experiencing afferent limb failure had higher immediate mortality rates and higher mortality rates at hospital discharge, with no significant differences. No significant differences were found for the other parameters. Conclusion: The incidence of cardiac arrest and the mortality rate were higher in patients experiencing failure of the afferent limb of the Medical Emergency Team. This study highlights the need for health units to invest in the training of all healthcare professionals regarding the Medical Emergency Team activation criteria and emergency medical response system operations.