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High Volume Injection (Hydrodissection) for Tarsal Tunnel Syndrome Using Peripheral Nerve Stimulation: Treatment Protocol
Ian Reilly, Akram Uddin
Subject: Medicine & Pharmacology, Allergology Keywords: tarsal tunnel syndrome; compression neuropathy; high volume injection; hydrodissection; hydrodilatation; nerve stimulator
Tarsal tunnel syndrome is a focal compressive neuropathy of the posterior tibial nerve or one of its associated branches. Brief mention is made in the literature of the use of corticosteroid injections for this condition. The basic technique of hydrodissection is used for other nerve entrapments and includes identifying the region of nerve compression, and the injection of a fluid medium to dissect between structures or fascial planes. We introduce our treatment protocol using a methylprednisolone/sterile water/ropivacaine hydrochloride injectate mix and peripheral nerve stimulation to a perform hydrodissection technique for tarsal tunnel syndrome.
Establishment of a Sheep Model for Hind limb Peripheral Nerve Injury: Common Peroneal Nerve
Rui D. Alvites, Mariana V. Branquinho, Ana Catarina Sousa, Federica Zen, Monica Maurina, Stefania Raimondo, Carla Mendonça, Luís Miguel Atayde, Stefano Geuna, Artur S. P. Varejão, Ana Colette Maurício
Subject: Life Sciences, Biochemistry Keywords: Peripheral Nerve Injury; Peripheral Nerve Regeneration; Peroneal Common Nerve; Animal Model; Sheep Model; Nerve Anatomy; Neurological Exam; Nerve Stereology
Thousands of people worldwide suffer from injuries in the peripheral nerve and deal daily with the resulting physiological and functional deficits. Recent advances in this field are still insufficient to guarantee effective outcomes, and the development of new and effective therapeutic options requires the use of valid preclinical models that effectively replicate the characteristics and challenges associated with these injuries in humans. In this study, we established a sheep model for common peroneal nerve injuries that can be applied in preclinical research with the advantages associated with the use of large animal models. In an integrative way, this article includes a detailed description of the anatomy and functionality of the peripheral nerves of sheep's hind limb, the surgical protocol for accessing the common peroneal nerve, the induction of different types of nerve damage and the application of possible therapeutic options. A neurological exam protocol directed to the common peroneal nerve was also established, allowing to identify the changes and deficits related with the nerve injury and to evaluate the functional progression over time. Finally, a preliminary stereological study was carried out to establish control values for the healthy peroneal common nerves of this model and to identify preliminary differences between therapeutic methods. The ultimate goal is to demonstrate that sheep is a valid model of peripheral nerve injury to be used in pre-clinical and translational works and to evaluate the efficacy and safety of nerve injury therapeutic options before its clinical application in human and veterinary patients.
Peripheral Nerve Injury Treatments and Advances: One Health Perspective
Bruna Lopes, Patrícia Sousa, Rui Alvites, Mariana Branquinho, Ana Sousa, Carla Mendonça, Luís Miguel Atayde, Ana Lúcia Luís, Artur S. P. Varejão, and Ana Colette Maurício
Subject: Life Sciences, Biotechnology Keywords: Mesenchymal stem cells; Nerve Guide Conduits; Nerve recovery; One Health; Peripheral nerve injury; Secretome
Peripheral nerve injuries (PNI) can have several etiologies, such as trauma and iatrogenic interventions that can lead to the loss of structure and/or function impairment. These changes can cause a partial or complete loss of motor and sensory functions, physical disability, and neuropathic pain, what in turn can affect the quality of life. For those reasons, PNI is a major public health concern. This review aims to revisit the concepts associated with the PNI. First, the anatomy of the peripheral nerve is detailed to explain the different types of injury. Then, some of the available therapeutic strategies are explained, including surgical methods, pharmacological therapies, and the use of cell-based therapies alone or in combination with biomaterials in the form of tube guides. Nevertheless, even with the various available treatments, it is difficult to achieve a perfect outcome with complete functional recovery. This review aims to explain the urge for new approaches and to understand the methods to evaluate nerve regeneration in a One Health perspective. In vitro models followed by in vivo models are very important to be able to translate the achievements to human medicine.
A Single Postoperative Application of Defocused Low-Energy ESWT Does Not Significantly Enhance Regeneration of the Rat Median Nerve Following Reconstruction with Autologous Nerve Grafts or Muscle-In-Vein Conduits
Johannes Christoph Heinzel, Viola Oberhauser, Claudia Keibl, Barbara Schädl, Nicole Victoria Swiadek, Gregor Längle, Helen Frick, Cyrill Slezak, Cosima Prahm, Johannes Grillari, Jonas Kolbenschlag, David Hercher
Subject: Biology, Other Keywords: nerve repair; median nerve; rat; autologous nerve graft; muscle-in-vein conduit; extracorporeal shock wave therapy; grasping test; gait analysis; CatWalk, nerve regeneration
Investigations reporting positive effects of Extracorporeal Shock Wave Therapy (ESWT) on nerve regeneration are limited to the rat sciatic nerve model. The effects of ESWT on muscle-in-vein conduits (MVCs) have also not been investigated yet. This study aimed to evaluate the effects of ESWT after repair of the rat median nerve with either autografts (ANGs) or MVCs. In male Lewis rats, a 7-mm segment of the right median nerve was reconstructed either with an ANG or MVC. For each reconstructive technique, one group of animals received one application of ESWT while the other rats served as controls. Animals were observed for 12 weeks and nerve regeneration was assessed via computerized gait analysis, the grasping test, electrophysiological evaluations and histological quantification of axons, blood vessels and lymphatic vasculature. Here we provide for the first time a comprehensive analysis of ESWT effects on nerve regeneration in a rat model of median nerve injury. Furthermore, this study is among the first reporting the quantification of lymphatic vessels following peripheral nerve injury and reconstruction in vivo. While we found no significant direct positive effects of ESWT on peripheral nerve regeneration, results following nerve repair with MVCs were significantly inferior to those after ANG repair.
Effects of Olfactory Mucosa Stem/Stromal Cell and Olfactory Ensheating Cells Secretome on Peripheral Nerve Regeneration
Rui D. Alvites, Mariana Branquinho, Ana Catarina Sousa, Bruna Lopes, Patrícia Sousa, Justina Prada, Isabel Pires, Giulia Ronchi, Stefania Raimondo, Ana Lúcia Luís, Stefano Geuna, Artur S. P. Varejão, Ana Colette Maurício
Subject: Life Sciences, Biotechnology Keywords: Peripheral Nerve Injury; peripheral nerve regeneration; sciatic nerve; Olfactory Mucosa Mesenchymal Stem/Stromal Cells; Olfactory Ensheating Cells; secretome; conditioned medium; nerve guidance conduit; tibial cranial muscle; rat
Cell secretome has been explored as a cell-free technique with high scientific and medical interest for Regenerative Medicine. In this work, the secretome produced and collected from Olfactory Mucosa Mesenchymal Stem Cells and Olfactory Ensheating Cells was analyzed and therapeutically applied to promote peripheral nerve regeneration. The analysis of the conditioned medium revealed the production and secretion of several factors with immunomodulatory functions, capable of intervening beneficially in the phases of nerve regeneration. Subsequently, the conditioned medium was applied to sciatic nerves of rats after neurotmesis, using Reaxon® as tube-guides. Over 20 weeks, the animals were subjected to periodic functional assessments, and after this period, the sciatic nerves and cranial tibial muscles were evaluated stereologically and histomorphometrically, respectively. The results obtained allowed to confirm the beneficial effects resulting from the application of this therapeutic combination. The administration of conditioned medium from Olfactory Mucosal Mesenchymal Stem Cells led to the best results in motor performance, sensory recovery, and gait patterns. Stereological and histomorphometric evaluation also revealed the ability of this therapeutic combination to promote nervous and muscular histologic reorganization during the regenerative process. The therapeutic combination discussed in this work shows promising results and should be further explored to clarify irregularities found in the outcomes and to allow establishing the use of cell secretome as a new therapeutic field applied in the treatment of peripheral nerves after injury.
On the Estimation of Ultra-Short-Term Heart Rate Variability
Enrico Maria Staderini, Harish Kambampati, Amith K. Ramakrishnaiah, Stefano Mugnaini, Andrea Magrini, Sandro Gentili
Subject: Medicine & Pharmacology, Cardiology Keywords: heart rate variability; vagus nerve response; vagus nerve event evoked responses; Valsalva manoeuvre; signal analysis
Heart rate variability (HRV) is commonly intended as the variation in the heart rate (HR) and it is evaluated in the time and frequency domains with various well known methods. In the present paper, we first consider an abstract model in which the HR is the instantaneous frequency of an otherwise periodic signal such as the electrocardiogram (ECG). Thus the ECG is assumed as a frequency modulated signal, or carrier signal, where HRV or HRVt is a supposed time-domain signal which is frequency modulating the carrier ECG signal around its average frequency. Hence we describe an algorithm able to frequency demodulate the ECG signal to extract a continuous signal HRVt with possibly enough time resolution to analyse fast time-domain variations in the instantaneous HR. After exhaustive testing of the method on simulated frequency modulated sinusoidal signals, we have applied the procedure on actual ECG tracings. The purpose of the work is to eventually use the heart as a kind of biological sensor of the fast activity of the autonomous nervous system (ANS) to study the ANS ultra-short-term event-evoked responses. A few preliminary, not clinical, real examples are also given.
A Historical Perspective on Sacral Nerve Stimulation (SNS) for Bowel Dysfunction
Elroy Patrick Weledji
Subject: Medicine & Pharmacology, Allergology Keywords: pelvic floor; bowel; dysfunction; sacral nerve; stimulation
Prevention of obstetric trauma from damage to the pelvic floor is not always possible and sacral nerve stimulation (SNS) may be necessary later in life. Sacral nerve stimulation has been a promising innovation in the management of moderate to severe faecal incontinence and following sphincter repair failure. Although the indication spectrum for SNS is expanding, the success of neuromodulation for constipation is limited. Adverse events of SNS requiring re-intervention are not common but a long-term successful outcome may depend on interventions for maintenance of the device.
Preprint CASE REPORT | doi:10.20944/preprints202301.0379.v1
Combined Invasive Peripheral Nerve Stimulation in the Management of Chronic Post-Intracranial Disorder Headache. A Case Report.
Athanasia Alexoudi, Eustathios Vlahakis, Stamatios Banos, Konstantinos Oikonomou, Panayiotis Patrikelis, Anastasia Verentzioti, Maria Stefanatou, Stylianos Gatzonis, Stefanos Korfias, Damianos Sakas
Subject: Medicine & Pharmacology, Clinical Neurology Keywords: Combined Peripheral Nerve Stimulation; occipital nerve stimulation; secondary headache disor-ders; chronic post-intracranial disorder headache and case report
The introduction of ventricular shunts dramatically changed the outcome and quality of life of hydrocephalic patients. However, shunt surgery continues to be associated with numerous adverse events. Headache is one of the most common complications after shunt operation. It is often over a prolonged duration, the symptoms resemble migraine, and pain does not respond to medication. We propose invasive peripheral nerve stimulation as a possible solution in the treatment of patients suffering from chronic headache associated with shunted hydrocephalus. A young woman with daily holocephalic headache with diffuse pain exacerbated by lying down. Imaging revealed panventricular enlargement and possible stenosis of the aqueduct. When a ventriculoperitoneal shunt was placed, clinical symptoms resolved. Nevertheless, she gradually exacerbated after a second valve replacement due to wound infection. Imaging revealed decompressed ventricles and appropriate shunt placement. The diagnosis of chronic post-intracranial disorder headache was set. Therefore, occipital nerve stimulation was applied and considering that the patient had not a total response, bilateral parietal stimulation was added. Three months after the combined PNS she experienced total remission of headache. Combined PNS eases refractory headaches much more than occipital nerve stimulation alone and could be considered as a solution for shunted hydrocephalus associated headache.
Preprint SHORT NOTE | doi:10.20944/preprints202206.0048.v1
Morphometric Characterization of the Asymmetry in the Mandible of the Ferret (Mustela putorius furo Linnaeus, 1758)
Pere M. Parés-Casanova
Subject: Biology, Anatomy & Morphology Keywords: craniofacial; laboratory animal; mental foramen; mental nerve; polecat
In order to analyse asymmetries between hemimandibles, a sample of 24 mandibles from ferrets was studied by means of geometric morphometric methods, using a set of 3 landmarks and 14 semilandmarks, on the lateral aspect. Results showed that both size and shape played a significative role in mandibular asymmetry. For shape, there appeared significative fluctuating and directional asymmetries, with an especially high level for this latter. Landmarks corresponding to muscular attachments showed greater landmark asymmetry. This it is supported the hypothesis of a chewing side preference, e.g., a mastication-related driver for mandibular shape asymmetry.
Repeated Oral Administration of Flavan-3-ols Induces Browning in Mice Adipose Tissues Through Sympathetic Nerve Activation
Yuko Ishii, Orie Muta, Tomohiro Teshima, Nayuta Hirasima, Minayu Odaka, Taiki Fushimi, Yasuyuki Fujii, Naomi Osakabe
Subject: Life Sciences, Endocrinology & Metabolomics Keywords: flavan-3-ols; adipose; browning; catecholamine; sympathetic nerve
We previously found increases in uncoupling protein (Ucp)-1 transcription in brown adipose tissue (BAT) of mice following a single oral dose of flavan 3-ols (FL), a fraction of catechins and procyanidins. It was confirmed that these changes were totally reduced by co-treatment of adrenaline blockers. According to these previous results, FL possibly activates sympathetic nervous system (SNS). In this study, we confirmed the marked increase in urinary catecholamine (CA) s projecting SNS activity following a single dose of 50 mg/kg FL. In addition, we examined the impact of the repeated administration of 50 mg/kg FL for 14 days on adipose tissues in mice. In BAT, FL tended to increase the level of Ucp-1 along with thermogenic transcriptome factors, such as peroxisome proliferator-activated receptor γ coactivator (PGC)-1α and PR domain-containing (PRDM)1. Transcription of browning markers, such as CD137 and transmembrane protein (TMEM) 26 in addition to PGC-1α were increased in epididymal adipose (eWAT) by FL. A multilocular morphology with cell size reduction was shown in the inguinal adipose (iWAT), together with increasing the level of Ucp-1 following administration of FL. These results suggest that FL produces browning in adipose through activation of the SNS.
Occurrence of Lymphangiogenesis in Peripheral Nerve Autografts Contrasts Schwann Cell-induced Apoptosis of Lymphatic Endothelial Cells in vitro
Carina Hromada, Jaana Hartmann, Johannes Oesterreicher, Anton Stoiber, Anna Daerr, Barbara Schädl, Eleni Priglinger, Andreas H. Teuschl-Woller, Wolfgang Holnthoner, Johannes Heinzel, David Hercher
Subject: Medicine & Pharmacology, Other Keywords: peripheral nerve regeneration; lymphangiogenesis; Schwann cells; lymphatic endothelial cells
Peripheral nerve injuries pose a major clinical concern world-wide, and functional recovery after segmental peripheral nerve injury is often unsatisfactory, even in case of autografting. Although it is well established that angiogenesis plays a pivotal role during nerve regeneration, the influence of lymphangiogenesis is strongly underinvestigated. In this study, we analyzed the presence of lymphatic vasculature in healthy and regenerated murine peripheral nerves, revealing that nerve autografts contained increased numbers of lymphatic vessels after segmental damage. This led us to elucidate the interaction between lymphatic endothelial cells (LECs) and Schwann cells (SCs) in vitro. We show that SC and LEC secretomes do not influence the respective other cell types' migration and proliferation in 2D scratch assay experiments. Furthermore, we successfully created lymphatic microvascular structures in SC-embedded 3D fibrin hydrogels in the presence of supporting cells, whereas SCs seemed to exert anti-lymphangiogenic effects when cultured with LECs alone. Here, we describe for the first time increased lymphangiogenesis after peripheral nerve injury and repair. Furthermore, our findings indicate a potential lymph-repellent property of SCs, thereby providing a possible explanation for the lack of lymphatic vessels in the healthy endoneurium. Our results highlight the importance to elucidate the molecular mechanisms of SC-LEC interaction.
Predictive Utility of Changes in Optic Nerve Sheath Diameter after Cardiac Arrest for Neurologic Outcomes
Heekyung Lee, Joonkee Lee, Hyungoo Shin, Changsun Kim, Hyuk Joong Choi, Bo Seung Kang
Subject: Medicine & Pharmacology, Clinical Neurology Keywords: Heart arrest; optic nerve sheath diameter; Patient outcome assessment
Optic nerve sheath diameter (ONSD) can help predict the neurologic outcome of patients with post-cardiac arrest (CA) return of spontaneous circulation (ROSC). We aimed to investigate the effect of ONSD changes before and after CA on neurologic outcomes in patients with ROSC after CA using brain computed tomography (CT). The study included patients hospitalized after CA, who had undergone pre- and post-CA brain CT from January 2001 to September 2020. The patients were divided into good and poor neurologic outcome (GNO and PNO, respectively) groups based on the neurologic outcome at hospital discharge. We performed between-group comparisons of the amount and rate of ONSD changes on brain CT and calculated the area under the curve (AUC) to determine their predictive value for neurologic outcomes. Among the 96 enrolled patients, 25 had GNO. Compared to the GNO group, the PNO group showed significantly higher amount (0.30 vs. 0.63 mm; p=0.030) and rate of change (5.26 vs. 12.29 %; p=0.041). The AUC for predicting PNO was 0.64 (95% CI=0.53–0.73; p=0.04) and patients with a rate of ONSD change >27.2% had PNO with 100% specificity and positive predictive value. Hence, ONSD changes may predict neurologic outcomes in patients with post-CA ROSC.
Effects of Meditation on Mental Health and Cardiovascular Balance in Caregivers
Lourdes Díaz-Rodríguez, Keyla Vargas-Román, Juan Carlos Sanchez-Garcia, Raquel Rodríguez-Blanque, Guillermo Arturo Cañadas- De la Fuente, Emilia I. De La Fuente-Solana
Subject: Medicine & Pharmacology, Allergology Keywords: meditation; vagal nerve activity; high-burden caregivers; mental health.
Background: Caring for a loved one can be rewarding but also associated with substantial caregiver burden, developing mental outcomes and affecting happiness. Eventually, these physical and psychological disorders can lead to an imbalance of the autonomic nervous system. Meditation has been found to offer multiple benefits to relieve these disorders and reduce the risk of cardiovascular disease. The aim of this study was to determine the effects of a four-week 16-hour presential meditation program on physiological and psychological parameters and vagal nerve activity in high-burden caregivers, comparing the results with those not receiving this program. Methods: A non-randomized repeated-measures controlled clinical trial was conducted, dividing participants between intervention and control groups by convenience allocation because random assignment was ethically inappropriate. Results: After the meditation program, the experimental group showed a significant reduction in anxiety levels (F= 24.92, p<0.001), a non-significant amelioration of depression levels (F= 1.75, p=0.19), and significantly improved heart rate variability (F= 8.40, p<0.05) and SDNN (F=15.59, p<0.05). Conclusions: Meditation can be a useful therapy to enhance the mental health and autonomic nervous system balance of informal caregivers, improving symptoms of physical and mental overload.
Short but Continuous Natural Pain during Meditation Sittings for Depression Treatment: A Case Report
Mingwei Huang
Subject: Medicine & Pharmacology, Psychiatry & Mental Health Studies Keywords: pain; depression; treatment; meditation; synaptic plasticity and homeostasis; nerve stimulation
Major depressive disorder (MDD) is a common mental disorder, which results in seriously impaired condition in the patients and great global disability burden. In light of its quite diverse etiologies, comorbidity with many other diseases, and complex underlying pathology, it has been a great challenge to understand the physiological basis of MDD, which may be a complex of related diseases, rather than a single one. In addition to the partial understanding of MDD, the individual heterogeneities among patients may render the development of a universal treatment an elusive goal. But studying how each of currently available treatments affects the disease can generate useful information to stratify patients into different subtypes for individualized treatments. In this case report, we present the first report of repeated success of using meditation as the only treatment of MDD, compared to initial success but no remission with other conventional antidepressants on the same patient. We hypothesized that the short but continuous natural pain during one-hour meditation sittings has the therapeutic effect to treat depression in the case of this patient and potentially others with MDD. This special opportunity of eliminating tremendous heterogeneity among different individuals has enabled us to probe deeply into the potential mechanism of depression treatments and the complex physiology of depression itself, both of which have likely profound implications in the treatment of other MDD patients as well. More importantly, this case report helps us dissect one specific component of meditation for its long-known and well-established benefit against depression.
Laryngeal Paralysis Recovered Two Years After a Head Trauma by Growth Hormone Treatment and Neurorehabilitation
Joaquín Guerra, Hortensia Lema, Carlos Agra, Pedro Martínez, Jesús Devesa
Subject: Life Sciences, Biochemistry Keywords: Growth Hormone; Recurrent nerve injury; Speech therapy; Neurostimulation; Vocal cord paralysis
The aim of this study is to describe the cognitive and speech results obtained after growth hormone (GH) treatment and neurorehabilitation in a man that suffered a traumatic brain injury (TBI). 17 months after the accident, the patient was treated with growth hormone (GH), together with neurostimulation and speech therapy. At admission, the left vocal cord revealed paralyzed, in the paramedian position, a situation compatible with a recurrent nerve injury. Clinical and rehabilitation assessments revealed a prompt improvement in speech and cognitive functions, and following completion of treatment, endoscopic examination showed recovery of vocal cord mobility. These results, together with previous results from our group, indicate that GH treatment is safe and effective for helping neurorehabilitation in chronic speech impairment due to central laryngeal paralysis, as well as impaired cognitive functions.
Cell Therapy Replacement for Retinal and Optic Nerve Diseases: Cell Sources, Clinical Trials and Challenges
Rosa M. Coco-Martin, Salvador Pastor-Idoate, Jose C. Pastor Jimeno
Subject: Medicine & Pharmacology, Allergology Keywords: stem cells; retinal diseases; optic nerve diseases; cell replacement; cell sources
The aim of this review was to provide an update on the potential of cell therapies to restore or replace damaged and/or lost cells in retinal degenerative and optic nerve diseases, describing the available cell sources and the challenges involved in such treatments when these techniques are applied in real clinical practice. Sources include human fetal retinal stem cells, allogenic cadaveric human cells, adult hippocampal neural stem cells, human CNS stem cells, ciliary pigmented epithelial cells, limbal stem cells, retinal progenitor cells (RPCs), human pluripotent stem cells (PSCs) (including both human embryonic stem cells (ESCs) and human induced pluripotent stem cells (iPSCs)) and mesenchymal stem cells (MSCs). Of these, RPCs, PSCs and MSCs have already entered early-stage clinical trials since they can all differentiate into RPE, photoreceptors or ganglion cells, and have demonstrated safety, while showing some indicators of efficacy. Stem/progenitor cell therapies for retinal diseases still have some drawbacks, such as the inhibition of proliferation and/or differentiation in vitro (with the exception of RPE) and the limited long-term survival and functioning of grafts in vivo. Some other issues remain to be solved concerning the clinical translation of cell-based therapy, including (1) the ability to enrich for specific retinal subtypes; (2) cell survival; (3) cell delivery, which may need to incorporate a scaffold to induce correct cell polarization, which increases the size of the retinotomy in surgery and, therefore, the chance of severe complications; (4) the need to induce retinal detachment to perform the subretinal placement of the transplanted cell; and (5) the evaluation of the risk of tumor formation caused by the undifferentiated stem cells and prolific progenitor cells. Despite these challenges, stem/progenitor cells represent the most promising strategy for retinal and optic nerve disease treatment in the near future, and therapeutics assisted by gene techniques, neuroprotective compounds and artificial devices can be applied to fulfil clinical needs.
Nano PGE1 Enhances Phosphorylation of ERK1/2 and Akt to Promote Recovery from Motor Dysfunction and Muscle Atrophy Induced by Sciatic Nerve Injury
Mitsuko Takenaga, Tsutomu Ishihara, Jun Niimi, Akemi Hamaguchi, Teita Asano, Reiko Tsuchiya, Yuki Ohta, Tohru Mizushima, Kazuo Yudoh
Subject: Medicine & Pharmacology, Pharmacology & Toxicology Keywords: drug delivery system, muscle atrophy, nanoparticle, prostaglandin E1, sciatic nerve injury
The effect of prostaglandin E1 (PGE1) encapsulated in nanoparticles (Nano PGE1) on motor dysfunction and muscle atrophy induced by sciatic nerve injury (SNI) was investigated in rats, and was compared with PGE1 encapsulated in lipid microspheres (Lipo PGE1) or PGE1 clathrated in cyclodextrin (PGE1-CD). The hind limb muscle weight ratio decreased until 2 weeks after SNI. All 3 PGE1 formulations significantly improved SNI-induced motor dysfunction. Nano PGE1 significantly promoted recovery from muscle atrophy at 2 and 3 weeks after SNI. Lipo PGE1 was also effective, but multiple doses were required. Compared with the SNI control group, the Nano PGE1 group showed upregulation of vascular endothelial growth factor (VEGF) and agrin expression in the injured sciatic nerve and atrophic muscles. Nano PGE1 accumulated prominently at the site of nerve injury and persisted for longer than Lipo PGE1 or PGE1-CD. Expression of all EP receptors was detected in the normal sciatic nerve, and EP2 expression increased after SNI. Finally, Nano PGE1 promoted ERK1/2 and Akt phosphorylation. These findings suggest that PGE1 released from nanoparticles accumulates at sites of nerve injury and increases VEGF production by augmenting ERK1/2 phosphorylation via EP receptor signaling, thus promoting tissue repair and regeneration.
The Relative Contribution of Blood Pressure and Renal Sympa-Thetic Nerve Activity on Proximal Tubular Sodium Reabsorption through NHE3 Actions
Roberto B. Pontes, Erika E. Nishi, Renato O Crajoinas, Maycon I. O Milanez, Adriana C. C. Girardi, Ruy R Campos, Cassia T Bergamaschi
Subject: Life Sciences, Molecular Biology Keywords: NHE3; glomerular filtration rate; bicuculline; PVN of the hypothalamus; sympathetic nerve activity.
This study aimed to verify the effects of an acute increase in blood pressure (BP) and/or renal sympathetic nerve activity (rSNA) on the renal excretion of sodium and water and its potential effect on the regulation of NHE3 activity. Uninephectomized anesthetized male Wistar rats were divided into three experimental groups: 1) Sham, the rats had their BP and rSNA recorded, and urine was collected for 2 h; 2) bicuculline (Bic) paraventricular nucleus of the hypothalamus (PVN), rat BP, and rSNA were recorded, and urine was collected for 1 h at baseline conditions and 1 h after bicuculline injection into the PVN; 3) RNS + Bicuculine injection into the PVN, BP, and rSNA were recorded, and urine was collected 1h after RNS and 1 h after bicuculline injection into the PVN. Renal nerve stimulation (RNS) decreased sodium and water excretion independent of changes in BP. However, after Bic in the PVN during RNS stimulation, BP and rSNA increased up to 30% and 60%, respectively, increasing diuresis (5-fold) and natriuresis (2.3-fold), accompanied by a significant reduction in the NHE3 activity independent of GFR changes. In conclusion, an acute increase in BP overcomes such effects, generating diuresis, natriuresis, and NHE3 activity inhibition.
Factors Associated with Lamina Cribrosa Displacement After Trabeculectomy Measured by Optical Coherence Tomography in Advanced Primary Open Angle Glaucoma
Hamed Esfandiari, Ali Efatizadeh, Azadeh Doozandeh, Mehdi Yaseri, Nils A. Loewen
Subject: Medicine & Pharmacology, Ophthalmology Keywords: glaucoma; lamina cribrosa; optic nerve head; optical coherence tomography; corneal hysteresis; visual field; trabeculectomy
Purpose: To investigate the relationship of lamina cribrosa displacement to corneal biomechanical properties and visual function after mitomycin C-augmented trabeculectomy. Method: Eighty-one primary open angle eyes were imaged before and after trabeculectomy using an enhanced depth spectral-domain optical coherence tomography (SDOCT). Corneal biomechanical properties were measured with the Ocular Response Analyser before the surgery. The anterior lamina cribrosa (LC) was marked at several points in each of six radial scans to evaluate LC displacement in response to Intraocular pressure (IOP) reduction. A Humphrey visual field test (HVF) was performed before the surgery as well as three and six months postoperatively. Results: Factors associated with a deeper baseline anterior lamina cribrosa depth (ALD) were cup-disc ratio (P=0.04), baseline IOP (P= 0.01), corneal hysteresis (P= 0.001), and corneal resistance factor (P= 0.001). After the surgery, the position of LC became more anterior (negative), posterior (positive) or remained unchanged. The mean LC displacement was -42 μm (P= 0.001) and was positively correlated with the magnitude of IOP reduction (regression coefficient: 0.251, P=0.02), and negatively correlated with age (regression coefficient: - 0.224, P= 0.04) as well as baseline cup-disk ratio (Regression coefficient: -0.212,P= 0.05) Eyes with a larger negative LC displacement were more likely to experience an HVF improvement of more than 3 dB gain in mean deviation (P= 0.002). Conclusion: A lower SDOCT cup-disc ratio, younger age, and a larger IOP reduction were correlated with a larger negative LC displacement and improving HVF. Corneal biomechanics did not predict LC displacement.
Optic Nerve Injury Enhanced Mitochondrial Fission and Increased Mitochondrial Density without Altering the Uniform Mitochondrial Distribution in the Unmyelinated Axons of Retinal Ganglion Cells in a Mouse Model
Takahiro Tsuji, Tomoya Murase, Yoshiyuki Konishi, Masaru Inatani
Subject: Medicine & Pharmacology, Ophthalmology Keywords: glaucoma; optic neuropathy; mitochondria; optic nerve crush; confocal scanning ophthalmoscope; distribution; Thy1-mito-YFP mice
Glaucomatous optic neuropathy, a major cause of blindness, is characterized by the loss of retinal gan-glion cells (RGCs) and degeneration of their axons. Mitochondria are deeply involved in maintaining RGCs and their axons. Therefore, lots of attempts have been made to develop diagnostic tools and therapies tar-geting mitochondria. Recently, we reported that mitochondria are uniformly distributed in unmyelinated axons of RGCs, possibly owing to the ATP gradient. Thus, using transgenic mice expressing yellow fluo-rescent protein targeting mitochondria exclusively in RGCs within the retina, we assessed the alteration of mitochondrial distributions induced by optic nerve crush (ONC) via in vitro flat-mount retinal sections and in vivo fundus images captured through the cornea with a confocal scanning ophthalmoscope. We observed that the mitochondrial distribution in unmyelinated axons of RGCs that survived the ONC remained uni-form, although their density increased. Furthermore, via in vitro analysis, we discovered that the mitochon-drial size is attenuated following ONC. These results suggest that ONC induces mitochondrial fission without disrupting the uniform mitochondrial distribution. This mechanism may help to prevent axonal degeneration and apoptosis. The in vivo visualization system of axonal mitochondria in RGCs may be ap-plicable in the diagnosis of progression of optic neuropathy.
Negative mpMRI Rules Out Extra-Prostatic Extension in Prostate Cancer Before Robot-Assisted Radical Prostatectomy
Eoin Dinneen, Clare Allen, Tom Strange, Daniel Heffernan-Ho, Jelena Banjeglav, Jamie Lindsay, John-Patrick Mulligan, Tim Briggs, Senthil Nathan, Ashwin Sridhar, Jack Grierson, Aiman Haider, Christos Panayi, Dominic Patel, Alex Freemna, Jonathan Aning, Rajendra Persad, Imran Ahmad, Lornezo Dutto, Neil Oakley, Alessandro Ambrosi, Tom Parry, Veeru Kasivisvanathan, Francesco Giganti, Greg Shaw, Shonit Punwani
Subject: Medicine & Pharmacology, Urology Keywords: extra-prostatic extension; magnetic resonance imaging; radical prostatectomy; nerve-sparing; prostate cancer; staging; diagnostic accuracy
The accuracy of multi-parametric MRI (mpMRI) in pre-operative staging of prostate cancer (PCa) remains controversial. Objective: To evaluate the ability of mpMRI to accurately predict PCa extra-prostatic extension (EPE) on a side-specific basis using a risk-stratified 5-point Likert scale. This study also aimed to assess the influence of mpMRI scan quality on diagnostic accuracy. Patients and Methods: We included 124 men who underwent robot-assisted RP (RARP) as part of the NeuroSAFE PROOF study at our centre. Three radiologists retrospectively reviewed mpMRI blinded to RP pathology and assigned a Likert score (1-5) for EPE on each side of the prostate. Each scan was also ascribed a Prostate Imaging Quality (PI-QUAL) score for assessing the quality of the mpMRI scan, where 1 represents poorest and 5 represents best diagnostic quality. Outcome measurements and statistical analyses: Diagnostic performance is presented for binary classification of EPE including 95% confidence intervals and area under the receiver operating characteristic curve (AUC). Results: A total of 231 lobes from 121 men (mean age 56.9 years) were evaluated. 39 men (32.2%), or 43 lobes (18.6%) had EPE. Likert score ≥3 had sensitivity (SE), specificity (SP), NPV, PPV of 90.4%, 52.3%, 96%, 29.9%, respectively, and AUC was 0.82 (95% CI: 0.77-0.86). AUC was 0.63 (95% CI: 0.37-0.9), 0.77 (0.71-0.84) and 0.92 (0.88-0.96) for biparametric scans, PI-QUAL 1-3 and PI-QUAL 4-5 scans, respectively. Conclusions: MRI can be used effectively by genitourinary radiologists to rule out EPE and help inform surgical planning for men undergoing RARP. EPE prediction was more reliable when the MRI scan was a) multi-parametric and b) of a higher image quality according to the PI-QUAL scoring system.
Neuroscience and Neuroimmunology Solutions for Osteoarthritis Pain: Biological Drugs, Growth Factors, Peptides and Monoclonal Antibodies Targeting Peripheral Nerves
Ali Mobasheri
Subject: Medicine & Pharmacology, Allergology Keywords: neuroscience; rheumatology; osteoarthritis; pain; peripheral nerve; biological drug; growth factor; peptide; monoclonal antibody; ion channel
Neuroscience is a vast discipline that deals with the anatomy, biochemistry, molecular biology, physiology and pathophysiology of central and peripheral nerves. Advances made through basic, translational, and clinical research in the field of neuroscience have great potential for long-lasting and beneficial impacts on human health. The emerging field of biological therapy is intersecting with the disciplines of neuroscience and rheumatology, creating new horizons for interdisciplinary and applied research. Biological drugs, growth factors, neuropeptides and monoclonal antibodies are being developed and tested for the treatment of painful arthritic and rheumatic diseases. This concise communication focuses on the solutions provided by the fields of neuroscience and neuroimmunology for real-world clinical problems in the field of rheumatology, focusing on synovial joint pain and the emerging biological treatments that specifically target pathways implicated in osteoarthritis pain in peripheral nerves.
The Nerve Growth Factor Receptor (NGFR/P75ntr): A Major Player in Alzheimer's Disease
Francesco Bruno, Paolo Abondio, Alberto Montesanto, Donata Luiselli, Amalia Cecilia Bruni, Raffaele Maletta
Subject: Life Sciences, Cell & Developmental Biology Keywords: Alzheimer's disease; Nerve growth factor receptor; NGFR; p75NTR; amyloid-beta; expression; signaling pathways; neuropathology; diagnosis; treatment.
Alzheimer's disease (AD) represents the most prevalent type of dementia in elderly people, primarily characterized by brain accumulation of beta-amyloid (Aβ) peptides, derived from Amyloid Precursor Protein (APP), in the extracellular space (amyloid plaques) and intracellular deposits of the hyperphosphorylated form of the protein tau (p-tau; tangles or neurofibrillary aggregates). The Nerve growth factor receptor (NGFR/p75NTR) represents a low-affinity receptor for all known mammalians neurotrophins (i.e., pro-NGF, NGF, BDNF, NT-3 e NT-4/5) and it is involved in pathways that determine both survival and death of neurons. Interestingly, also Aβ peptides can blind to NGFR/p75NTR making it the "ideal" candidate in mediating Aβ-induced neuropathology. Besides pathogenesis and neuropathology, several data indicated that NGFR/p75NTR could play a key role in AD also from a genetic perspective. Other studies suggested that NGFR/p75NTR could represent a good diagnostic tool, as well as a promising therapeutic target for AD. Here, we comprehensively summarize and review the current experimental evidence on this topic.
Neuromuscular Fatigue at Task Failure and During Immediate Recovery after Isometric Knee Extension Trials
Christian Froyd, Fernando G. Beltrami, Timothy D. Noakes
Subject: Medicine & Pharmacology, Sport Sciences & Therapy Keywords: maximal voluntary contraction; peripheral fatigue; neuromuscular activation; femoral nerve electrical stimulation; critical peripheral fatigue threshold; electromyography
We asked whether the level of peripheral fatigue would differ when three consecutive exercise trials were completed to task failure, and whether there would be delayed recovery in maximal voluntary contraction (MVC) force, neuromuscular activation and peripheral fatigue following task failure. Ten trained sport students performed three consecutive knee extension isometric trials (T1, T2, T3) to task failure without breaks between trials. T1 and T2 consisted of repeated 5-s contractions followed by 5-s rest. In T1, contractions were performed at a target force at 60% pre-exercise MVC. In T2, all contractions were MVCs, and task failure occurred at 50% MVC. T3 was a sustained MVC performed until force fell below 15% MVC. Evoked force responses to supramaximal electrical femoral nerve stimulation were recorded to assess peripheral fatigue. Electromyography signals were normalized to M-wave amplitude to assess neuromuscular activation. Lower levels of evoked peak forces were observed at T3 compared to T2 and T1. Within 5 s of task failure in T3, MVC force and neuromuscular activation recovered substantially without any recovery in evoked peak force. Neuromuscular activation 5-10 s after T3 was unchanged from pre-exercise values, but evoked peak forces were substantially reduced. These results challenge the existence of a critical peripheral fatigue threshold that reduces neuromuscular activation. Since neuromuscular activation changed independently of any change in evoked peak force, immediate recovery in force production after exercise is due to increased central recruitment and not to peripheral mechanisms.
Expression and Signaling Pathways of Nerve Growth Factor (NGF) And Pro-NGF in Breast Cancer: A Systematic Review
Francesco Bruno, Domenico Arcuri, Francesca Vozzo, Antonio Malvaso, Alberto Montesanto, Raffaele Maletta
Subject: Life Sciences, Molecular Biology Keywords: breast cancer; Nerve Growght Factor (NGF); TrkA; p75NTR; NGFR; pro-NGF; angiogenesis; invasion; metastasis; diagnosis; prognosis; treatment
Breast cancer represents the most frequent cancer and the leading cause of cancer death among women. Thus, the prevention and early diagnosis of breast cancer appears to be of primary urgency as well as the development of new treatments able to improve its prognosis. Nerve Growth Factor (NGF) is a neurotrophic factor that plays a key role in the regulation of neuronal functions thought the binding to the Tropomyosin receptor kinase A (TrkA) and the Nerve Growth Factor receptor or Pan-Neurotrophin Receptor 75 (NGFR/p75NTR). Also, its precursor (pro-NGF) can extert biological activity by forming a trimeric complex with NGFR/p75NTR and sortilin or by binding to TrkA receptors with low affinity. Both in vitro and in vivo studies showed that NGF is synthesized and released by breast cancer cells and has mitogen, antiapoptotic and angiogenic effects on these cells through the activation of different signaling cascades that involve TrkA and NGFR/p75NTR receptors. Conversely, pro-NGF signaling has been related to breast cancer invasion and metastasis. Other studies suggested that NGF and its receptors could represent a good diagnostic and prognostic tool, as well as promising therapeutic targets for breast cancer. Here, we comprehensively summarize and systematically review the current experimental evidence on this topic.
Assessment of the Effectiveness of Obstructive Sleep Apnea Treatment Using Optical Coherence Tomography to Evaluate Retinal Findings
Gloria Tejero-Garcés, Francisco J Ascaso, Paula Casas, Maria I Adiego, Peter Baptista, Carlos O'Connor-Reina, Eugenio Vicente, Guillermo Plaza
Subject: Medicine & Pharmacology, Other Keywords: Retina; Retinal nerve fiber layer; Obstructive sleep apnea syndrome; Optical coherence tomography; OCT; CPAP; Upper airway surgery.
Retinal findings may change in patients with obstructive sleep apnea syndrome (OSAS). The present study aims to evaluate several retinal findings such as macula layer thickness, peripapillary retinal nerve fiber layer, and the optic nerve head in patients with OSAS using optical coherence tomography (OCT) and monitor the result of several types of treatment of OSAS with OCT. A prospective comparative study was designed. Patients were recruited at a Sleep Unit of a University Hospital and underwent comprehensive ophthalmological examinations. Following exclusion criteria, fifty-two patients with OSAS were finally included. Patients were examined by OCT twice: first, before treatment; secondly, after six months of treatment. In mild-moderate patients, where retinal swelling has been demonstrated, retinal thicknesses decreased [fovea (p=0.026), as well as inner ring macula (p=0.007), outer ring macula (p=0.015), and macular volume (p=0.015)]. In severe patients, where retinal atrophy had been observed, retinal thickness increased [fovea (p<0.001)]. No statistically significant differences in efficacy between treatments were demonstrated. In conclusion, OCT can evaluate the retina in patients with OSAS and help monitor results after treatment. In severe OSAS, retinal thickness increased six months after treatment.
The Microbiota-Gut-Brain Axis and Alzheimer Disease. From Dysbiosis to Neurodegeneration: Focus on the Central Nervous System Glial Cells
Maria Grazia Giovannini, Daniele Lana, Chiara Traini, Maria Giuliana Vannucchi
Subject: Life Sciences, Biochemistry Keywords: amyloid-β; endotoxin; short chain fatty acids; clasmatodendrosis; cytokines; neurovascular unit; vagus nerve; Toll-like Receptor 4
Much evidence has accumulated over the past decade in favor of a significant association between dysbiosis, neuroinflammation and neurodegeneration. Presently, the pathogenetic mechanisms triggered by molecules produced by the altered microbiota, also responsible for the onset and evolution of Alzheimer Disease will be described. Our attention will be focused on the role of astrocytes and microglia. Numerous studies have progressively demonstrated how these glial cells are important to ensure an adequate environment for neuronal activity in healthy conditions. Furthermore, it is becoming evident how both cell types can mediate the onset of neuroinflammation and lead to neurodegeneration when subjected to pathological stimuli. Based on this information, the role of major microbiota products in shifting the activation profiles of astrocytes and microglia from a healthy to a diseased state will be discussed focussing on Alzheimer Disease pathogenesis.
Association of Heart Rate Variability with Pulmonary Function Impairment and Symptomatology Post-COVID-19 Hospitalization
Estelle A.M.C. Adang, Maud T. A. Strous, Joop van den Bergh, Debbie Gach, Vivian E.M. Van Kampen, Roel E.P. van Zeeland, Dennis G. Barten, Frits H. M van Osch
Subject: Medicine & Pharmacology, General Medical Research Keywords: Heart rate variability; COVID-19; post-COVID-19 condition; long COVID; autonomic dysfunction; vagal nerve activity; symptomatology; lung function
Persistence of symptoms beyond three months after COVID-19 infection, often referred to as post-COVID-19 condition (PCC), is commonly experienced. It is hypothesized that PCC results from autonomic dysfunction with decreased vagal nerve activity, which can be indexed by low heart rate variability (HRV). The aim of this study was to assess the association of HRV upon admission with pulmonary function impairment and number of reported symptoms beyond three months after initial hospitalization for COVID-19 between February and December 2020. Follow-up took place three to five months after discharge and included pulmonary function tests and the assessment of persistent symptoms. HRV analysis was performed on one 10s electrocardiogram obtained upon admission. Analyses were performed using multivariable and multinomial logistic regression models. Among 171 patients who received follow-up, and with an electrocardiogram at admission, decreased diffusion capacity of the lung for carbon monoxide (DLCO) (41%) was most frequently found. After a median of 119 days (IQR 101-141), 81% of the participants reported at least one symptom. HRV was not associated with pulmonary function impairment or persistent symptoms three to five months after hospitalization for COVID-19.
SARS-CoV-2 Infection Reaches the Human Nervous System: How?
Vladimir N. Uversky, Fatma Elrashdy, Abdullah Aljadawi, Syed Moasfar Ali, Rizwan Hasan Khan, Elrashdy M. Redwan
Subject: Life Sciences, Virology Keywords: COVID-19; SARS-CoV-2; neurotropic virus; Blood-nervous system barrier; bloodcerebrospinal-fluid-barrier; blood-brain-barrier; blood-nerve barrier; olfactory route; Lymphatic brain drainage route; Peripheral nerve or neuronal retrograde route; Macrophage/monocytes cargo route; Double membrane vesicles cargo route; nicotinic acetylcholine receptor
Without protective and/or therapeutic agents the SARS-CoV-2 infection known as coronavirus disease 2019 (COVID-19) is quickly spreading worldwide. It has surprising transmissibility potential, since it could infect all ages, gender, and human sectors. It attacks respiratory, gastrointestinal, urinary, hepatic, and endovascular systems and can reach the peripheral nervous system (PNS) and central nervous system (CNS) through known and unknown mechanisms. The reports on the neurological manifestations and complications of the SARS-CoV-2 infection are increasing exponentially. Herein, we enumerate seven candidate routes, which the mature or immature SARS-CoV-2 components could use to reach the CNS and PNS, utilizing the within-body crosstalk between organs. The majority of SARS-CoV-2 infected patients suffer from some neurological manifestations (e.g., confusion, anosmia, and ageusia). It seems that although the mature virus did not reach the CNS or PNS of the majority of patients, its unassembled components and/or the accompanying immune-mediated responses may be responsible for the observed neurological symptoms. The viral particles and/or its components have been specifically documented in endothelial cells of lung, kidney, skin, and CNS. This means that the blood-endothelial-barrier may be considered as the main route for SARS-CoV-2 entry into the nervous system, with the barrier disruption being more logical than barrier permeability, as evidenced by postmortem analyses.
Neurotherapeutics for Attention Deficit Hyperactivity Disorder (ADHD): a Review
Katya Rubia, Samuel Westwood, Pascal-M. Aggensteiner, Daniel Brandeis
Subject: Medicine & Pharmacology, Allergology Keywords: Attention Deficit Hyperactivity Disorder (ADHD); functional magnetic resonance imaging (fMRI); Neurofeedback; EEG-Neurofeedback; fMRI-Neurofeedback; brain stimulation; transcranial magnetic stimulation (TMS); transcranial direct current stimulation (tDCS); trigeminal nerve stimulation (TNS).
This review focuses on the evidence for neurotherapeutics for Attention Deficit Hyperactivity Disorder (ADHD). EEG-Neurofeedback has been tested for about 45 years with latest meta-analyses of randomised controlled trials (RCT) showing small/medium effects compared to non-active controls only. Three small studies piloted neurofeedback of frontal activations in ADHD using functional magnetic resonance imaging or near-infrared spectroscopy, finding no superior effects over control conditions. Brain stimulation has been applied to ADHD using mostly repetitive transcranial magnetic and direct current stimulation (rTMS/tDCS). rTMS has shown mostly negative findings on improving cognition or symptoms. Meta-analyses of tDCS studies targeting mostly dorsolateral prefrontal cortex show small effects on cognitive improvements with only two out of three studies showing clinical improvements. Trigeminal nerve stimulation has shown to improve ADHD symptoms with medium effect in one RCT. Modern neurotherapeutics are attractive due to their relative safety and potential neuroplastic effects. However, they need to be thoroughly tested for clinical and cognitive efficacy across settings and beyond core symptoms and for their potential for individualised treatment.
The Added Value of Subcutaneous Peripheral Nerve Field Stimulation Combined with SCS, as Salvage Therapy, for Refractory Low Back Pain Component in Persistent Spinal Pain Syndrome Implanted Patients: A Randomized Controlled Study (CUMPNS Study) Based on 3D-Mapping Composite Pain Assessment
Philippe Rigoard, Amine Ounajim, Lisa Goudman, Benedicte Bouche, Manuel Roulaud, Philippe Page, Bertille Lorgeoux, Sandrine Baron, Kevin Nivole, Mathilde Many, Nihel Adjali, Elodie Charrier, Delphine Rannou, Laure Poupin, Chantal Wood, Romain David, Dylan Héraud, Maarten Moens, Maxime Billot
Subject: Medicine & Pharmacology, General Medical Research Keywords: spinal cord stimulation (SCS); peripheral nerve field stimulation (PNfS); SubQ-stimulation; hybrid stimulation; multidimensional pain assessment; pain mapping; pain software; persistent spinal pain syndrome - T2 (PSPS-T2); failed back surgery syndrome; failed spinal cord stimulation syndrome (FSCSS); salvage therapy; salvage algorithm
While Spinal Cord Stimulation (SCS) provides satisfaction to almost 2/3 of Persistent Spinal Pain Syndrome-Type 2 (PSPS-T2) patients implanted for refractory chronic back and/or leg pain when not adequately addressed the back pain component, leaves patients in a therapeutic cul-de-sac. Peripheral Nerve field Stimulation (PNfS) has shown interesting results addressing back pain in the same population. Far from placing these two techniques in opposition, we suggest that these approaches could be combined to better treat PSPS-T2 patients. We designed a RCT (CUMPNS), with a 12-month follow-up, to assess the potential added value of PNfS, as a salvage therapy, in PSPS-T2 patients experiencing a "Failed SCS Syndrome" in the back pain component. Fourteen patients were included in this study and randomized into 2 groups ("SCS + PNfS" group/n=6 vs "SCS only" group/n=8). The primary objective of the study was to compare the percentage of back pain surface decrease after 3 months, using a computerized interface to obtain quantitative pain mappings, combined with multi-dimensional SCS outcomes. Back pain surface decreased significantly greater for the "SCS+PNfS" group (80.2% ± 21.3%) compared to the "SCS only" group (13.2% ± 94.8%) (p=0.012), highlighting the clinical interest of SCS+PNfS, in cases where SCS fails to address back pain.


Telescoped recordings of the top air personalities at major market radio stations.
A listing of the most downloaded and listened to air personalities.
A menu of the most frequently recorded markets.
Information on how to submit an aircheck to RADIO ONLINE.


Dr. Peters is a specialist in human security in Africa and has written extensively on economic development, democratization, and HIV/AIDS. She has more than twenty years experience teaching, conducting research, and managing projects in southern and West Africa. An expert on political and economic development in Zimbabwe, she has provided political analyses to the government of South Africa and the private sector, and is regularly featured in local and international media including the South African Broadcasting Corporation news, New York Times, Voice of America, and Radio France International.
Dr. Peters has developed proposals for and managed democratization and community development programs in South Africa, Darfur, Sierra Leone, and Liberia, among other countries.
Dr. Peters is the Program Director for SPExS's online Measurement and Evaluation Programs, and she is an expert in qualitative methods, which she regularly teaches. She has taught in several Washington Semester Programs, including Global Economics and Business, US Foreign Policy, Peace and Conflict Resolution, and International Environment and Development. She also teaches distance education courses in African governance and international development. She was one of the winners of American University's 2013 Jack Child Teaching with Technology Award and 2013 Mobile Technology Award.
She has taught at American University since 1999.


amanda was born & still lives in pennsylvania where she dreams up this, that or the other thing. she runs words dance / verve bath press w/ the love of the word & the lust of spreading it on the brain.
some of amanda's work has popped up in poesy, remark, nerve cowboy, zygote in my coffee & my favorite bullet.


Even as the use of cashless payments like ez-link card and Nets has grown in the Jurong West hawker centre that is blazing the trail for e-payments, patrons and hawkers there say cash remains king.
When it opened last October, the hawker centre in Jurong West Street 61 was among the first to embrace the push to go cashless. Stalls there accepted eight different kinds of e-payments including ez-link cards and Apple Pay.
The centre was cast in the spotlight this week when EZ-Link and Nets announced a partnership that would allow customers to tap their ez-link cards on Nets terminals at an initial 1,000 hawker stalls.
When The Straits Times visited the hawker centre this week to see how the cashless payment experiment was working, stallholders and patrons painted a mixed picture - making it clear the promises and challenges of cashless payments were playing out there.
Some hawkers say up to four in 10 of customers pay using e-payment systems; others say the number is closer to two in 10. Three out of 20 stalls open for lunch yesterday had removed their cashless payment terminals. "Our e-payment terminal has been down for a few weeks," said a herbal soup stall owner who wanted to be known only as Mr Tan. "It jammed up a few times because it couldn't scan a card."
Hawkers, such as Mr Tan, cite some of the common drawbacks of cashless payments as the reasons they are sticking to cash - some e-payment systems incur fees, while others do not credit the accounts of the stallholders instantly.
Japanese food stall owner Richard Chee sees only 20 per cent of customers opting for cashless payment, and even fewer using ez-link cards. "The profits we get from the cashless options... we use to offset the rental of the payment kiosk."
Our e-payment terminal has been down for a few weeks.
MR TAN, a herbal soup stall owner.
Queues go by very fast because all customers have to do is tap their cards or put cash in the slots.
MR ILIYAS DZAHIRON, 33, an employee at a seafood barbecue stall. He says he can focus on food preparation without the bother of handling and counting change.
The kiosk consists of both cash slots and the cashless terminal.
"Our real profits come from our cash transactions," Mr Chee added.
Many diners, meanwhile, say that they still prefer to use cash despite the cashless options available.
Finance manager Maurice Wong, 46, told The Straits Times he has used his bank card there once or twice, when he does not have cash.
"I would rather use go cashless for things like online shopping, where I'm not physically there and things cost more than a hawker centre meal," he said.
The hawker centre is managed by Koufu subsidiary Hawker Management, a social enterprise. Mr Noel Chin, a staff of the social enterprise, said: "Most customers have to use the kiosk for both cash and cashless payments. Initially, the hawkers were not used to it, but now, they seem quite happy with the kiosks."
Mr Iliyas Dzahiron, 33, who works at a seafood barbecue stall, said: "Queues go by very fast because all customers have to do is tap their cards or put cash in the slots."
He can then focus on food preparation without the hassle of handling and counting change, he said.
An EZ-Link spokesman told The Straits Times the response at the centre has been "very positive".
"It is a great step towards a cashless society as we slowly integrate cashless payments in daily lives by starting in the heartland."


text:
Australia's bushfires are producing so much smoke that NASA expects it to travel all the way round the world and return to Australia
Leave a Comment on Australia's bushfires are producing so much smoke that NASA expects it to travel all the way round the world and return to Australia
Australia's fires are producing so much smoke that it will travel all the way around the earth and back to Australia, NASA said.
NASA said that the smoke had already travelled "halfway around Earth" last week, reaching South America, and will "make at least one full circuit around the globe, returning once again to the skies over Australia."
The fires have devastated Australia, killing dozens of people and an estimated one billion animals, burning thousands of miles of land and creating hazardous air quality.
The effects have reached other countries, including turning the sky red and glaciers black with smoke in New Zealand and affecting sunrises and sunsets in South America.
NASA predicts that the massive bushfires devastating Australia will produce enough smoke to make at least one full circuit around the planet and return to Australia.
NASA's Goddard research center said that the smoke had already "travelled halfway around Earth" as of January 8, "crossing South America, turning the skies hazy and causing colorful sunrises and sunsets."
"The smoke is expected to make at least one full circuit around the globe, returning once again to the skies over Australia."
NASA noted that the fires in Australia are "not just causing devastation locally," blaming the "unprecedented conditions" of "heat combined with historic dryness."
Bushfire season began in the country in September 2019. The season has particularly intense thanks to a period of prolonged drought that helped fires spread, leading to unprecedented damage and the death of an estimated one billion animals.
The fires have killed at least 28 people and destroyed thousands of homes.
Satellite images have shown clouds of smoke from the fires drifting away from the continent:
They're so big that they have created their own weather, in the form of giant thunderstorms that can then create new fires.
These …read more
Source:: Business Insider
After months of devastating bushfires Australia is… Australia is finally getting rain — but it's likely not enough to extinguish the fires devastating the country and might result in its own extreme weather. Firefighters have welcomed the rain in areas like Victoria and New South Wales, where they say it is helping to weaken fires. But it is not enough to extinguish the blazes across the country that have killed at least 29 people, and an estimated one billion animals. The rain has caused some flooding and damage, and authorities are warning that the heavy rain on burnt and destroyed ground could cause flash flooding and mudslides,…
An astronaut in space photographed the giant smoke… New images from NASA astronaut Christina Koch, who's onboard the International Space Station, show the scale of the Australian bushfires from space. Smoke from the blazes covers nearly 70% of the country. NASA models suggest that global wind patterns will carry the smoky air on a full circuit of the globe. Climate change worsens the conditions that lead to severe fires like these. Visit Business Insider's homepage for more stories. NASA astronaut Christina Koch shared a brief yet powerful message from space on Tuesday: "Australia. Our hearts and thoughts are with you." Koch, who is living on the International Space…
A 17-year-old intern at NASA discovered a new planet… A 17-year-old intern at NASA discovered a new planet on his third day on the job. Wolf Cukier, then a junior in high school, was interning at NASA's Goddard Space Flight Center in Maryland when he made the discovery. The planet, since named TOI 1338 b, is the first circumbinary planet to ever have been found at the agency. This means the planet orbits two stars instead of one. See Business Insider's homepage for more stories.; Seventeen-year-old Wolf Cukier was on the third day of his internship at NASA when he discovered a new planet previously unknown to scientists. According…
Climate change is making Australia's weird weather… Australia's climate is prone to extremes, but ongoing warming has made them worse, fueling the ongoing bushfires across the country. | Saeed Khan/AFP via Getty Images Fires, heat, drought, and flooding are nothing new to Australia. But climate change is making them worse. The gargantuan bushfires across Australia continue to rage. They've burned at least 17.9 million acres, destroyed more than 3,000 homes, and killed at least 28 people since September. The choking smoke from these blazes is causing a health crisis and has literally circled the world. At the Australian Open in Melbourne this week, Slovenia's Dalila Jakupovic forfeited…
Capital One Spark Miles for Business review: With a… The Capital One® Spark® Miles for Business is a great option if you're looking for a business credit card that earns you bonus rewards without lots of hoops to jump through. The card is currently offering an increased sign-up bonus of up to 200,000 miles. You'll earn 50,000 miles after spending $5,000 in the first three months, and 150,000 miles after spending $50,000 in the first six months. However, you only have until January 27 to apply for this offer. This Spark Miles for Business earns 2 miles for every dollar you spend, and you can redeem miles to cover…
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redpajama_set_name: RedPajamaCommonCrawl


text:
EFFICIENT ALGORITHMS FOR CHANNEL ROUTING.
Takeshi Yoshimura, Ernest S. Kuh
In the layout design of LSI chips, channel routing is one of the key problems. The problem is to route a specified net list between two rows of terminals across a two-layer channel. Nets are routed with horizontal segments on one layer and vertical segments on the other. Connections between two layers are made through via holes. Two new algorithms are proposed. These algorithms merge nets instead of assigning horizontal tracks to individual nets. The algorithms were coded in Fortran and implemented on a VAX 11/780 computer. Experimental results are quite encouraging. Both programs generated optimal solutions in 6 out of 8 cases, using examples in previously published papers. The computation times of the algorithms for a typical channel (300 terminals, 70 nets) are 1. 0 and 2. 1 s, respectively.
IEEE Transactions on Computer-Aided Design of Integrated Circuits and Systems
CAD-1
Yoshimura, T., & Kuh, E. S. (1982). EFFICIENT ALGORITHMS FOR CHANNEL ROUTING. IEEE Transactions on Computer-Aided Design of Integrated Circuits and Systems, CAD-1(1), 25-35.
EFFICIENT ALGORITHMS FOR CHANNEL ROUTING. / Yoshimura, Takeshi; Kuh, Ernest S.
In: IEEE Transactions on Computer-Aided Design of Integrated Circuits and Systems, Vol. CAD-1, No. 1, 01.1982, p. 25-35.
Yoshimura, T & Kuh, ES 1982, 'EFFICIENT ALGORITHMS FOR CHANNEL ROUTING.', IEEE Transactions on Computer-Aided Design of Integrated Circuits and Systems, vol. CAD-1, no. 1, pp. 25-35.
Yoshimura T, Kuh ES. EFFICIENT ALGORITHMS FOR CHANNEL ROUTING. IEEE Transactions on Computer-Aided Design of Integrated Circuits and Systems. 1982 Jan;CAD-1(1):25-35.
Yoshimura, Takeshi ; Kuh, Ernest S. / EFFICIENT ALGORITHMS FOR CHANNEL ROUTING. In: IEEE Transactions on Computer-Aided Design of Integrated Circuits and Systems. 1982 ; Vol. CAD-1, No. 1. pp. 25-35.
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abstract = "In the layout design of LSI chips, channel routing is one of the key problems. The problem is to route a specified net list between two rows of terminals across a two-layer channel. Nets are routed with horizontal segments on one layer and vertical segments on the other. Connections between two layers are made through via holes. Two new algorithms are proposed. These algorithms merge nets instead of assigning horizontal tracks to individual nets. The algorithms were coded in Fortran and implemented on a VAX 11/780 computer. Experimental results are quite encouraging. Both programs generated optimal solutions in 6 out of 8 cases, using examples in previously published papers. The computation times of the algorithms for a typical channel (300 terminals, 70 nets) are 1. 0 and 2. 1 s, respectively.",
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