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Current Issues in Molecular Biology Jun 2024Amyotrophic lateral sclerosis (ALS) represents a neurodegenerative disorder characterized by the progressive loss of both upper and lower motor neurons, resulting in... (Review)
Review
Amyotrophic lateral sclerosis (ALS) represents a neurodegenerative disorder characterized by the progressive loss of both upper and lower motor neurons, resulting in muscular atrophy and eventual paralysis. While much research has concentrated on investigating the impact of major mutations associated with ALS on motor neurons and central nervous system (CNS) cells, recent studies have unveiled that ALS pathogenesis extends beyond CNS imbalances, encompassing dysregulation in other tissues such as skeletal muscle. Evidence from animal models and patients supports this broader perspective. Skeletal muscle, once considered solely as an effector organ, is now recognized as possessing significant secretory activity capable of influencing motor neuron survival. However, the precise cellular and molecular mechanisms underlying the detrimental effects observed in muscle and its associated structures in ALS remain poorly understood. Additionally, emerging data suggest that extracellular vesicles (EVs) may play a role in the establishment and function of the neuromuscular junction (NMJ) under both physiological and pathological conditions and in wasting and regeneration of skeletal muscles, particularly in neurodegenerative diseases like ALS. This review aims to explore the key findings about skeletal muscle involvement in ALS, shedding light on the potential underlying mechanisms and contributions of EVs and their possible application for the design of biosensors.
PubMed: 38921029
DOI: 10.3390/cimb46060358 -
Cells Jun 2024Proinflammatory T-lymphocytes recruited into the brain and spinal cord mediate multiple sclerosis (MS) and currently there is no cure for MS. IFN-γ-producing Th1 cells...
Proinflammatory T-lymphocytes recruited into the brain and spinal cord mediate multiple sclerosis (MS) and currently there is no cure for MS. IFN-γ-producing Th1 cells induce ascending paralysis in the spinal cord while IL-17-producing Th17 cells mediate cerebellar ataxia. STAT1 and STAT3 are required for Th1 and Th17 development, respectively, and the simultaneous targeting of STAT1 and STAT3 pathways is therefore a potential therapeutic strategy for suppressing disease in the spinal cord and brain. However, the pharmacological targeting of STAT1 and STAT3 presents significant challenges because of their intracellular localization. We have developed a STAT-specific single-domain nanobody (SBT-100) derived from camelids that targets conserved residues in Src homolog 2 (SH2) domains of STAT1 and STAT3. This study investigated whether SBT-100 could suppress experimental autoimmune encephalomyelitis (EAE), a mouse model of MS. We show that SBT-100 ameliorates encephalomyelitis through suppressing the expansion of Th17 and Th1 cells in the brain and spinal cord. Adoptive transfer experiments revealed that lymphocytes from SBT-100-treated EAE mice have reduced capacity to induce EAE, indicating that the immunosuppressive effects derived from the direct suppression of encephalitogenic T-cells. The small size of SBT-100 makes this STAT-specific nanobody a promising immunotherapy for CNS autoimmune diseases, including multiple sclerosis.
Topics: Animals; Encephalomyelitis, Autoimmune, Experimental; Single-Domain Antibodies; Mice; Th17 Cells; Mice, Inbred C57BL; Female; Camelids, New World; STAT3 Transcription Factor; Th1 Cells; Neuroinflammatory Diseases; STAT1 Transcription Factor; Spinal Cord
PubMed: 38920670
DOI: 10.3390/cells13121042 -
Toxicon : Official Journal of the... Jun 2024Snakebite is a significant health concern in Africa, particularly due to neurotoxic envenomation which can lead to neuromuscular paralysis and respiratory failure. In... (Review)
Review
Snakebite is a significant health concern in Africa, particularly due to neurotoxic envenomation which can lead to neuromuscular paralysis and respiratory failure. In Nigeria, snakes from the Elapidae family are a notable cause of envenomation cases, though these incidents are underreported. This review examined case reports of neurotoxic envenomation in Africa, highlighting the clinical impacts and the efficacy of available antivenoms. Preclinical studies showed that the polyvalent antivenom from the South African Institute for Medical Research (SAIMR) was highly effective against neurotoxicity with a protective efficacy (R) of 1346.80 mg/mL, while clinical assessment emphasized the need for high-dose antivenom therapy along with supportive measures like mechanical ventilation. Unlike hemorrhagic envenomation, where antivenom promptly resolves bleeding, neurotoxic cases often require additional interventions. The review underscores the necessity for tailored approaches in antivenom therapy to address the complexities of neurotoxic snakebites and reduce their public health burden in Africa.
PubMed: 38917892
DOI: 10.1016/j.toxicon.2024.107811 -
International Immunopharmacology Jun 2024Spinal cord injury (SCI) is a devastating neurotraumatic condition characterized by severe motor dysfunction and paralysis. Accumulating evidence suggests that DNA...
Spinal cord injury (SCI) is a devastating neurotraumatic condition characterized by severe motor dysfunction and paralysis. Accumulating evidence suggests that DNA damage is involved in SCI pathology. However, the underlying mechanisms remain elusive. Although checkpoint kinase 1 (Chk1)-regulated DNA damage is involved in critical cellular processes, its role in SCI regulation remains unclear. This study aimed to explore the role and potential mechanism of Chk1 in SCI-induced motor dysfunction. Adult female C57BL/6J mice subjected to T9-T10 spinal cord contusions were used as models of SCI. Western blotting, immunoprecipitation, histomorphology, and Chk1 knockdown or overexpression achieved by adeno-associated virus were performed to explore the underlying mechanisms. Levels of p-Chk1 and γ-H2AX (a cellular DNA damage marker) were upregulated, while ferroptosis-related protein levels, including glutathione peroxidase 4 (GPX4) and x-CT were downregulated, in the spinal cord and hippocampal tissues of SCI mice. Functional experiments revealed increased Basso Mouse Scale (BMS) scores, indicating that Chk1 downregulation promoted motor function recovery after SCI, whereas Chk1 overexpression aggravated SCI-induced motor dysfunction. In addition, Chk1 downregulation reversed the SCI-increased levels of GPX4 and x-CT expression in the spinal cord and hippocampus, while immunoprecipitation assays revealed strengthened interactions between p-Chk1 and GPX4 in the spinal cord after SCI. Finally, Chk1 downregulation promoted while Chk1 overexpression inhibited NeuN cellular immunoactivity in the spinal cord after SCI, respectively. Collectively, these preliminary results imply that Chk1 is a novel regulator of SCI-induced motor dysfunction, and that interventions targeting Chk1 may represent promising therapeutic targets for neurotraumatic diseases such as SCI.
PubMed: 38917519
DOI: 10.1016/j.intimp.2024.112521 -
Microbiology Spectrum Jun 2024Mycophenolate mofetil (MMF) is commonly utilized for the treatment of neuromyelitis optica spectrum disorders (NMOSD). However, a subset of patients experience...
Mechanisms of gastrointestinal toxicity in neuromyelitis optica spectrum disorder patients treated with mycophenolate mofetil: insights from a mouse model and human study.
UNLABELLED
Mycophenolate mofetil (MMF) is commonly utilized for the treatment of neuromyelitis optica spectrum disorders (NMOSD). However, a subset of patients experience significant gastrointestinal (GI) adverse effects following MMF administration. The present study aims to elucidate the underlying mechanisms of MMF-induced GI toxicity in NMOSD. Utilizing a vancomycin-treated mouse model, we compiled a comprehensive data set to investigate the microbiome and metabolome in the GI tract to elucidate the mechanisms of MMF GI toxicity. Furthermore, we enrolled 17 female NMOSD patients receiving MMF, who were stratified into non-diarrhea NMOSD and diarrhea NMOSD (DNM) groups, in addition to 12 healthy controls. The gut microbiota of stool samples was analyzed using 16S rRNA gene sequencing. Vancomycin administration prevented weight loss and tissue injury caused by MMF, affecting colon metabolomes and microbiomes. Bacterial β-glucuronidase from Bacteroidetes and Firmicutes was linked to intestinal tissue damage. The DNM group showed higher alpha diversity and increased levels of Firmicutes and Proteobacteria. The β-glucuronidase produced by Firmicutes may be important in causing gastrointestinal side effects from MMF in NMOSD treatment, providing useful information for future research on MMF.
IMPORTANCE
Neuromyelitis optica spectrum disorder (NMOSD) patients frequently endure severe consequences like paralysis and blindness. Mycophenolate mofetil (MMF) effectively addresses these issues, but its usage is hindered by gastrointestinal (GI) complications. Through uncovering the intricate interplay among MMF, gut microbiota, and metabolic pathways, this study identifies specific gut bacteria responsible for metabolizing MMF into a potentially harmful form, thus contributing to GI side effects. These findings not only deepen our comprehension of MMF toxicity but also propose potential strategies, such as inhibiting these bacteria, to mitigate these adverse effects. This insight holds broader implications for minimizing complications in NMOSD patients undergoing MMF therapy.
PubMed: 38916339
DOI: 10.1128/spectrum.04307-23 -
European Archives of... Jun 2024Among the complications of parotid surgery, facial palsy is frequent and burdened by high functional and social impact for the patient. There are few data on the...
OBJECTIVES
Among the complications of parotid surgery, facial palsy is frequent and burdened by high functional and social impact for the patient. There are few data on the efficacy of facial neuromuscular retraining (FNR) in patients with facial palsy after parotid surgery, and no data exist on its impact in timing and extent of recovery.
MATERIAL AND METHODS
A retrospective study was conducted on patients undergoing FN sparing parotid surgery and suffering from postoperative facial palsy. Among 400 patients undergoing surgery between July 2016 and May 2023, those with the preservation of the FN and onset of facial palsy were selected. Nerve function was evaluated during 2 years follow up using the House-Brackman (H&Bs) and Sunnybrook scales (SBs).
RESULTS
A total of 46 patients undergoing partial or total parotidectomy were included. At discharge 18 patients (39,1%) had IV to VI grade paralysis according to the H&Bs and the mean SBs value was 54. At 2 and 6 months after surgery, the average value of Sunnybrook increased to 76.5 and 95.4 respectively. After 12 months no patients with IV to VI grade paralysis were represent in our cohort. Two years after surgery, only five patients (10.9%) had persistent grade II paralysis according to HBs.
CONCLUSIONS
Our study supports the efficacy of FNR in the rehabilitation of facial paralysis after nerve-sparing parotidectomy. The greater functional improvement is achieved within the first 6 months of rehabilitation. A significant improvement is detected still after 18 months, supporting the importance of long rehabilitation for patients without complete recovery after the first year.
PubMed: 38914817
DOI: 10.1007/s00405-024-08758-y -
Revista Brasileira de Ortopedia Jun 2024To identify the location of the Riché-Cannieu anastomosis (RCA) in relation to the Cardinal Kaplan Line (KCL) and the Y line. A total of 20 hands of 10...
To identify the location of the Riché-Cannieu anastomosis (RCA) in relation to the Cardinal Kaplan Line (KCL) and the Y line. A total of 20 hands of 10 recently-deceased adult male cadavers aged between 27 and 66 years were dissected for the investigation of the relationship of the most distal point of the RCA with the KCL and with the Y line, drawn from the axis of the third metacarpal head, following the longitudinal axis of the hand. In 20 limbs, the most distal point of the nerve communication was positioned distally in relation to the KCL. The Y line was positioned on the radial side in relation to the most distal point of the RCA in 14 limbs, and it was positioned on the ulnar side in relation to the Y line in 6 limbs. The crossing between the KCL and the Y line occurred proximal to the RCA in 18 limbs; in 1 hand, it was positioned distal to the intersection between these lines; and in another hand, the KCL was positioned exactly on the RCA. Knowledge of these anatomical relationships can prevent damage to nerve branches and thus also prevent paralysis of intrinsic muscles in surgical procedures in the palm of the hand.
PubMed: 38911877
DOI: 10.1055/s-0044-1785512 -
Frontiers in Immunology 2024Bilateral facial palsy with paresthesia (FDP) is a rare variant of GBS, characterized by simultaneous bilateral facial palsy and paresthesia of the distal limbs....
Bilateral facial palsy with paresthesia (FDP) is a rare variant of GBS, characterized by simultaneous bilateral facial palsy and paresthesia of the distal limbs. Mounting evidence indicates that the presence of anti-GT1a IgG has a pathogenic role as an effector molecule in the development of cranial nerve palsies in certain patients with GBS, whereas anti-GT1a antibody is rarely presented positive in FDP. Here, we report the case of a 33-year-old male diagnosed with FDP presented with acute onset of bilateral facial palsy and slight paresthesias at the feet as the only neurological manifestation. An antecedent infection with no identifiable reason for the fever or skin eruptions was noted in the patient. He also exhibited cerebrospinal fluid albuminocytologic dissociation and abnormal nerve conduction studies. Notably, the testing of specific serum anti-gangliosides showed positive anti-GT1a IgG/IgM Ab. The patient responded well to intravenous immunoglobulin therapy. This case brings awareness to a rare variant of GBS, and provides the first indication that anti-GT1a antibodies play a causative role in the development of FDP. The case also suggests that prompt management with IVIG should be implemented if FDP is diagnosed.
Topics: Humans; Male; Adult; Paresthesia; Facial Paralysis; Autoantibodies; Gangliosides; Immunoglobulins, Intravenous; Immunoglobulin G; Guillain-Barre Syndrome
PubMed: 38911860
DOI: 10.3389/fimmu.2024.1410634 -
Journal of Neuroendovascular Therapy 2024To report the rare case of a patient with a perianeurysmal cyst following stent-assisted coil embolization of an unruptured vertebral artery aneurysm.
OBJECTIVE
To report the rare case of a patient with a perianeurysmal cyst following stent-assisted coil embolization of an unruptured vertebral artery aneurysm.
CASE PRESENTATION
A 63-year-old woman underwent stent-assisted coil embolization for an unruptured vertebral artery aneurysm embedded in the brainstem (pons). Complete occlusion of the aneurysm was successfully achieved. However, subsequent magnetic resonance imaging (MRI) conducted 8 months after the procedure showed perilesional edematous changes surrounding the aneurysm, and at 20 months, cyst formation was observed in the vicinity of the aneurysm. Progressive enlargement of the cyst eventually led to the development of paralysis and dysphagia, necessitating cyst fenestration surgery. Although postoperative reduction in the cyst size was achieved, the patient experienced complications in the form of aspiration pneumonia and bacterial meningitis, which resulted in a life-threatening condition.
CONCLUSION
Aneurysms embedded in the brain parenchyma should be carefully followed up, recognizing the risk of perianeurysmal cyst formation after coil embolization.
PubMed: 38911484
DOI: 10.5797/jnet.cr.2023-0088 -
Clinical Case Reports Jun 2024Melkersson-Rosenthal syndrome can cause recurring bilateral facial paralysis. When steroids fail, surgical decompression of facial nerve is recommended, with endoscopic...
KEY CLINICAL MESSAGE
Melkersson-Rosenthal syndrome can cause recurring bilateral facial paralysis. When steroids fail, surgical decompression of facial nerve is recommended, with endoscopic trans-canal decompression as a safe, minimally invasive, and effective option.
ABSTRACT
Melkersson-Rosenthal syndrome (MRS) is a rare neuro-mucocutaneous disorder, clinically diagnosed by a triad of orofacial swelling, recurrent facial palsy, and fissured tongue. Due to the lack of a comprehensive understanding of MRS, there is no accepted standard of care. In this study we report a 30-year-old female patient, who was referred to the otolaryngology clinic of Rasool Akram Hospital, with classical triad of MRS that was managed by endoscopic trans-canal facial nerve decompression. Bilateral endoscopic trans-canal facial nerve decompression was done when we did not find any improvement with systemic steroids. Endoscopic trans-canal facial nerve decompression could be a safe, reliable minimal invasive treatment of facial paralysis in MRS patients. It needs no external incision or temporal bone drilling which makes this method more convenient for patients with shorter recovery time.
PubMed: 38910833
DOI: 10.1002/ccr3.9032