NMR-based metabolomic investigation of dogs with acute flaccid paralysis due to tick paralysis.

BACKGROUND: Acute flaccid paralysis (AFP) is a complex clinical syndrome with various aetiologies. If untreated, AFP may lead to death due to failure of respiratory muscles. Tick paralysis, which is a noninfectious neurologic syndrome of AFP, occurs following tick attachment, engorgement, and injection of tick saliva toxins. There is no specific diagnostic test for tick paralysis, and mortality increases as definitive diagnosis is delayed. Although metabolomic investigation of tick saliva was conducted, there is a lack of research on metabolomic evaluation of hosts affected by tick paralysis. OBJECTIVES: Thus, the aim of this study is to investigate metabolomic changes in serum samples of dogs with tick paralysis due to Rhipicephalus sanguineus using NMR-based metabolomics and to identify potential diagnostic/prognostic markers. MATERIALS AND METHODS: Forty dogs infested with R. sanguineus, with clinical findings compatible with AFP and with a confirmed tick paralysis diagnosis ex juvantibus, constituted the Paralysis Group. Ten healthy dogs, which were admitted either for vaccination and/or check-up purposes, constituted the Control Group. After the confirmation tick paralysis, medical history, vaccination and nutritional status, body surface area and estimated tick numbers of all the dogs were noted. Physical examination included body temperature, heart and respiratory rate, capillary refill time evaluation and Modified Glasgow Coma Scale calculation. Serum samples were extracted from venous blood samples of all the dogs and were prepared for NMR analysis, and NMR-based metabolomics identification and quantification were performed. RESULTS: NMR-based serum metabolomics of the present study revealed distinct up/down-regulated expressions, presenting a promising avenue. Moreover, it was observed that energy metabolism and especially liver functions were impaired in dogs with tick paralysis, and not only the respiratory system but also the kidneys were affected. CONCLUSION: It was concluded that the present approach may help to better understand the pathological mechanisms developing in cases of AFP due to tick paralysis.

Single-cell and spatial atlases of spinal cord injury in the Tabulae Paralytica.

Here, we introduce the Tabulae Paralytica-a compilation of four atlases of spinal cord injury (SCI) comprising a single-nucleus transcriptome atlas of half a million cells, a multiome atlas pairing transcriptomic and epigenomic measurements within the same nuclei, and two spatial transcriptomic atlases of the injured spinal cord spanning four spatial and temporal dimensions. We integrated these atlases into a common framework to dissect the molecular logic that governs the responses to injury within the spinal cord1. The Tabulae Paralytica uncovered new biological principles that dictate the consequences of SCI, including conserved and divergent neuronal responses to injury; the priming of specific neuronal subpopulations to upregulate circuit-reorganizing programs after injury; an inverse relationship between neuronal stress responses and the activation of circuit reorganization programs; the necessity of re-establishing a tripartite neuroprotective barrier between immune-privileged and extra-neural environments after SCI and a failure to form this barrier in old mice. We leveraged the Tabulae Paralytica to develop a rejuvenative gene therapy that re-established this tripartite barrier, and restored the natural recovery of walking after paralysis in old mice. The Tabulae Paralytica provides a window into the pathobiology of SCI, while establishing a framework for integrating multimodal, genome-scale measurements in four dimensions to study biology and medicine.

Palsy of Both the Tibial Nerve and Common Peroneal Nerve Caused by a Ganglion Cyst in the Popliteal Area.

A ganglion cyst is a benign mass consisting of high-viscosity mucinous fluid. It can originate from the sheath of a tendon, peripheral nerve, or joint capsule. Compressive neuropathy caused by a ganglion cyst is rarely reported, with the majority of documented cases involving peroneal nerve palsy. To date, cases demonstrating both peroneal and tibial nerve palsies resulting from a ganglion cyst forming on a branch of the sciatic nerve have not been reported. In this paper, we present the case of a 74-year-old man visiting an outpatient clinic complaining of left-sided foot drop and sensory loss in the lower extremity, a lack of strength in his left leg, and a decrease in sensation in the leg for the past month without any history of trauma. Ankle dorsiflexion and great toe extension strength on the left side were Grade I. Ankle plantar flexion and great toe flexion were Grade II. We suspected peroneal and tibial nerve palsy and performed a screening ultrasound, which is inexpensive and rapid. In the operative field, several cysts were discovered, originating at the site where the sciatic nerve splits into peroneal and tibial nerves. After successful surgical decompression and a series of rehabilitation procedures, the patient's neurological symptoms improved. There was no recurrence.

VP1 is the primary determinant of neuropathogenesis in a mouse model of enterovirus D68 acute flaccid myelitis.

Enterovirus D68 (EV-D68) is an emerging pathogen that can cause severe respiratory and neurologic disease [acute flaccid myelitis (AFM)]. Intramuscular (IM) injection of neonatal Swiss Webster (SW) mice with US/IL/14-18952 (IL52), a clinical isolate from the 2014 EV-D68 epidemic, results in many of the pathogenic features of human AFM, including viral infection of the spinal cord, death of motor neurons, and resultant progressive paralysis. In distinction, CA/14-4231 (CA4231), another clinical isolate from the 2014 EV-D68 outbreak, does not cause paralysis in mice, does not grow in the spinal cord, and does not cause motor neuron loss following IM injection. A panel of chimeric viruses containing sequences from IL52 and CA4231 was used to demonstrate that VP1 is the main determinant of EV-D68 neurovirulence following IM injection of neonatal SW mice. VP1 contains four amino acid differences between IL52 and CA4231. Mutations resulting in substituting these four amino acids (CA4231 residues into the IL52 polyprotein) completely abolished neurovirulence. Conversely, mutations resulting in substituting VP1 IL52 amino acid residues into the CA4231 polyprotein created a virus that induced paralysis to the same degree as IL52. Neurovirulence following infection of neonatal SW mice with parental and chimeric viruses was associated with viral growth in the spinal cord. IMPORTANCE: Emerging viruses allow us to investigate mutations leading to increased disease severity. Enterovirus D68 (EV-D68), once the cause of rare cases of respiratory illness, recently acquired the ability to cause severe respiratory and neurologic disease. Chimeric viruses were used to demonstrate that viral structural protein VP1 determines growth in the spinal cord, motor neuron loss, and paralysis following intramuscular (IM) injection of neonatal Swiss Webster (SW) mice with EV-D68. These results have relevance for predicting the clinical outcome of future EV-D68 epidemics as well as targeting retrograde transport as a potential strategy for treating virus-induced neurologic disease.

The evolution, facilitators, barriers, and additional activities of acute flaccid paralysis surveillance platform in polio eradication programme Bangladesh: a mixed-method study.

BACKGROUND: The Global Polio Eradication Initiative (GPEI) helped develop the standard acute flaccid paralysis surveillance (AFP) system worldwide, including, knowledge, expertise, technical assistance, and trained personnel. AFP surveillance can complement any disease surveillance system. OBJECTIVE: This study outlines AFP surveillance evolution in Bangladesh, its success and challenging factors, and its potential to facilitate other health goals. METHODS: This mixed-method study includes a grey literature review, survey, and key informant interviews (KIIs). We collected grey literature from online websites and paper documentation from GPEI stakeholders. Online and in-person surveys were conducted in six divisions of Bangladesh, including Dhaka, Rajshahi, Rangpur, Chittagong, Sylhet, and Khulna, to map tacit knowledge ideas, approaches, and experiences. We also conducted KIIs, and Data were then combined on focused emerging themes, including the history, challenges, and successes of AFP surveillance programme. RESULTS: According to the grey literature review, survey, and KII, AFP surveillance successfully contributed to decreasing polio in Bangladesh. The major facilitating factors were multi-sectoral collaboration, Surveillance Immunization Medical Officer (SIMO) network activities, social environment, community-based surveillance, and promising political commitment. On the other hand, high population growth, hard-to-reach areas, people residing in risky zones, and polio transition planning were significant challenges. Bangladesh is also utilizing these polio surveillance assets for other vaccine-preventable diseases. CONCLUSION: As the world is so close to eradicating polio, the knowledge, and other assets of the AFP surveillance, could be used for other health programmes. In addition, its strengths can be leveraged for combating new and emerging diseases.

Main findings: The research found that Bangladesh has achieved a world-standard surveillance system, with facilitating factors including multi-sectoral collaboration, GPEI partners, and political and community support. However, high population growth, hard-to-reach areas and people, and polio transition planning were found to be challenges.Added knowledge: In addition, Bangladesh is now utilizing these polio surveillance assets to monitor other vaccine-preventable diseases.Global health impact for policy and action: Since polio is still a threat to some LMICs, the knowledge gained from AFP surveillance of Bangladesh could assist those countries in eradicating the cases of polio from the earth and serve VPDs and other health programmes as well.

A Virtual Reality-Based Protocol to Determine the Preferred Control Strategy for Hand Neuroprostheses in People With Paralysis.

Hand neuroprostheses restore voluntary movement in people with paralysis through neuromodulation protocols. There are a variety of strategies to control hand neuroprostheses, which can be based on residual body movements or brain activity. There is no universally superior solution, rather the best approach may vary from patient to patient. Here, we propose a protocol based on an immersive virtual reality (VR) environment that simulates the use of a hand neuroprosthesis to allow patients to experience and familiarize themselves with various control schemes in clinically relevant tasks and choose the preferred one. We used our VR environment to compare two alternative control strategies over 5 days of training in four patients with C6 spinal cord injury: (a) control via the ipsilateral wrist, (b) control via the contralateral shoulder. We did not find a one-fits-all solution but rather a subject-specific preference that could not be predicted based only on a general clinical assessment. The main results were that the VR simulation allowed participants to experience the pros and cons of the proposed strategies and make an educated choice, and that there was a longitudinal improvement. This shows that our VR-based protocol is a useful tool for personalization and training of the control strategy of hand neuroprostheses, which could help to promote user comfort and thus acceptance.

A guiding light for stimulating paralyzed muscles.

Improving the performance of closed-loop optogenetic nerve stimulation can reproduce desired muscle activation patterns.

[Cause analysis and clinical intervention of C 5 palsy after cervical surgery].

Objective: To review the research progress of C 5 palsy (C 5P) after cervical surgery, providing new clinical intervention ideas for the C 5P patients. Methods: The relevant literature domestically and abroad was extensively consulted and the latest developments in the incidence, risk factors, manifestations and diagnosis, prevention, and intervention measures of C 5P were systematically expounded. Results: C 5P is characterized by weakness in the C 5 nerve innervation area after cervical decompression surgery, manifested as limited shoulder abduction and elbow flexion, with an incidence rate more than 5%, often caused by segmental spinal cord injury or mechanical injury to the nerve roots. For patients with risk factors, careful operation and preventive measures can reduce the incidence of C 5P. Most of the patients can recover with conservative treatment such as drug therapy and physical therapy, while those without significant improvement after 6 months of treatment may require surgical intervention such as foraminal decompression and nerve displacement. Conclusion: Currently, there has been some advancement in the etiology and intervention of C 5P. Nevertheless, further research is imperative to assess the timing of intervention and surgical protocol.

Venous Sinus Stent to Treat Paralysis.

Transvenous treatment of paralysis is a concept less than a decade old. The Stentrode (Synchron, Inc, New York, USA) is a novel electrode on stent device intended to be implanted in the superior sagittal sinus adjacent to the motor cortex. Initial animal studies in sheep demonstrated the safety of the implant as well as its accuracy in detecting neural signals at both short and long term. Early human trials have shown the safety of the device and demonstrated the use of the Stentrode system in facilitating patients with paralysis to carry out daily activities such as texting, email, and personal finance. This is an emerging technology with promise, although certainly more research is required to better understand the capabilities and limitations of the device.

3-Hydroxyanthranilic Acid Delays Paralysis in Caenorhabditis elegans Models of Amyloid-Beta and Polyglutamine Proteotoxicity.

Age is the primary risk factor for neurodegenerative diseases such as Alzheimer's and Huntington's disease. Alzheimer's disease is the most common form of dementia and a leading cause of death in the elderly population of the United States. No effective treatments for these diseases currently exist. Identifying effective treatments for Alzheimer's, Huntington's, and other neurodegenerative diseases is a major current focus of national scientific resources, and there is a critical need for novel therapeutic strategies. Here, we investigate the potential for targeting the kynurenine pathway metabolite 3-hydroxyanthranilic acid (3HAA) using Caenorhabditis elegans expressing amyloid-beta or a polyglutamine peptide in body wall muscle, modeling the proteotoxicity in Alzheimer's and Huntington's disease, respectively. We show that knocking down the enzyme that degrades 3HAA, 3HAA dioxygenase (HAAO), delays the age-associated paralysis in both models. This effect on paralysis was independent of the protein aggregation in the polyglutamine model. We also show that the mechanism of protection against proteotoxicity from HAAO knockdown is mimicked by 3HAA supplementation, supporting elevated 3HAA as the mediating event linking HAAO knockdown to delayed paralysis. This work demonstrates the potential for 3HAA as a targeted therapeutic in neurodegenerative disease, though the mechanism is yet to be explored.

Neurologic recovery following laminectomy and tumor resection of a pediatric cervical synovial osteochondromatosis causing paralysis.

PURPOSE: To report the surgical outcome of synovial osteochondromatosis, a rare tumor of the cervical spine, in a 6-year-old boy. METHODS: A 6-year-old boy presented with muscle weakness in the right deltoid (2) and biceps (4) during a manual muscle test. Magnetic resonance imaging showed a 3 × 2 × 1.5 cm mass within the spinal canal at the C4-6 level, compressing the cervical spinal cord from the right side. Computed tomography revealed hyperintense areas within the tumor and ballooning of the right C4-5 and C5-6 facet joints. RESULTS: After a biopsy confirmed the absence of malignancy, a gross total resection was performed. The pathological diagnosis of synovial osteochondromatosis was established. Postoperatively, muscle weakness improved fully in the manual muscle test, and there were no neurological findings after 3 months. However, the patient is under careful follow-up owing to the detection of a regrowth site within the right C4-5 and C5-6 intervertebral foramen 2 years postoperatively. CONCLUSIONS: Synovial osteochondromatosis of the cervical spine in children is rare, and this is the first report of its regrowth after surgery. Synovial osteochondromatosis should be included in the differential diagnosis of pediatric cervical spine tumors.

Assessing pain in paralyzed critically ill patients receiving neuromuscular blocking agents: A monocenter prospective cohort.

INTRODUCTION: Given the absence of established recommendations for pain assessment in pharmacologically paralyzed Intensive-Care-Units (ICU) patients under Neuro-Muscular-Blocking Agents (NMBA), this study assessed the validity of various parameters for evaluating pain in this specific population. PATIENTS AND METHODS: Four electrophysiological parameters (instant-Analgesia-Nociception-Index (ANI), Bispectral index (BIS), Heart Rate (HR) and Mean Arterial Blood Pressure (ABP)) and one clinical parameter (Behavioural-Pain-Scale (BPS)) were recorded during tracheal-suctioning in all consecutive ICU patients who required a continuous infusion of cisatracurium, before and just after paralysis recovery measured by Train-of-Four ratio. The validity of the five pain-related parameters was assessed by comparing the values recorded during different situations (before/during/after the nociceptive procedure) (discriminant-validity, primary outcome), and the effect of paralysis was assessed by comparing values obtained during and after paralysis (reliability, secondary outcome). RESULTS: Twenty patients were analyzed. ANI, BIS, and HR significantly changed during the nociceptive procedure in both paralysis and recovery, while BPS changed only post-recovery. ANI and HR were unaffected by paralysis, unlike BIS and BPS (mixed-effect model). ANI exhibited the highest discriminant-validity, with values (min 0/max 100) decreasing from 71 [48-89] at rest to 41 [25-72] during tracheal suctioning in paralyzed patients, and from 71 [53-85] at rest to 40 [31-52] in non-paralyzed patients. CONCLUSIONS: ANI proves the most discriminant parameter for pain detection in both paralyzed and non-paralyzed sedated ICU patients. Its significant and clinically relevant decrease during tracheal suctioning remains unaltered by NMBA use. Pending further studies on analgesia protocols based on ANI, it could be used to assess pain during nociceptive procedures in ICU patients receiving NMBA.

Detection and genetic diversity of parechoviruses in children with acute flaccid paralysis in Cameroon.

Human Parechoviruses (HPeVs) have rarely been considered in the virological investigation of Acute Flacid Paralysis (AFP) cases in Africa, where enteric infections are very common. This study investigated the prevalence and genetic diversity of HPeV in 200 children aged ≤ 15 years with AFP in Cameroon from 2018 to 2019. HPeVs were detected in their faecal RNA using 5'-untranslated real-time RT-PCR. Detected HPeVs were typed by phylogenetic comparison with homologous sequences from homotypic reference strains. Overall, HPeV RNA was detected in 11.0% (22/200) of the 200 stool samples tested. Twelve HPeVs were successfully sequenced and reliably assigned to HPeV-A1, A4, A5, A10, A14, A15, A17 and A18 genotypes. Phylogenetic analyses revealed a high genetic variability among the studied HPeVs, as well as between the studied HPeVs and their previously reported counterparts from Cameroon in 2014. These findings suggest that different HPeV genotypes co-circulate in Cameroon without documented epidemics.

Genetic analysis of 37 cases with primary periodic paralysis in Chinese patients.

BACKGROUND: Primary periodic paralysis (PPP) is an inherited disorders of ion channel dysfunction characterized by recurrent episodes of flaccid muscle weakness, which can classified as hypokalemic (HypoPP), normokalemic (NormoPP), or hyperkalemic (HyperPP) according to the potassium level during the paralytic attacks. However, PPP is charactered by remarkable clinical and genetic heterogeneity, and the diagnosis of suspected patients is based on the characteristic clinical presentation then confirmed by genetic testing. At present, there are only limited cohort studies on PPP in the Chinese population. RESULTS: We included 37 patients with a clinical diagnosis of PPP. Eleven (29.7%) patients were tested using a specific gene panel and 26 (70.3%) by the whole-exome sequencing (WES). Twenty-two cases had a genetic variant identified, representing a diagnostic rate of 59.5% (22/37). All the identified mutations were either in the SCN4A or the CACNA1S gene. The overall detection rate was comparable between the panel (54.5%: 6/11) and WES (61.5%: 16/26). The remaining patients unresolved through panel sequencing were further analyzed by WES, without the detection of any mutation. The novel atypical splicing variant c.2020-5G > A affects the normal splicing of the SCN4A mRNA, which was confirmed by minigene splicing assay. Among 21 patients with HypoPP, 15 patients were classified as HypoPP-2 with SCN4A variants, and 6 HypoPP-1 patients had CACNA1S variants. CONCLUSIONS: Our results suggest that SCN4A alleles are the main cause in our cohort, with the remainder caused by CACNA1S alleles, which are the predominant cause in Europe and the United States. Additionally, this study identified 3 novel SCN4A and 2 novel CACNA1S variants, broadening the mutation spectrum of genes associated with PPP.

The effect of common paralytic agents used for fluorescence imaging on redox tone and ATP levels in Caenorhabditis elegans.

One aspect of Caenorhabditis elegans that makes it a highly valuable model organism is the ease of use of in vivo genetic reporters, facilitated by its transparent cuticle and highly tractable genetics. Despite the rapid advancement of these technologies, worms must be paralyzed for most imaging applications, and few investigations have characterized the impacts of common chemical anesthetic methods on the parameters measured, in particular biochemical measurements such as cellular energetics and redox tone. Using two dynamic reporters, QUEEN-2m for relative ATP levels and reduction-oxidation sensitive GFP (roGFP) for redox tone, we assess the impact of commonly used chemical paralytics. We report that no chemical anesthetic is entirely effective at doses required for full paralysis without altering redox tone or ATP levels, and that anesthetic use alters the detected outcome of rotenone exposure on relative ATP levels and redox tone. We also assess the use of cold shock, commonly used in combination with physical restraint methods, and find that cold shock does not alter either ATP levels or redox tone. In addition to informing which paralytics are most appropriate for research in these topics, we highlight the need for tailoring the use of anesthetics to different endpoints and experimental questions. Further, we reinforce the need for developing less disruptive paralytic methods for optimal imaging of dynamic in vivo reporters.

Thirteen-year surveillance results of acute flaccid paralysis cases in Southeast Turkey and the effect of refugee movements on surveillance results.

OBJECTIVE: Acute flaccid paralysis (AFP) is a major neurological problem. Turkey has accepted over 4 million refugees since 2011 due to the wars in neighbouring countries. In the long term, refugees can have adverse effects on the limited resources of health, sanitation, water supply, foodstuff, and shelter services of host countries, precipitating the transmission and spread of enteroviruses causing AFP. This study examines the 13-year surveillance and incidence of AFP cases in southeast Turkey, and questions possible impact of refugee movements on these parameters, comparing the periods before (2007-2010) and after (2011-2019) 2011, when the refugee movements emerged. METHODS: The records of cases reported from southeast part of Turkey with suspected AFP between January 2007 and December 2019 were reviewed retrospectively. RESULTS: Of the patients, 121 (58.5%) were male. Mean age was 80.36 ± 46.67 months. Eighty-five (41.1%) were aged 60 months or younger. The number of patients under 60 months increased significantly after 2011. Mean incidence was calculated as 0.88 cases/100,000 person years versus 1.58 cases/100,000 person years in the period before and after 2011, respectively. Guillain-Barré syndrome (GBS) was the most common cause of AFP in both periods. As of 2011, however, the incidence of acute transverse myelitis increased approximately 4 times and GBS decreased proportionally. Non-polio enteroviruses were the most frequent isolates, detected from 9.1% of stool samples. CONCLUSION: Although refugee movements appear to may have adverse effects on AFP incidence and surveillance outcomes, larger studies involving the whole country, particularly at places where no refugees settled, are needed to achieve more conclusive evidence.